Consumer medicine information

Morphine MR Mylan

Morphine sulfate pentahydrate

BRAND INFORMATION

Brand name

Morphine MR Mylan

Active ingredient

Morphine sulfate pentahydrate

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Morphine MR Mylan.

MORPHINE MR MYLAN modified release tablets

MORPHINE MR MYLAN modified release tablets

 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 MORPHINE MR MYLAN tablets?

MORPHINE MR MYLAN tablets contain the active ingredient morphine sulfate pentahydrate. MORPHINE MR MYLAN tablets are used for the management of pain severe enough to require daily, long-term opioid treatment and for which other forms of treatment have failed or are otherwise inappropriate to provide sufficient management of pain.

For more information, see Section 1. Why am I using MORPHINE MR MYLAN tablets? in the full CMI.

 2. What should I know before I use MORPHINE MR MYLAN tablets?

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 MORPHINE MR MYLAN tablets? in the full CMI.

 3. What if I am taking other medicines?

Some medicines may interfere with MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets?
  • Your doctor will tell you exactly how much to take.
  • Follow the instructions given to you by your doctor or your pharmacist.
  • You must only take MORPHINE MR MYLAN tablets by mouth.

More instructions can be found in Section 4. How do I use MORPHINE MR MYLAN tablets? in the full CMI.

 5. What should I know while using MORPHINE MR MYLAN tablets?

Things you should do
  • Remind any doctor or dentist you visit that you are using MORPHINE MR MYLAN tablets.
  • 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
  • MORPHINE MR MYLAN tablets 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 25°C.
  • Keep it where young children cannot reach it.

For more information, see Section 5. What should I know while using MORPHINE MR MYLAN tablets? in the full CMI.

 6. Are there any side effects?

MORPHINE MR MYLAN tablets 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

MORPHINE MR MYLAN tablets 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

MORPHINE MR MYLAN tablets 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

MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets

Using MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets.

MORPHINE MR MYLAN modified release tablets

Active ingredient: morphine sulfate pentahydrate

 Consumer Medicine Information (CMI)

This leaflet provides important information about using MORPHINE MR MYLAN tablets. 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 MORPHINE MR MYLAN tablets.

Where to find information in this leaflet:

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

 1. Why am I using MORPHINE MR MYLAN tablets?

MORPHINE MR MYLAN tablets contains the active ingredient morphine sulfate pentahydrate. Morphine belongs to a group of medicines called opioid analgesics.

MORPHINE MR MYLAN tablets are indicated for the management of severe pain where:

  • other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain, and
  • the pain is opioid-responsive, and
  • requires daily, continuous, long-term treatment.
 2. What should I know before I use MORPHINE MR MYLAN tablets?

Warnings

Do not use MORPHINE MR MYLAN tablets 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 stop 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.

MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets even if you take it exactly as prescribed. MORPHINE MR MYLAN tablets may become habit forming causing mental and physical dependence. If abused, it may become less able to reduce pain.

Dependence

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

Tolerance

Tolerance to MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets and affect how it works.

Using MORPHINE MR MYLAN tablets 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.

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

MORPHINE MR MYLAN tablets may increase the anticoagulant activity of coumarin and other anticoagulants (medicines used to prevent blood clots).

MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets.

 4. How do I use MORPHINE MR MYLAN tablets?

How much to take

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

When to take MORPHINE MR MYLAN tablets

  • Take MORPHINE MR MYLAN tablets every 12 hours or as directed by your doctor.
  • Take MORPHINE MR MYLAN tablets at about the same time each day.

How to take MORPHINE MR MYLAN tablets

Swallow MORPHINE MR MYLAN tablets whole and be careful not to break, chew, crush or dissolve the tablets.

MORPHINE MR MYLAN tablets are only designed to work properly if swallowed whole. The tablets may release all their contents at once if broken, chewed, crushed or dissolved, which can be dangerous and cause serious problems, such as an overdose which may be fatal.

If you have trouble swallowing your tablets whole, talk to your doctor.

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

If you forget to use MORPHINE MR MYLAN tablets

You should take MORPHINE MR MYLAN tablets at the same time each day. If you miss your dose at the usual time, you may take MORPHINE MR MYLAN tablets as soon as you remember.

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 MORPHINE MR MYLAN tablets (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 MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets?

Things you should do

Call your doctor straight away if you:

  • become pregnant
  • feel your pain is getting worse.

Remind any doctor, dentist or pharmacist you visit that you are using MORPHINE MR MYLAN tablets.

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 MORPHINE MR MYLAN tablets suddenly, your pain may worsen and you may experience withdrawal symptoms.

Do not take MORPHINE MR MYLAN tablets 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 MORPHINE MR MYLAN tablets affects you.

MORPHINE MR MYLAN tablets 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 25°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.

Getting rid of any unwanted medicine

If the medicine is damaged, 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 behaviour 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 MORPHINE MR MYLAN tablets contains

Active ingredient
(main ingredient)		morphine sulfate pentahydrate
Other ingredients
(inactive ingredients)		Lactose monohydrate (except 100 mg)
Hyetellose
Povidone
Magnesium stearate
Purified talc
Hypromellose
Colorants in coating:
10 mg: Opadry buff OY-3607
30 mg: Opadry violet OY-6708
60 mg: Opadry orange OY-3533
100 mg: Opadry grey OY-8238
Potential allergens10 mg, 30 mg and 60 mg tablets contain sugars (as lactose monohydrate).

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

What MORPHINE MR MYLAN tablets look like

MORPHINE MR MYLAN modified release tablets are film-coated and biconvex in shape and are available in four strengths packed in blister packs of 20, 28 or 60 tablets.

MORPHINE MR MYLAN tablets 10 mg - Buff coloured, biconvex, smooth, round, film coated tablets with 10 on one face (AUST R 225421)

MORPHINE MR MYLAN tablets 30 mg - Violet coloured, biconvex, smooth, round, film coated tablets with 30 on one face (AUST R 225422)

MORPHINE MR MYLAN tablets 60 mg - Orange coloured, biconvex, smooth, round, film coated tablets with 60 on one face (AUST R 225423)

MORPHINE MR MYLAN tablets 100 mg - Grey coloured, biconvex, smooth, round, film coated tablets with 100 on one face (AUST R 225424)

Who distributes MORPHINE MR MYLAN tablets

Alphapharm Pty Ltd
Level 1, 30 The Bond
30-34 Hickson Road
Millers Point NSW 2000
www.mylan.com.au

The sponsor is:
Southern Cross Pharma Pty Ltd
Suite 5/118 Church St
Hawthorn VIC 3122
info@southernxp.com

This leaflet was prepared in December 2020.

Published by MIMS February 2021

BRAND INFORMATION

Brand name

Morphine MR Mylan

Active ingredient

Morphine sulfate pentahydrate

Schedule

S8

 

1 Name of Medicine

Morphine sulfate pentahydrate.

2 Qualitative and Quantitative Composition

Each modified release tablet contains 10 mg, 30 mg, 60 mg or 100 mg of morphine sulfate pentahydrate as the active ingredient.
Morphine sulfate pentahydrate 100 mg corresponds to 75 mg of morphine free base.

List of excipients with known effect.

Sugars as lactose monohydrate (except for the 100 mg strength tablet).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

10 mg tablet.

Buff coloured, biconvex, smooth, round, film coated modified release tablets with 10 on one face.

30 mg tablet.

Violet coloured, biconvex, smooth, round, film coated modified release tablets with 30 on one face.

60 mg tablet.

Orange coloured, biconvex, smooth, round, film coated modified release tablets with 60 on one face.

100 mg tablet.

Grey coloured, biconvex, smooth, round, film coated modified release tablets with 100 on one face.

4 Clinical Particulars

4.1 Therapeutic Indications

Morphine MR Mylan is indicated for the management of severe pain where:
other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain; and
the pain is opioid-responsive; and
requires daily, continuous, long-term treatment.
Morphine MR Mylan is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
Morphine MR Mylan is not indicated as an as-needed (PRN) analgesia.

4.2 Dose and Method of Administration

Morphine MR Mylan modified release tablets are intended for oral administration.
Administration and dosing of morphine should be individualised, bearing in mind the properties of the drug. In addition, the nature and severity of the pain or pains experienced, and the total condition of the patient must be taken into account. Of special importance is other medication given previously or concurrently.

Initial dose in adults.

Individual dosing requirements vary considerably based on each patient's age, weight, severity of pain, and medical and analgesic history. The most frequent initial dose is 30 mg every 12 hours.
Patients aged over 50 years tend to require much lower doses of morphine than the younger age group. In elderly and debilitated patients and those with impaired respiratory function or significantly decreased renal function, the initial dose should be one-half the usual recommended dose.

Initial dose in children.

Over 25 kg.

The initial dose will depend upon the degree of morphine tolerance and should be titrated in accordance with the patient's needs (see Dose titration).

25 kg or less.

There are no controlled trials of the use of morphine sulfate pentahydrate in children weighing 25 kg or less, nor in children with chronic severe nonmalignant pain.
Patients currently receiving other oral morphine formulations may be transferred to Morphine MR Mylan at the same total daily morphine dosage, equally divided into two Morphine MR Mylan doses given every 12 hours.
For patients who are receiving an alternate opioid, the oral morphine sulfate pentahydrate equivalent of the analgesic presently being used should be determined. Having determined the total daily dosage of the present analgesic, the following equivalence in Table 1 can be used to calculate the approximate daily oral morphine sulfate pentahydrate dosage that should provide equivalent analgesia. The total daily oral morphine dosage should then be equally divided into two Morphine MR Mylan doses given every 12 hours.

Dose titration.

Dose titration is the key to success with morphine therapy. Proper optimisation of doses scaled to the relief of the individual's pain should aim at the regular administration of the lowest dose of morphine which will maintain the patient free of pain at all times. Dose adjustments should be based on the patient's clinical response. Higher doses may be justified in some patients to cover periods of physical activity.
Because of the sustained release properties of Morphine MR Mylan, dosage adjustments should generally be separated by 48 hours. If dose increments are required, they should be proportionately greater at the lower dose level (in terms of percentage of previous dose), than when adjusting a higher dose.
The usual recommended dose (every 12 hours) increments are 5, 10, 15, 20, 30, 40, 60, 90, 120, 150, 180, 200 mg. Above the 200 mg/dose (400 mg/day) increments should be by 30 to 60 mg.
Morphine MR Mylan tablets are designed to allow dosing every 12 hours. If breakthrough pain repeatedly occurs at the end of a dose interval, it is generally an indication for a dosage increase, not more frequent administration. However, where judged necessary for optimisation of drug effects, Morphine MR Mylan may be administered every eight hours. More frequent (than every eight hours) administration of Morphine MR Mylan is neither rational nor recommended.

Dosage adjustment or reduction.

During the first two or three days of effective pain relief, the patient may exhibit drowsiness or sleep for prolonged periods. This can be misinterpreted as the effect of excessive analgesic dosing rather than the first sign of relief in a pain exhausted patient. The dose, therefore, should be maintained for at least three days before reduction, provided the sedation is not excessive or associated with unsteadiness and confusional symptoms, and respiratory activity and other vital signs are adequate. If excessive sedation persists, the reason(s) for such an effect must be sought (see Section 4.8 Adverse Effects (Undesirable Effects), Sedation).
Following successful relief of severe pain, periodic attempts to reduce the opioid dose should be made. Smaller doses or complete discontinuation of the opioid analgesic may become feasible due to a change in the patient's condition or improved mental state.

Note.

Morphine MR Mylan tablets should be swallowed intact, not chewed, crushed or broken.

4.3 Contraindications

Hypersensitivity to opiate narcotics, or any of the excipients; acute bronchial asthma or other obstructive airways disease, respiratory depression; severe respiratory disease; acute respiratory disease; cor pulmonale; cardiac arrhythmias; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; brain tumour; delayed gastric emptying; suspected surgical and acute abdomen; paralytic ileus, severe liver disease, incipient hepatic encephalopathy; severe renal dysfunction; concurrent (or within 14 days of therapy) monoamine oxidase inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions); children under one year of age; pregnancy.
Not recommended for preoperative use or for the first 24 hours postoperatively.
Patients with chronic pain not due to malignancy, who have a prior history of substance and alcohol abuse.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Morphine MR Mylan contains the opioid morphine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Morphine MR Mylan at recommended doses.
The risk of addiction is increased in patients with a personal or family history of substance abuse (including alcohol and prescription and illicit drugs) or mental illness. The risk also increases the longer the drug is used and with higher doses. Patients should be assessed for their risks for opioid abuse or addiction prior to being prescribed Morphine MR Mylan.
All patients receiving opioids should be routinely monitored for signs of misuse and abuse. Opioids are sought by people with addiction and may be subject to diversion. Strategies to reduce these risks include prescribing the drug in the smallest appropriate quantity and advising the patient on the safe storage and proper disposal of any unused drug (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal). Caution patients that abuse of oral or transdermal forms of opioids by parenteral administration can result in serious adverse events, which may be fatal.
Patients should be advised not to share Morphine MR Mylan 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 Morphine MR Mylan 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.

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

Concomitant use of opioids and benzodiazepines or other CNS depressants, including alcohol, may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing of morphine with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active anti-emetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Morphine MR Mylan 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 Morphine MR Mylan.

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 nonpharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of 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).
A single doctor should be responsible for the prescription and monitoring of the patient's opioid use.
Doctors prescribing Morphine MR Mylan should consult appropriate clinical guidelines on the use of opioid analgesics in such patients (e.g. Australian Pain Society publication).

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 Morphine MR Mylan in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Morphine MR Mylan, especially by children, can result in a fatal overdose of morphine. Patients and their caregivers should be given information on safe storage and disposal of unused Morphine MR Mylan (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 (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Endocrine effects.

Opioids, such as morphine sulfate pentahydrate, may influence the hypothalamic-pituitary-adrenal or -gonadal axes. Some changes that can be seen include an increase in serum prolactin, and decreases in plasma cortisol and testosterone. Clinical symptoms may manifest from these hormonal changes.

Head injury and increased intracranial pressure.

The respiratory depressant effects of morphine and the capacity to elevate cerebrospinal fluid pressure, may be greatly increased in the presence of an already elevated intracranial pressure produced by trauma. Also, morphine may produce confusion, miosis, vomiting and other side effects which obscure the clinical course of patients with head injury. In such patients, morphine must be used with extreme caution and only if it is judged essential.

Hypotensive effect.

Morphine administration may result in severe hypotension in patients whose ability to maintain adequate blood pressure is compromised by reduced blood volume, or concurrent administration of such drugs as phenothiazines or certain anaesthetics.

Abdominal conditions.

Morphine may obscure the diagnosis or clinical course of patients with acute abdominal conditions. Where there is a possibility of paralytic ileus occurring, morphine should not be used. Should paralytic ileus be suspected or occur during use, morphine should be discontinued immediately. As with all oral morphine preparations, Morphine MR Mylan tablets should be used with caution post-operatively and 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.

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, other interruption of pain transmission pathways or other pain relieving surgical procedures should not receive Morphine MR Mylan tablets within 24 hours of the procedure. Pain in the immediate preoperative period and any symptoms of opioid withdrawal should be managed with short acting analgesic agents. If further treatment with Morphine MR Mylan tablets is indicated, the dosage should be adjusted to the new post-operative requirement.

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, operations on the biliary tract and acute pancreatitis.

Acute ulcerative colitis.

Morphine may cause toxic dilatation in patients with acute ulcerative colitis.

Acute chest syndrome (ACS) in patients with sickle cell disease (SCD).

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

Special risk groups.

Morphine should be administered with caution and in reduced dosages to elderly or debilitated patients, to patients with Addison's disease, hypothyroidism, prostatic hypertrophy or urethral stricture.
Morphine should be used with caution in patients with convulsive disorders, inflammatory bowel disorders (including constipation), adrenocortical insufficiency, hypotension with hypovolaemia, diseases of the biliary tract, pancreatitis and opioid dependency.
Morphine may lower the seizure threshold in patients with a history of epilepsy.

Formulation.

The modified release tablets must be swallowed whole, and not broken, chewed or crushed. The administration of broken, chewed or crushed modified release morphine tablets leads to a rapid release and absorption of a potentially fatal dose of morphine.
It is not possible to ensure bioequivalence between different brands of modified release morphine products. Therefore, caution is needed when changing between different brands of sustained or modified release morphine, or other strong opioid analgesic preparations, and the patient should be re-titrated and clinically re-assessed.

Lactose.

Morphine MR Mylan tablets (10 mg, 30 mg and 60 mg tablets only) contain lactose. Patients with rare hereditary problems including galactose intolerance, Lapp lactase deficiency or glucose-galactose malasorption should not take these strengths of Morphine MR Mylan tablets.

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.
Morphine-6-glucuronide may accumulate in patients with renal failure, leading to CNS and respiratory depression.

Use in the elderly.

Morphine should be administered with caution and in reduced dosages to elderly patients. See also Special risk groups above; see Section 4.2 Dose and Method of Administration; Section 4.8 Adverse Effects (Undesirable Effects).

Paediatric use.

There are no controlled trials of the use of morphine modified release tablets in children weighing 25 kg or less, nor in children with chronic, severe, non-malignant pain. Morphine MR Mylan is contraindicated for use in children under one year of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Acidifying or alkalising agents.

Generally, the effects of morphine may be antagonised by acidifying agents and potentiated by alkalinising agents. Concurrent administration of antacids may result in a more rapid release of morphine than otherwise expected; dosing should, therefore, be separated by a minimum of two hours.

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, antiparkinsonians and antiemetics, may interact with morphine to potentiate anticholinergic adverse events.

Cimetidine.

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

CNS depressants.

CNS depressants which include, but are not limited to opioids, anaesthetics, sedatives (including benzodiazepines), anxiolytics, hypnotics, barbiturates, phenothiazines, antidepressants (including tricyclic antidepressants), chloral hydrate, antipsychotics, glutethimide, tranquilisers, muscle relaxants, antihypertensives, gabapentinoids (such as pregabalin), 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, coma or death 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.

Nonselective 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 nonselective MAOIs or within 14 days of stopping such treatment. It is unknown whether there is an interaction between the newer selective MAOIs (e.g. moclobemide and selegiline) and morphine, therefore caution is advised with such drug combinations.

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, coadministration of ritonavir and morphine may result in decreased morphine serum concentrations 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. In male rats, reduced fertility and chromosomal damage in gametes have been reported.
(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 Morphine MR Mylan tablets should be avoided to the extent possible in patients who are pregnant. Long-term use of opioids in pregnancy may result in a neonatal opioid withdrawal state.

Use during labour/delivery.

Morphine crosses the placental barrier and its administration during labour can produce respiratory depression in the neonate. These products should only be used during labour after weighing the needs of the mother against the risk to the foetus.
 Morphine has been detected in human breast milk; caution should be exercised if morphine is administered to a nursing mother and use of morphine sulfate should be avoided to the extent possible.

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 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 or parenteral use of morphine.

Very common adverse effects requiring medical attention.

The most frequently observed side effects 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 that 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 aged over 50 years, an appropriate dose in this age group may be as low as one-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 prescription of an antiemetic should be considered. Patients taking the equivalent of a single dose of morphine of 20 mg or more (Morphine MR Mylan 60 mg every 12 hours) usually require an antiemetic during early therapy. Small doses of prochlorperazine or haloperidol are the most frequently prescribed antiemetics.
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 patients, particularly elderly or bedridden patients, faeces 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. Softeners, laxatives and other appropriate measures should be used as required.

Other adverse effects include.

Cardiac disorders.

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

Ear and labyrinth disorders.

Uncommon: vertigo.

Endocrine disorders.

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

Eye disorders.

Uncommon: visual disturbance or impairment.
Not known: miosis.

Gastrointestinal disorders.

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

General disorders and administration site conditions.

Common: asthenic conditions (fatigue, malaise), pruritus.
Uncommon: peripheral oedema.
Not known: drug tolerance, oedema, drug withdrawal syndrome, drug withdrawal syndrome neonatal.

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, seizures.
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: ureteric spasm, urinary retention or hesitance.

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 on chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered. Tolerance to the effects of morphine may develop.
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.

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, pneumonia aspiration, miotic pupils, 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. An appropriate dose of one of the antagonists should therefore be administered, preferably by the intravenous route. The usual initial intravenous adult dose of naloxone is 0.4 mg or higher (please refer to naloxone Product Information for further information). Concomitant efforts at respiratory resuscitation should be carried out. Since the duration of action of morphine, particularly sustained release formulations, may exceed that of the antagonist, the patient should be under continued surveillance and doses of the antagonist 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 the 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.
A solution of activated charcoal will aid the removal of morphine. A saline cathartic or sorbitol added to the first dose of activated charcoal may speed gastrointestinal passage of the product.

Toxicity.

Morphine toxicity may result from overdosage, but because of the greater inter-individual variation in sensitivity to opioids, it is difficult to determine an exact dose of any opioid that is toxic or lethal. Chewing or crushing and taking the contents of a modified release dosage form leads to the release of morphine in an immediate fashion; this might result in a fatal overdose.
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 3,000 mg/day with no apparent toxicity.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Morphine sulfate pentahydrate is a narcotic analgesic.
Morphine is a phenanthrene alkaloid obtained from opium. Morphine and related compounds interact with specific receptors primarily found in the brain, spinal cord and the myenteric plexus of the gut wall. Morphine has considerably higher affinity for mu receptors than for other opioid receptors. In humans, the principal pharmacological actions of morphine are in the central nervous system (CNS): analgesia, drowsiness, mood changes (including euphoria and dysphoria), mental clouding, respiratory depression, nausea or emesis, miosis and on smooth muscle; increased gastrointestinal tone with a reduction in propulsive motion, increased biliary pressure and increased tone of the ureter and vesical sphincter, and alterations of the endocrine and autonomic nervous system.
Morphine induced analgesia is a result of increases in both the pain threshold and pain tolerance. Morphine alters the affective response to pain, in that patients remain aware of its existence but are less distressed. Morphine relieves most types of pain but is more effective against dull constant pain than sharp intermittent pain.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Morphine is readily absorbed from the gastrointestinal tract, nasal mucosa and lung, and after subcutaneous or intramuscular injection. Due to first pass metabolism, the effect of an oral dose is less than that of the same dose given parenterally. The parenteral to oral morphine potency ratio has been reported to range from 1:6 to 1:2. In general, the greatest difference between parenteral and oral potency is seen in acute studies. With chronic dosing, oral morphine is about one-half to one-third as potent as when given by injection.
At steady state, morphine sulfate pentahydrate SR tablets produce peak morphine concentrations approximately three to five hours postdose, and therapeutic levels tend to persist for a 12 hour period.

Distribution.

Following absorption, approximately 30 to 35% of morphine is reversibly bound to plasma proteins. Free morphine readily leaves the circulation and is concentrated in the liver, kidney, lung, spleen and, to a lesser extent, skeletal muscle. In adults, only small quantities of morphine pass the blood-brain barrier.

Metabolism.

Conjugation with glucuronic acid is the major metabolic pathway for morphine. The major metabolite is morphine-3-glucuronide. Other metabolites include normorphine, morphine-6-glucuronide, morphine-3,6-diglucuronide and morphine-3-ethereal sulfate.

Excretion.

The mean elimination half-life of morphine is two to three hours, with great interpatient variability. The major route of excretion is via the kidney. Approximately 7 to 10% is excreted in the faeces via the bile. Conjugated morphine excreted in the bile may be hydrolysed and reabsorbed from the large bowel.

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

Excipients contained in each of the four strengths of Morphine MR Mylan tablets are lactose monohydrate (except the 100 mg), hyetellose, hypromellose, povidone, purified talc and magnesium stearate. The tablet coatings contain a different colourant for each strength, as follows: 10 mg - Opadry buff OY-3607; 30 mg - Opadry violet OY-6708; 60 mg - Opadry orange OY-3533; 100 mg - Opadry grey OY-8238.

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.

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

Morphine MR Mylan modified release (sustained release) tablets come in blisters of PVC/Aluminium in cartons containing 20*, 28 or 60* tablets.
* Not currently marketed in Australia.

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 sulfate pentahydrate is a white, odourless, crystalline powder or needle-like crystals. It is soluble in water and ethanol. It is practically insoluble in ether or chloroform.

Chemical structure.


The chemical name of morphine sulfate pentahydrate is: Di(7,8-didehydro-4,5α-epoxy-17-methylmorphinan-3,6α-diol) sulfate pentahydrate.
Molecular formula: C34H40N2O10S.5H2O. Molecular Weight: 759.

CAS number.

6211-15-0.

7 Medicine Schedule (Poisons Standard)

S8 (Controlled Drug).

Summary Table of Changes