Consumer medicine information

Sevredol Tablets

Morphine sulfate pentahydrate

BRAND INFORMATION

Brand name

Sevredol

Active ingredient

Morphine sulfate pentahydrate

Schedule

SUMMARY CMI

SEVREDOL^® 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 SEVREDOL?

SEVREDOL contains the active ingredient morphine sulfate pentahydrate. SEVREDOL is used for the treatment of chronic severe pain of cancer.

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

2. What should I know before I use SEVREDOL?

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 SEVREDOL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with SEVREDOL 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 SEVREDOL?

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 SEVREDOL by mouth.

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

5. What should I know while using SEVREDOL?

Things you should do	Remind any doctor or dentist you visit that you are using SEVREDOL. 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	SEVREDOL may cause drowsiness. If affected, do not drive a vehicle or operate machinery.
Drinking alcohol	Avoid alcohol. Alcohol may make you feel more sleepy and could increase the risk of serious side effects, such as shallow breathing with the risk of stopping breathing and loss of consciousness.
Looking after your medicine	Store below 30°C. Keep it where young children cannot reach it.

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

6. Are there any side effects?

SEVREDOL 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

SEVREDOL 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

SEVREDOL 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

SEVREDOL 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 SEVREDOL 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 SEVREDOL

Using SEVREDOL 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 SEVREDOL.

FULL CMI

SEVREDOL^® tablets

Active ingredient: morphine sulfate pentahydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using SEVREDOL. 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 SEVREDOL.

Where to find information in this leaflet:

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

1. Why am I using SEVREDOL?

SEVREDOL contains the active ingredient morphine sulfate pentahydrate. Morphine belongs to a group of medicines called opioid analgesics.

SEVREDOL is used for the treatment of chronic severe pain of cancer.

2. What should I know before I use SEVREDOL?

Warnings

Do not use SEVREDOL 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.

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

Tolerance

Tolerance to SEVREDOL 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 SEVREDOL and affect how it works.

Using SEVREDOL 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.

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

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

SEVREDOL 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 SEVREDOL.

4. How do I use SEVREDOL?

How much to take

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

When to take SEVREDOL

Take SEVREDOL every 4 hours or as directed by your doctor.
Take SEVREDOL at about the same time each day.

How to take SEVREDOL

Swallow SEVREDOL tablets with a glass of water.
SEVREDOL can be taken before or after food, but try to take it the same way every time.

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

If you forget to use SEVREDOL

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

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

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

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

If you use too much SEVREDOL (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 SEVREDOL 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 SEVREDOL 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 SEVREDOL?

Things you should do

Call your doctor straight away if you:

become pregnant
feel your pain is getting worse.

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

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 SEVREDOL suddenly, your pain may worsen and you may experience withdrawal symptoms.

Do not take SEVREDOL 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 SEVREDOL affects you.

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

Drinking alcohol

Tell your doctor if you drink alcohol.

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

Looking after your medicine

Store below 30°C.

Follow the instructions on 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 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 effects

What to do

Gastrointestinal and urinary related:

constipation
nausea or vomiting
difficulty urinating

Neurological and behavior related:

dizziness
drowsiness
headache
becoming extremely sensitive to touch

Allergy related:

sweating

Breathing related:

sleep apnoea (temporarily stop breathing while you sleep)

Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effects

What to do

Breathing related:

difficulty breathing or shallow breathing

Neurological and behavior related:

light-headedness, fainting or dizziness especially when standing up
changes in mood
drowsiness or feeling extremely sedated
feeling disorientated and having nightmares

Heart related:

slow or noticeable heartbeats

Gastrointestinal and urinary related:

severe stomach pain with nausea or vomiting
difficulty urinating

Allergy related:

shortness of breath, swelling of the face, lips, tongue or other parts of the body

Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What SEVREDOL contains

Active ingredient (main ingredient)	Morphine sulfate pentahydrate
Other ingredients (inactive ingredients)	Pregelatinised maize starch Povidone Magnesium stearate Purified talc Titanium dioxide Additionally, the 10 mg tablet contains hypromellose, macrogol 400 and brilliant blue FCF (CI42090 / E133); the 20 mg tablet contains macrogol 3350, polyvinyl alcohol, erythrosine aluminium lake (CI45430 / E127) and sunset yellow aluminium lake (CI15985 / E110)
Potential allergens	Lactose

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

What SEVREDOL looks like

SEVREDOL 10 mg tablets are blue, film coated, biconvex capsule-shaped tablets with a scoreline and marked with 'IR' and '10' on one side (Aust R 47543)

SEVREDOL 20 mg tablets are pink, film coated, biconvex capsule-shaped tablets with a scoreline and marked 'IR' and '20' on one side (Aust R 214089)

Who distributes SEVREDOL

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

This leaflet was prepared in May 2023.

® SEVREDOL is a trade mark of MUNDIPHARMA.
SEVREDOL-CMIv1-CCDSv19

Published by MIMS July 2023

BRAND INFORMATION

Brand name

Sevredol

Active ingredient

Morphine sulfate pentahydrate

Schedule

1 Name of Medicine

Morphine sulfate pentahydrate.

2 Qualitative and Quantitative Composition

Sevredol 10 mg tablets contain 10 mg morphine sulfate pentahydrate.
Sevredol 20 mg tablets contain 20 mg morphine sulfate pentahydrate.
Sevredol tablets contain the following excipients: tablet core: lactose, pregelatinised maize starch, povidone, magnesium stearate and purified talc;
10 mg film coat: Opadry complete film coating system 06B20843 blue (ARTG PI No: 10036).
20 mg film coat: Opadry II complete film coating system 85F240092 pink (ARTG PI No: 109108).

Excipients with known effect.

Sugars as lactose.

3 Pharmaceutical Form

Sevredol 10 mg: blue film-coated, biconvex capsule shaped tablets with a scoreline and "IR" to the left and "10" to the right.
Sevredol 20 mg: pink film-coated, biconvex capsule shaped tablets with a scoreline and "IR" to the left and "20" to the right.

4 Clinical Particulars

4.1 Therapeutic Indications

Treatment of chronic severe pain of cancer.

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.
As with other strong opioid analgesics, use of morphine for the management of persistent pain should be preceded by a thorough assessment of the patient and diagnosis of the specific pain or pains and their causes. Use of opioids for the relief of chronic pain, including cancer pain, all important as it may be, should be only one part of a comprehensive approach to pain control including other treatment modalities or drug therapy, nonpharmacological measures and psychosocial support.
Individual dosing requirements vary considerably based on each patient's age, weight, severity of pain, and medical and analgesic history.
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.
For patients who are receiving an alternative 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 (Table 1) can be used to calculate the approximate daily oral morphine sulfate pentahydrate dosage that should provide equivalent analgesia.

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. Some of these are: concomitant sedative medications, hepatic or renal failure, exacerbated respiratory failure, higher doses than tolerated by 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.
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.
Opioid agents do not effectively relieve dysesthetic pain, postherpetic neuralgia, stabbing pains, activity related pain, and some forms of headache. This is not to say that patients with advanced cancer suffering from some of these forms of pain should not be given an adequate trial of opiate analgesics, but it may be necessary to refer such patients at an early time for other forms of pain therapy. Pain without nociception is usually not opioid responsive.

Adults and children over 12 years of age.

Sevredol tablets should be used at four hourly intervals. A patient presenting with severe pain should normally be started on a dosage of one tablet 10 mg four hourly. Increasing severity of pain or tolerance to morphine will require increases in the dosage of Sevredol tablets, using 10 mg and 20 mg alone or in combination to achieve the desired reduction in levels of pain.
Patients receiving Sevredol tablets in place of parenteral morphine should be given a sufficiently increased dosage to compensate for any reduction in analgesic effects associated with oral administration. Usually such increased requirement is of the order of 50% to 100%. In such patients, individual dose adjustments are required.

Elderly.

A reduction in adult dosage may be advisable.

4.3 Contraindications

Morphine should not be given to patients with hypersensitivity to opioids; known hypersensitivity to any of the excipients; acute bronchial asthma; other obstructive airway disease; severe respiratory disease, acute respiratory disease, 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 abdominal conditions; severe liver disease; severe renal dysfunction; incipient hepatic encephalopathy; 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). Not recommended in pregnancy or for children below three years of age.
Sevredol tablets should not be used for the treatment of chronic non-cancer pain (CNCP).
Sevredol tablets should be used with caution preoperatively and within the first 24 hours postoperatively.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

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

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 Sevredol 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 Sevredol 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 Sevredol 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. Also see Section 4.8 Adverse Effects (Undesirable Effects), Endocrine disorders.

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 should 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 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, Sevredol tablets should be discontinued immediately. As with all oral morphine preparations, Sevredol tablets should be used with caution postoperatively including, but not limited to, following abdominal surgery, as morphine impairs intestinal motility and should not be used until the physician is assured of normal bowel function.
Decreased gastric emptying associated with morphine may be expected to increase the risks of aspiration either associated with morphine induced CNS depression/coma, or during or after general anaesthesia.

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 Sevredol tablets within 24 hours of the procedure. If further treatment with Sevredol tablets is indicated then the dosage should be adjusted to the new postoperative requirements.

Biliary tract disorders.

Morphine can cause an increase in intrabiliary pressure and spasm as a result of its effects on the sphincter of Oddi. 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, and 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.

Lactose.

Sevredol tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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.

Paediatric use.

Not recommended for children below three years 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, antiparkinsonian drugs 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, 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, 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 MAO inhibitors (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 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, coadministration 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.
Animal studies have shown that morphine may reduce fertility. In male rats, reduced fertility and chromosomal damage in gametes have been reported.
(Category C)
Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human foetus or neonate without causing malformations. These effects may be reversible.
Opioid analgesics may cause respiratory depression in the newborn infant. Morphine has been associated with foetal CNS effects in rodent studies.
In humans it is not known whether morphine can cause foetal harm when administered during pregnancy or can affect reproductive capacity. Use of Sevredol 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.

Not indicated. Morphine crosses the placental barrier and its administration during labour can produce respiratory depression in the neonate. Sevredol tablets 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 Sevredol 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 and 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 from 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 antiemetic should be considered. Patients taking the equivalent of a single dose of 20 mg or more of morphine usually require an antiemetic during early therapy. Small doses of prochlorperazine or haloperidol are 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 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 include.

Cardiac disorders.

Not known: bradycardia, palpitations, supraventricular 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.

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

Hepatobiliary disorders.

Uncommon: increased hepatic enzyme.
Not known: biliary pain, biliary spasm, biliary tract cramps, sphincter of Oddi dysfunction.

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, 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 and breast disorders.

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

Respiratory, thoracic and mediastinal disorders.

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

Skin and subcutaneous tissue disorders.

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

Vascular disorders.

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

Withdrawal (abstinence) syndrome.

Physical dependence with or without psychological dependence tends to occur with chronic administration. An abstinence syndrome may be precipitated when opioid administration is discontinued or opioid antagonists administered. 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 overdose 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 overdose 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 overdose 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 (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.
Evacuation of gastric contents may be useful in removing unabsorbed drug, particularly when a sustained release formulation has been taken.

Toxicity.

Morphine toxicity may result from overdose but because of the great inter-individual variation in sensitivity to opioids it is difficult to determine an exact dose of any opioid that is toxic or lethal.
The presence of pain or tolerance tends to diminish the toxic effects of morphine. Published data suggest that in a morphine naïve, 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, 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 pains than sharp, intermittent pain.

Clinical trials.

No data included.

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. Morphine given parenterally has been reported to be from two to six times more potent than oral administration. In general, the greatest difference between parenteral and oral potency is seen in acute studies. With chronic dosing, oral morphine is about ½ to 1/3 as potent as when given by injection.

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. Minor 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 elimination 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

See Section 2 Qualitative and Quantitative Composition.

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 30°C.

6.5 Nature and Contents of Container

Blister packs (PVC/PVdC/Al) of 20 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

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.

CAS number.

6211-15-0.

7 Medicine Schedule (Poisons Standard)

S8.

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Sevredol Tablets

Morphine sulfate pentahydrate

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Sevredol 10 mg

Sevredol 20 mg