Consumer medicine information

MS Contin modified release tablets

Morphine sulfate pentahydrate

BRAND INFORMATION

Brand name

MS Contin

Active ingredient

Morphine sulfate pentahydrate

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using MS Contin modified release tablets.

What is in this leaflet

This leaflet answers some common questions about MS Contin modified release tablets ("tablets").

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 MS Contin tablets are taken for

MS Contin tablets contain morphine sulfate pentahydrate. Morphine belongs to a group of medicines called opioid analgesics.

MS Contin tablets are taken to treat chronic severe pain.

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

As with all strong painkillers, your body may become used to you taking MS Contin tablets. Taking it may result in physical dependence. Physical dependence means that you may experience withdrawal symptoms if you stop taking MS Contin tablets 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 MS Contin tablets 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 heartbeats or changes in the way the heart beats
  • have heart disease 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 alcohol withdrawal
  • suffer from convulsions, fits or seizures
  • have a head injury, brain tumour, increased pressure in your head or spine
  • have sudden, 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 severe kidney or liver disease or a disease of the brain caused by liver disease
  • are about to have an operation or have had one within the last 24 hours including surgery on your spine for pain relief
  • take a medicine for depression called a 'monoamine oxidase inhibitor' or have taken any in the last two weeks.

Do not take MS Contin tablets if you are allergic to morphine, opioid painkillers, or any of the ingredients listed at the end of this leaflet.

Some of the strengths of this medicine also contain lactose so consider this if you are lactose intolerant.

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 this medicine if you are pregnant or intend to become pregnant whilst taking this medicine. Like most medicines of this kind, MS Contin tablets are not recommended to be taken during pregnancy. Your doctor will discuss the risks of using it if you are pregnant.

Do not give this medicine to a child under one year of age or weighing less than 25 kg. Safety and effectiveness in children under one year of age or weighing less than 25 kg 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 or recent surgery of your gall bladder or bile duct
  • inflammation of the pancreas
  • underactive adrenal glands
  • underactive thyroid gland
  • inflammatory bowel disease or recent abdominal surgery
  • galactose intolerance, lactase deficiency or have problems with glucose-galactose absorption
  • an addiction or history of abuse of alcohol or drugs
  • sickle cell disease.

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

Tell your doctor if you are breastfeeding or 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 MS Contin tablets.

Taking other medicines

Tell your doctor or pharmacist 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, alcohol and MS Contin tablets 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 MS Contin tablets are taken
  • medicines to help you sleep
  • 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 (take antacids at least two hours before or after taking MS Contin tablets)
  • medicines to treat Parkinson's disease
  • medicines to treat urinary incontinence
  • medicines to stop nausea or vomiting e.g. metoclopramide or prochlorperazine
  • rifampicin, a medicine to treat tuberculosis
  • other pain relievers including other opioids
  • alcohol
  • medicines to treat HIV infection and AIDS e.g. ritonavir or zidovudine.

These medicines, dietary supplements or alcohol may be affected by MS Contin tablets, may affect how well MS Contin tablets work 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 and dietary supplements to be careful with or avoid while taking this medicine.

How to take MS Contin tablets

How much to take

Your doctor will tell you exactly how much to take.

Follow the instructions your doctor or pharmacist gives you exactly.

How to take it

Swallow MS Contin tablets whole. Do not break, chew, crush or dissolve them.

MS Contin 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.

You must only take MS Contin tablets 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 MS Contin tablets every 12 hours.

Take MS Contin tablets regularly to control the pain.

Taking them at the same time each day will assist in ensuring the best effect in improving your pain. If, however, you begin to experience worsening pain and you are taking your MS Contin tablets as prescribed, contact your doctor as your dosage may have to be reviewed.

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 your dose, contact your doctor or pharmacist for advice.

Do not take a double dose to make up for the dose you have 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 time each morning and evening such as 8 a.m. and 8 p.m.

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 your nearest hospital, if you think that you or anyone else may have taken too many MS Contin tablets.

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 accidentally taken the tablets that were 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 or die.

When seeking medical attention, take this leaflet and any remaining tablets 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 MS Contin tablets exactly as your doctor has prescribed.

Before you start on a new medicine, remind your doctor and pharmacist that you are taking MS Contin tablets.

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

If you are about to have any blood tests, tell your doctor that you are being given this medicine. It may interfere with the results of some tests.

If you are going to have surgery, tell the surgeon or 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 of 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 MS Contin tablets.

Tolerance to morphine may develop which means that the effect of the medicine may decrease. If this happens, your doctor may review your dose so that you get adequate pain relief.

Keep enough MS Contin tablets with you to last over weekends and holidays.

Things you must not do

Do not drink alcohol while you are taking MS Contin tablets. Drinking alcohol whilst taking MS Contin tablets 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 MS Contin tablets 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, take more than your doctor has told you to, or change the dosage without checking with your doctor.

Over time your body may become used to 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

Do not drive or operate machinery until you know how MS Contin tablets affect you. MS Contin tablets 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 drowsiness, dizziness and unsteadiness, 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 MS Contin tablets. If you vomit after taking your dose, your pain may come back as you may not have absorbed your medicine. If this happens, speak to your doctor. Your doctor may prescribe some medicine to help stop vomiting.

Tell your doctor if taking MS Contin tablets 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 MS Contin tablets.

This medicine helps most people with severe pain, but it may have unwanted side effects in a few people. Other side effects not listed here may also occur in some people.

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

Tell your doctor if you notice any of the following 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 or other hormonal changes
  • muscle twitching or muscle stiffness
  • swelling, including but not only of legs or ankles
  • feeling pain from something that is ordinarily painless, for example, bedsheets being pulled across the skin.

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
  • fatigue, generally feeling unwell
  • 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 difficult 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
  • you have sickle cell disease and you experience painful or rapid breathing, fever, cough, or bluish changes to the colour of your skin.

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 tablets with you to show the doctor.

After taking it

Storage

Keep your tablets in the blister pack until it is time to take them. If you take the tablets out of the blister pack they may not keep well.

Keep your tablets in a cool, dry place where the temperature stays below 25°C.

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

Do not leave it in the car. Heat and damp can destroy some medicines.

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

Disposal

If your doctor tells you to stop taking the tablets or the tablets have passed their expiry date, ask your pharmacist how to dispose of medicines no longer required.

Product Description

What it looks like

MS Contin® modified release tablets are film-coated and biconvex in shape and are available in seven strengths:

5 mg - white, marked 5 mg on one side

10 mg - light tan, marked 10 mg on one side

15 mg - light green, marked 15 mg on one side

30 mg - purple, marked 30 mg on one side

60 mg - orange, marked 60 mg on one side

100 mg - grey, marked 100 mg on one side

200 mg - teal green, marked 200 mg on one side.

MS Contin® modified release tablets are available in boxes containing blister packs of 28 tablets.

Ingredients

Active ingredients:

  • 5 mg tablets contain 5 mg morphine sulfate pentahydrate
  • 10 mg tablets contain 10 mg morphine sulfate pentahydrate
  • 15 mg tablets contain 15 mg morphine sulfate pentahydrate
  • 30 mg tablets contain 30 mg morphine sulfate pentahydrate
  • 60 mg tablets contain 60 mg morphine sulfate pentahydrate
  • 100 mg tablets contain 100 mg morphine sulfate pentahydrate
  • 200 mg tablets contain 200 mg morphine sulfate pentahydrate.

Inactive ingredients:

  • lactose (except 100 and 200 mg)
  • hyetellose
  • cetostearyl alcohol
  • magnesium stearate
  • purified talc.

MS Contin® modified release tablets are coated with E171 (titanium dioxide), hypromellose (except 10 mg), macrogol 400 (except 10 mg), macrogol 3350 (10 mg only), polyvinyl alcohol (10 mg only) and purified talc (10 mg only).

In addition, the tablets also contain the colourants listed below:

10 mg tablet: E172 (iron oxide red, black and yellow)

15 mg tablet: E172 (iron oxide yellow), E104 (quinoline yellow), E132 (indigo carmine) and E133 (brilliant blue FCF)

30 mg tablet: E127 (erythrosine), E132 (indigo carmine) and E110 (sunset yellow FCF)

60 mg tablet: E110 (sunset yellow FCF), E104 (quinoline yellow) and E127 (erythrosine)

100 mg tablet: E172 (iron oxide black and yellow) and E132 (indigo carmine)

200 mg tablet: E104 (quinoline yellow) and E133 (brilliant blue FCF).

This medicine does not contain sucrose, gluten or tartrazine.

Supplier

MS Contin® tablets are supplied in Australia by:

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

® MS CONTIN is a trade mark of MUNDIPHARMA.

This leaflet was updated in July 2019.

Australian Register Numbers for MS Contin® modified release tablets:

5 mg: AUST R 51760

10 mg: AUST R 210776

15 mg: AUST R 78208

30 mg: AUST R 43086

60 mg: AUST R 43087

100 mg: AUST R 43088

200 mg: AUST R 78209

Orbis RA-0280-001

Published by MIMS October 2019

BRAND INFORMATION

Brand name

MS Contin

Active ingredient

Morphine sulfate pentahydrate

Schedule

S8

 

1 Name of Medicine

Morphine sulfate pentahydrate.

2 Qualitative and Quantitative Composition

MS Contin modified release tablets 5 mg contains 5 mg morphine sulfate pentahydrate.
MS Contin modified release tablets 10 mg contains 10 mg morphine sulfate pentahydrate.
MS Contin modified release tablets 15 mg contains 15 mg morphine sulfate pentahydrate.
MS Contin modified release tablets 30 mg contains 30 mg morphine sulfate pentahydrate.
MS Contin modified release tablets 60 mg contains 60 mg morphine sulfate pentahydrate.
MS Contin modified release tablets 100 mg contains 100 mg morphine sulfate pentahydrate.
MS Contin modified release tablets 200 mg contains 200 mg morphine sulfate pentahydrate.

Excipients with known effects.

Contains sugars as lactose (except 100 mg and 200 mg).
For the full list of excipients, see Section 6.1 List of Excipients.
MS Contin modified release tablets are also referred to as MS Contin tablets.

3 Pharmaceutical Form

MS Contin modified release tablets are film-coated, biconvex and imprinted with the dosage strength on one side.
MS Contin modified release tablets 5 mg (white, marked 5 mg on one side).
MS Contin modified release tablets 10 mg (light tan, marked 10 mg on one side).
MS Contin modified release tablets 15 mg (light green, marked 15 mg on one side).
MS Contin modified release tablets 30 mg (purple, marked 30 mg on one side).
MS Contin modified release tablets 60 mg (orange, marked 60 mg on one side).
MS Contin modified release tablets 100 mg (grey, marked 100 mg on one side).
MS Contin modified release tablets 200 mg (teal green, marked 200 mg on one side).

4 Clinical Particulars

4.1 Therapeutic Indications

MS Contin 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.
MS Contin tablets are not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
MS Contin tablets are not indicated as an as-needed (PRN) analgesia.

4.2 Dose and Method of 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.

MS Contin tablets (modified release).

Adult.

Initial adult dose.

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 MS Contin tablets every 12 hours. MS Contin 200 mg tablets should only be used in opioid-tolerant patients.
Patients over 50 and the elderly. Patients over the age of 50 tend to require much lower doses of morphine than in 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.
Children > 25 kg.

Initial paediatric dosage (children > 25 kg).

The initial dose will depend upon the degree of morphine tolerability and should be titrated in accordance with the patient's needs. (See Section 4.2 Dose and Method of Administration, Dose titration.)
Children ≤ 25 kg. There are no controlled trials of the use of MS Contin tablets in children weighing 25 kg or less, nor in children with chronic, severe, non-malignant pain.
Transferring to MS Contin tablets from alternate opioids. Patients currently receiving other oral morphine formulations may be transferred to MS Contin tablets at the same total daily morphine dosage, equally divided into two 12-hourly MS Contin tablet doses.
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 table (see 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 12-hourly MS Contin tablet doses.
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 control the pain with no or tolerable side effects. 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 MS Contin tablets, 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 (12-hourly) 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.
MS Contin tablets are designed to allow 12-hourly dosing. 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, MS Contin tablets may be administered 8-hourly. More frequent (than 8-hourly) administration of MS Contin tablets is neither rational nor recommended.
Adjustment or reduction of dosage. 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.
MS Contin tablets should be swallowed whole, not chewed, crushed or broken.

Treatment goals and discontinuation.

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

Duration of treatment.

Morphine should not be used longer than necessary.

4.3 Contraindications

MS Contin tablets should not be given to patients with: hypersensitivity to opioids or to any of the excipients; acute bronchial asthma or other obstructive airway disease, severe respiratory disease, acute respiratory disease and respiratory depression; cor pulmonale; cardiac arrhythmias; acute alcoholism; delirium tremens; severe CNS depression; convulsive disorders; increased cerebrospinal or intracranial pressure; head injury; brain tumour; paralytic ileus, delayed gastric emptying, suspected surgical and acute abdomen; severe liver disease, incipient hepatic encephalopathy; severe renal dysfunction; 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); children under one year of age; pregnancy.
Not recommended for pre-operative use or for the first 24 hours post-operatively.
MS Contin tablets are contraindicated in 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.

MS Contin tablets contain the opioid morphine and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed MS Contin tablets 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 MS Contin tablets.
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 MS Contin tablets 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 MS Contin tablets, 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.

Sleep-related breathing disorders.

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. 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.

Severe cutaneous adverse reactions (SCARs).

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

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 MS Contin tablets 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 MS Contin tablets concomitantly with any of the medicines, the lower 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 MS Contin tablets.

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 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 objections 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 prescribing and monitoring of the patient's opioid use. Prescribers should consult appropriate clinical guidelines on the use of opioid analgesics in such patients (e.g. those published by the Australian Pain Society).

Opioid use disorder (abuse and dependence).

Tolerance and physical and/or psychological dependence may develop upon repeated administration of opioids such as morphine.
Repeated use of morphine can lead to opioid use disorder (OUD). A higher dose and longer duration of opioid treatment can increase the risk of developing OUD. Abuse or intentional misuse of morphine may result in overdose and/or death. The risk of developing OUD is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g. major depression, anxiety and personality disorders).
Before initiating treatment with morphine and during the treatment, treatment goals and a discontinuation plan should be agreed with the patient (see Section 4.2 Dose and Method of Administration). Before and during treatment the patient should also be informed about the risks and signs of OUD. If these signs occur, patients should be advised to contact their physician.
Patients will require monitoring for signs of drug-seeking behaviour (e.g. too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

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 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 MS Contin tablets 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 MS Contin tablets, 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 MS Contin tablets (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.

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 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 considered 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 drugs such 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, MS Contin tablets should be discontinued immediately. As with all oral morphine preparations, MS Contin 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 or other pain-relieving surgical procedures should not receive MS Contin tablets 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 MS Contin tablets is indicated, the dosage should be adjusted to the new post-operative requirement.

Hepatobiliary disorders.

Morphine can cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. 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 pancreatitis. Patients with diseases of the biliary tract should be monitored for worsening of symptoms while administering morphine.

Acute ulcerative colitis.

Morphine may cause toxic dilation 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, in reduced dosages, to debilitated patients, and in 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 and pancreatitis.
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.

MS Contin tablets (5 mg, 10 mg, 15 mg, 30 mg and 60 mg tablets only) contain lactose. Patients with rare hereditary problems including galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take these strengths of MS Contin 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 in elderly patients.

Paediatric use.

There are no controlled trials of the use of MS Contin tablets in children weighing 25 kg or less, nor in children with chronic, severe, non-malignant pain. MS Contin 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 alkalising 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, anti-parkinsonian drugs and anti-emetics, 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, 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 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.

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 selective MAOIs (e.g. moclobemide and 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. 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 MS Contin 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 breastmilk. Caution should be exercised if morphine is administered to a nursing mother and use of MS Contin tablets 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 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 or parenteral use of morphine.

Very common adverse effects requiring medical attention.

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 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 (60 mg q12h of MS Contin tablets) 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 the 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 effects.

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 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, sphincter of Oddi dysfunction, spasm of sphincter of Oddi.

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, allodynia, central sleep apnoea syndrome.

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. Not known: acute generalised exanthematous pustulosis (AGEP).

Vascular disorders.

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

Drug dependence.

Repeated use of morphine can lead to drug dependence, even at therapeutic doses. The risk of drug dependence may vary depending on a patient's individual risk factors, dosage, and duration of opioid treatment (see Section 4.4 Special Warnings and Precautions for Use).

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. 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.
Toxic leukoencephalopathy has been observed with morphine overdose.

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 the antagonists should therefore be administered, preferably by the intravenous route. The usual initial intravenous (IV) 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 suspension 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 great 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 3000 mg/day with no apparent toxicity.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

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 man, 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, lung and after subcutaneous (SC) or intramuscular (IM) 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 1/2 to 1/3 as potent as when given by injection.
At steady-state, MS Contin tablets produce peak morphine concentrations approximately four to five hours post-dose and therapeutic levels tend to persist for a 12-hour period. Peak morphine concentrations are seen with MS Contin 5 mg and 15 mg tablets at approximately 2 hours post-dose.

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 inter-patient variability. The major route of excretion is via the kidney. About 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

The inactive ingredients in MS Contin modified release tablets (also referred as MS Contin tablets) are: lactose (except 100 mg and 200 mg); hyetellose; cetostearyl alcohol; magnesium stearate; and purified talc.
MS Contin tablets are coated with: hypromellose (except 10 mg); macrogol 400 (except 10 mg); macrogol 3350 (10 mg only); titanium dioxide; polyvinyl alcohol (10 mg only); and purified talc (10 mg only).
The tablet coatings also contain: iron oxide red (10 mg only); iron oxide black (10 mg and 100 mg only); iron oxide yellow (10 mg, 15 mg and 100 mg only); quinoline yellow (15 mg, 60 mg and 200 mg only); brilliant blue FCF (15 mg and 200 mg only); indigo carmine (15 mg and 30 mg only); indigo carmine aluminium lake (100 mg only); erythrosine (30 mg and 60 mg only); sunset yellow FCF (30 mg and 60 mg only).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of these medicines.

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

Blister packs (PVC/PVdC/Al) of 20, 28 and 60 (10 mg, 30 mg, 60 mg and 100 mg - hospital packs only; 5 mg, 15 mg and 200 mg - trade packs only) modified release tablets.
Not all presentations may be marketed.

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. Morphine sulfate pentahydrate is soluble 1:21 in water and 1:1000 in ethanol. It is practically insoluble in ether or chloroform.

Chemical structure.

The structural formula of morphine sulfate pentahydrate is:

CAS number.

CAS Registry Number: 6211-15-0.

7 Medicine Schedule (Poisons Standard)

S8.

Summary Table of Changes