Consumer medicine information

Kapanol

Morphine sulfate pentahydrate

BRAND INFORMATION

Brand name

Kapanol

Active ingredient

Morphine sulfate pentahydrate

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Kapanol.

SUMMARY CMI

KAPANOL®

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 KAPANOL?

KAPANOL contains the active ingredient morphine sulfate pentahydrate. KAPANOL 10, 20, 50 and 100 mg capsules are used for the relief of severe pain which is opioid-responsive. KAPANOL 10 and 20 mg capsules are also used for the relief of distressing chronic breathlessness in the palliative care of patients with severe chronic obstructive pulmonary disease (COPD), cardiac failure, malignancy or other causes. For more information, see Section 1. Why am I using KAPANOL? in the full CMI.

2. What should I know before I use KAPANOL?

Do not use if you have ever had an allergic reaction to morphine sulfate pentahydrate 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, are pregnant or plan to become pregnant or are breastfeeding. For more information, see Section 2. What should I know before I use KAPANOL? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with KAPANOL 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 KAPANOL?

Take KAPANOL by mouth. Your doctor will choose your dose and how often to take it. More instructions can be found in Section 4. How do I use KAPANOL? in the full CMI.

5. What should I know while using KAPANOL?

Things you should do
  • Remind any doctor, dentist, pharmacist, surgeon or anaesthetist you visit that you are using KAPANOL.
  • Tell your doctor if you become pregnant or are trying to become pregnant and if for any reason, you have not taken your medicine exactly as prescribed.
  • Keep all your doctor's appointments so that your progress can be checked.
  • Keep enough KAPANOL capsules with you to last over weekends and holidays.
Things you should not do
  • Do not stop taking KAPANOL or change the dose without first checking with your doctor.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use KAPANOL to treat any other complaints unless your doctor says to.
  • If taking KAPANOL to reduce chronic breathlessness, do not take additional doses of immediate release morphine.
Driving or using machines
  • Be careful driving or operating machinery until you know how KAPANOL affects you.
  • KAPANOL may cause dizziness or drowsiness.
Drinking alcohol
  • Do not drink alcohol while you are taking KAPANOL.
Looking after your medicine
  • Keep KAPANOL in a cool, dry place where it stays below 30°C.

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

6. Are there any side effects?

The most commonly reported side effects are: drowsiness, sweating, confusion, dizziness or unsteadiness, headache, nausea or vomiting, constipation, itchy skin, sedation, dysphoria and euphoria. Serious side effects include: blurred vision, flushing of the face, faintness or heart palpitations, hallucinations or abnormal thinking, changes in passing urine such as the volume passed, pain or feeling the need to urinate urgently and unusual weakness or loss of strength. 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 in treatment of pain

KAPANOL 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

KAPANOL 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

KAPANOL 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 KAPANOL 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 KAPANOL

Using KAPANOL 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 KAPANOL.



FULL CMI

KAPANOL®

Active ingredient: morphine sulfate pentahydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using KAPANOL. 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 KAPANOL.

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

Where to find information in this leaflet:

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

1. Why am I using KAPANOL?

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

KAPANOL 10, 20, 50 and 100 mg capsules are used for the relief of severe pain which is opioid-responsive, and requires daily, continuous, long-term treatment.

KAPANOL 10 and 20 mg capsules are also used for the relief of distressing chronic breathlessness in the palliative care of patients with severe chronic obstructive pulmonary disease (COPD), cardiac failure, malignancy or other causes.

KAPANOL should only be used after optimal treatments of the underlying causes and if other non-drug treatments are not effective.

Your doctor may have prescribed KAPANOL for another reason.

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

2. What should I know before I use KAPANOL?

Addiction

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

Tolerance

Tolerance to KAPANOL 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, blood pressure or pupil size.
  • watery eyes, runny nose, chills or yawning.
  • increased sweating.

Warnings

Do not use KAPANOL if:

  • you are allergic to morphine sulfate pentahydrate, or any of the ingredients listed at the end of this leaflet.
    Always check the ingredients to make sure you can use this medicine. Symptoms of an allergic reaction may be mild or severe. They usually include some or all of the following: wheezing, swelling of the lips/mouth, difficulty in breathing, hay fever, lumpy rash ("hives") or fainting.
  • you are pregnant, or trying to become pregnant, unless your doctor says you should. Your doctor will discuss the risks and benefits of using KAPANOL if you are pregnant.
  • you are severely drowsy or have a reduced level of consciousness.
  • you have an addiction or history of abuse of alcohol or drugs.
  • you suffer from convulsions, fits or seizures.
  • you have a head injury, brain tumour, increased pressure in your head or spine.
  • you have sudden, severe abdominal pain or have an obstruction of the bowel or a condition where it could occur, or you have biliary tract disease.
  • you are taking a medicine for depression called a 'monoamine oxidase inhibitor' or have taken one within the past two weeks.
  • you have heart problems which affect the rhythm of your heartbeat.
  • you have heart disease due to long term lung disease.
  • you have severe kidney or liver disease or a disease of the brain caused by liver disease.
  • you are about to have an operation or have had one within the last 24 hours, including surgery on your spine for relief.

Do not drink alcohol or take other central nervous system depressants (e.g. sleeping medications, tranquilisers), benzodiazepines, illicit drugs or other opioids whilst taking KAPANOL.

If you have any lung or breathing problems, you and your carer should discuss the risks and benefits of using KAPANOL in this situation with your doctor. The use of KAPANOL may help your breathing but may also cause uncomfortable side effects or side effects that may shorten your life.

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

Do not take KAPANOL if the packaging is torn or shows signs of tampering, or if the capsules look damaged or discoloured.

Speak to your doctor if you have tummy pains, vomiting or constipation.

If you're not sure whether you should be taking KAPANOL, talk to your doctor.

KAPANOL may cause serious, life-threatening, or fatal respiratory depression. This risk is increased when taken together with alcohol, or benzodiazepines, other central nervous system (CNS) depressants, or if the pellets in the KAPANOL capsules are chewed or crushed.

Check with your doctor if you:

  • are allergic to foods, dyes, preservatives or any other medicines.
  • have any other medical conditions (in particular: kidney or liver disease, under activity of the adrenal or thyroid gland, increased prostate size, narrowing of the urinary bladder tract, biliary tract disease or surgery or inflammation of the pancreas, a condition associated with fits or convulsions, or diarrhoea).
  • have inflammatory bowel disease or recent abdominal surgery.
  • have abnormal curvature of the spine or you have low blood pressure.
  • take any medicines for any other condition (including medicines called P2Y12 inhibitors)

KAPANOL frequently causes constipation, talk to your doctor about how this can be minimised.

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.

KAPANOL is not recommended to be taken during and immediately before labour. Morphine 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. Morphine can pass into your breast milk and can affect your baby. Your doctor can discuss the risks involved with you.

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 combinations of medicines may increase the risk of having serious side effects, such as respiratory depression, low blood pressure and profound sedation or coma. These serious side effects may be life-threatening. These combinations of medicines with KAPANOL include:

  • medicines which are central nervous system depressants, such as sedatives, benzodiazepines, hypnotics, general anaesthetics, phenothiazines, amphetamines, other tranquilisers and alcohol. Your doctor may reduce the dose of one or both of your medicines. Your doctor will advise you.

Some medicines, alcohol and KAPANOL 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 KAPANOL is taken.
  • other pain relievers including other opioids.
  • medicines used to relieve heartburn or treat stomach ulcers such as cimetidine or antacids (take antacids at least 2 hours before or after taking KAPANOL).
  • alkalinising agents used to manage disorders associated with low pH.
  • medicines to treat seizures, gabapentin or barbiturates.
  • medicines to help you sleep.
  • medicines to relax your muscles.
  • propranolol or other medicines to lower blood pressure.
  • medicines to prevent or relieve the symptoms of allergy such as antihistamines.
  • diuretics, medicines to reduce the amount of excess fluid in the body by increasing the amount of urine produced.
  • medicines to thin the blood, such as coumarin derivatives or warfarin.
  • medicines to treat HIV infection and AIDS, such as, ritonavir or zidovudine.
  • medicines to treat Parkinson's disease.
  • medicines to stop vomiting or nausea.
  • rifampicin, a medicine to treat tuberculosis.
  • St John's wort (Hypericum perforatum), a herbal remedy.
  • P2Y12 inhibitors, medicines used to prevent clots from forming and growing.

Immediate release oral morphine solution should NOT be used with KAPANOL when KAPANOL is prescribed for the reduction of chronic breathlessness.

These medicines may interfere with KAPANOL and affect how it works. You may need to take different amounts of your medicine, or you may need to take different medicines. Your doctor will advise you.

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

Use in children

KAPANOL is not to be used for children.

Use in elderly

KAPANOL should be taken with caution and in reduced dosages in elderly.

4. How do I use KAPANOL?

Before starting treatment and regularly during treatment, your doctor will discuss with you what you may expect from using KAPANOL, when and how long you need to take it, when to contact your doctor and when you need to stop it.

The Pharmacist's label on the pack will tell you how to take KAPANOL. If there is something you do not understand, ask your doctor or pharmacist.

How much to take

For Severe Pain

  • KAPANOL should be taken either once (every 24 hours) or twice (every 12 hours) daily, whichever your doctor has advised.
  • The amount of KAPANOL needed to give good pain relief varies. The doctor will take into account your age, weight, level of pain, any previous treatment for that pain and medical history when choosing your dose and how often to take it.
  • DO NOT take more capsules than your doctor tells you to. If pain occurs between doses DO NOT take extra doses of KAPANOL. Tell your doctor as soon as possible. Taking more KAPANOL than the doctor told you to can be dangerous.

For Chronic Breathlessness

  • The amount of KAPANOL needed to provide relief in chronic breathlessness varies. Your doctor will start you on one 10 mg capsule per day.
  • DO NOT take more capsules than your doctor tells you to. If this dose is not enough to relieve your breathlessness, your doctor may ask you to increase your dose of KAPANOL, after taking into account your response to the starting dose. You should not take more than 30mg daily to treat chronic breathlessness.

Follow the instructions provided and use KAPANOL until your doctor tells you to stop.

How to take KAPANOL

The individual pellets in KAPANOL capsules must not be chewed or crushed.

  • KAPANOL is designed to work properly only if swallowed whole. The capsules 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. Unless stated otherwise, they should be swallowed whole.

If you have difficulty swallowing the capsule whole, take it in one of the following ways:

  • Just before use, sprinkle the pellets from the capsule onto a small amount of soft food (such as yoghurt, custard, ice cream, apple sauce or jam), and swallow this without chewing or crushing the pellets. Rinse your mouth with water and swallow to ensure all the pellets are taken, or
  • Just before use, mix the pellets from the capsule into about 30 mL of water, orange juice or milk (1/8 of a standard 250 mL glass). Swirl the glass and swallow the pellets with the liquid, being careful not to chew or crush the pellets. To make sure that all the pellets are taken, rinse the glass with a little more liquid and again, swirl the glass and swallow the pellets with the liquid until all pellets are taken.
  • If you have a gastrostomy tube, your doctor may decide to administer your KAPANOL pellets through the tube.

When to take KAPANOL

  • KAPANOL can be taken before, with or after food. It should be taken at about the same time or times each day.

How long to take KAPANOL

  • It is important that KAPANOL is taken regularly, not 'as needed' to relieve symptoms. Taking KAPANOL at regular times means that the onset of symptoms is prevented.
  • If you feel your symptoms are less and you don't need as much KAPANOL, tell your doctor. You should not stop taking KAPANOL or reduce the dose suddenly without asking your doctor first.

If you forget to use KAPANOL

KAPANOL should be used regularly at the same time each day. If you forget to take a dose, contact your doctor or pharmacist for advice.

If you use too much KAPANOL

If you think that you have used too much KAPANOL, you may need urgent medical attention.

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.

5. What should I know while using KAPANOL?

Things you should do

Tell your doctor or pharmacist that you are taking KAPANOL if you are about to be started on any new medicines.

Call your doctor straight away if you:

  • become pregnant or are trying to become pregnant.
  • for any reason, have not taken your medicine exactly as prescribed. Otherwise, your doctor may think that it was not effective and change your treatment unnecessarily.

KAPANOL can cause sleep-related breathing disorders such as sleep apnoea (breathing pauses during sleep) and sleep related hypoxemia (low oxygen level in the blood). The symptoms can include breathing pauses during sleep, night awakening due to shortness of breath, difficulties to maintain sleep or excessive drowsiness during the day. If you or another person observe these symptoms, contact your doctor. A dose reduction may be considered by your doctor.

Acute generalized exanthematous pustulosis (AGEP) has been reported in association with morphine treatment. Symptoms usually occur within the first 10 days of treatment. Tell your doctor if you have ever developed a severe skin rash or skin peeling, blistering and/or mouth sores after taking KAPANOL or other opioids. Stop using KAPANOL and seek medical attention immediately, if you notice any of the following symptoms: blistering, widespread scaly skin or pus-filled spots together with fever.

Contact your doctor if you experience severe upper abdominal pain possibly radiating to the back, nausea, vomiting or fever as this could be symptoms associated with inflammation of the pancreas (pancreatitis) and the biliary tract system.

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

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

Keep enough KAPANOL capsules with you to last over weekends and holidays.

Remind any doctor, dentist, pharmacist, surgeon or anaesthetist you visit that you are using KAPANOL.

Things you should not do

  • Do not stop taking KAPANOL or change the dose without first checking with your doctor.
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
  • Do not use KAPANOL to treat any other complaints unless your doctor says to.
  • If taking KAPANOL to reduce chronic breathlessness, do not take additional doses of immediate release morphine.
  • Do not drink alcohol while you are taking KAPANOL.

Driving or using machines

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

KAPANOL may cause dizziness or drowsiness in some people and may affect your ability to drive a car or operate machinery.

Tell your doctor if you drink alcohol.

  • If you drink alcohol, dizziness or light-headedness may be worse. Morphine may have potential combined effects when used with other CNS depressants, including other opioids, phenothiazines, sedatives/hypnotics, benzodiazepines, alcohol and illicit drugs.
  • Do not take medicines that might make you drowsy while you are taking KAPANOL unless otherwise advised by your doctor.
  • If you are taking KAPANOL for breathlessness, you should not take any alcohol as the combination may dangerously suppress your breathing. You should not take any medicines that make you drowsy as these may also suppress your breathing unless you have discussed this with your doctor.

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

Looking after your medicine

  • Keep KAPANOL in a cool, dry place where it stays below 30°C.

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

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

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

Heat and dampness can destroy some medicines.

Keep your KAPANOL in its pack until it is time to take it.
If you take KAPANOL out of its pack it may not keep well.

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

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

Check with your doctor as soon as possible if you have any problems while taking KAPANOL, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

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

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

Less serious side effects

Less serious side effectsWhat to do
  • drowsiness
  • sweating
  • confusion
  • dizziness or unsteadiness
  • headache
  • nausea or vomiting
  • constipation
  • itchy skin
  • sedation
  • dysphoria
  • euphoria
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • blurred vision
  • flushing of the face, faintness or heart palpitations
  • hallucinations or abnormal thinking
  • changes in passing urine such as the volume passed, pain or feeling the need to urinate urgently
  • unusual weakness or loss of strength
  • sleep apnoea (breathing pauses during sleep)
  • severe skin reaction with blistering, widespread scaly skin, pus-filled spots together with fever. This could be a condition called Acute Generalized Exanthematous Pustulosis (AGEP)
  • symptoms associated with inflammation of the pancreas (pancreatitis) and the biliary tract system, e.g. severe upper abdominal pain possibly radiating to the back, nausea, vomiting or fever
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 immediately or go to the emergency department at your nearest hospital if you think you are having an allergic reaction to KAPANOL. Symptoms usually include some or all of the following:

  • wheezing, swelling of the lips/mouth, difficulty in breathing, hay fever, lumpy rash ("hives"), fainting
  • breathing slows or weakens
  • seizures, fits or convulsions

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.

Ask your doctor or pharmacist if you don't understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

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 KAPANOL contains

Each box contains 28 capsules.

Active ingredient
(main ingredient)		morphine sulfate pentahydrate
Other ingredients
(inactive ingredients)		sucrose (sugar)
maize starch
hypromellose
ethylcellulose
methacrylic acid copolymer
macrogol 6000
diethyl phthalate
purified talc
purified water
gelatin
SW-9009 Black Ink
Potential allergensKAPANOL does not contain gluten or lactose

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

What KAPANOL looks like

KAPANOL capsules are available in four strengths:

  • The 10 milligram capsules are clear and have one black band and K10 printed on them (Aust R 68439).
  • The 20 milligram capsules are clear and have two black bands and K20 printed on them (Aust R 48134).
  • The 50 milligram capsules are clear and have three black bands and K50 printed on them (Aust R 48135).
  • The 100 milligram capsules are clear and have four black bands and K100 printed on them (Aust R 48136).

Who distributes KAPANOL

Mayne Pharma International Pty Ltd
1538 Main North Road
Salisbury South SA, 5106
www.maynepharma.com

The information provided applies only to: KAPANOL.

KAPANOL® is a registered trademark of Mayne Pharma International Pty Ltd.

This leaflet was prepared in November 2023.

Published by MIMS January 2024

BRAND INFORMATION

Brand name

Kapanol

Active ingredient

Morphine sulfate pentahydrate

Schedule

S8

 

1 Name of Medicine

Morphine sulfate pentahydrate.

2 Qualitative and Quantitative Composition

Kapanol capsules 10, 20, 50 and 100 mg contain identical polymer-coated sustained-release pellets of morphine sulfate pentahydrate for oral administration.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Modified release capsule.
Each capsule contains creamy-white to light tan spheroidal pellets.

10 mg morphine sulfate pentahydrate.

Size 4 capsule, clear cap imprinted with K10, and clear body imprinted with one black band.

20 mg morphine sulfate pentahydrate.

Size 4 capsule, clear cap imprinted with K20, and clear body imprinted with two black bands.

50 mg morphine sulfate pentahydrate.

Size 2 capsule, clear cap imprinted with K50, and clear body imprinted with three black bands.

100 mg morphine sulfate pentahydrate.

Size 0 capsule, clear cap imprinted with K100, and clear body imprinted with four black bands.

4 Clinical Particulars

4.1 Therapeutic Indications

Management of severe pain.

Kapanol 10, 20, 50 and 100 mg capsules 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.
Kapanol is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
Kapanol is not indicated as an as-needed (PRN) analgesia.

Symptom reduction of chronic breathlessness.

Kapanol 10 and 20 mg capsules are indicated for the symptomatic reduction of chronic breathlessness in the palliative care of patients with distressing breathlessness due to severe COPD, cardiac failure, malignancy or other cause. Kapanol should only be used after treatments for the underlying cause(s) of the breathlessness have been optimised and nonpharmacological treatments are not effective. Treatment with Kapanol in this setting should only be initiated by a specialist knowledgeable in its use.

4.2 Dose and Method of Administration

The sustained-release nature of Kapanol capsules allows for administration on a once daily (every 24 hours) or twice daily (every 12 hours) dosing interval.
Kapanol is not bioequivalent to other controlled-release morphine preparations.
The individual pellets in Kapanol capsules must not be chewed or crushed.

Management of severe pain.

Treatment goals and discontinuation.

Before initiating treatment with Kapanol, 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 Kapanol, 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).
The use of opioid analgesics for the management of severe pain, including cancer pain, should be prescribed as a component of a comprehensive multidisciplinary and multimodal pain management approach which should include other types of treatment or drug therapy, non-drug measures and psychosocial support.
Selection of the initial dose of Kapanol should take into account the following:
i. the total daily dose, potency and characteristics of previous opioid analgesics (e.g. pure agonists or mixed agonist/antagonist);
ii. the reliability of the relative potency estimate used to calculate the dose of morphine required (potency estimates vary with the route of administration);
iii. the degree of opioid tolerance;
iv. the patient's general medical condition;
v. concurrent medications;
vi. type and severity of pain.
The usual starting dose in opioid-naïve patients is Kapanol capsules 40 mg every 24 hours or 20 mg every 12 hours. The first dose of Kapanol may be taken with the last dose of any immediate-release opioid medication.
If signs of excessive opioid effects are observed early in the dosing interval, the next dose should be reduced. If this adjustment leads to inadequate analgesia, that is, 'breakthrough pain' occurs, a supplemental dose of a short acting analgesic may be given. The dosing interval of Kapanol should not be reduced below every 12 hours. As experience is gained, adjustments can be made to obtain an appropriate balance between pain relief and opioid side effects.
Because of the sustained-release properties of Kapanol, dosage increases should generally be separated by 24 hours.

Duration of treatment.

Kapanol should not be used longer than necessary.

Symptom reduction of chronic breathlessness.

Treatment should be initiated by a specialist knowledgeable in the use of potent opioids for the management of chronic breathlessness. The use of Kapanol for the reduction of chronic breathlessness should be only part of a complete approach to symptom control which should include non-drug measures and psychosocial support.
Kapanol should be commenced at 10 mg once daily in opioid-naïve patients. During initiation and up-titration, patients should be reviewed on a weekly basis and breathlessness evaluated using a validated tool such as a numerical rating scale (NRS). If a satisfactory clinical response (e.g. a one point reduction or greater in worst breathlessness in the previous 24 hours on the NRS) has not been achieved after 7 days, and the initial starting dose is well tolerated, an increase of the daily dose by 10 mg with evaluation over the next 7 days is suggested. The dose should be back-titrated if adverse effects become troublesome. Dosing can be once or twice daily but the maximum recommended dose for chronic breathlessness is 30 mg daily.
Initial prescription should be limited to a one week supply; when an effective dose has been determined, a one month supply should be prescribed. Prophylactic treatment for constipation should be commenced simultaneously and considered for nausea and vomiting depending on the patient's past experience with opioids.
Unlike the management of severe pain, immediate release oral morphine solution should not be co-prescribed with Kapanol when Kapanol is prescribed for the reduction of chronic breathlessness.
Kapanol should not be used for acute nor acute-on-chronic breathlessness.
Kapanol should be used with caution in settings where renal function may change unpredictably or rapidly.

Method of administration.

It is preferable for Kapanol capsules to be swallowed whole. However, if the capsules cannot be swallowed whole they may be administered in one of the following ways.
The pellets may be mixed into approximately 30 mL of water in a glass and taken within 30 minutes of mixing without chewing or crushing the pellets. As some of the pellets may stick to the sides of the glass, a further 30 mL of water should be added, the glass swirled and all the remaining pellets taken with the water. This procedure can also be performed using orange juice or milk.
The pellets may be sprinkled onto a small amount of soft food (such as yoghurt, custard, ice-cream, apple sauce or jam) and taken within 30 minutes of sprinkling. The pellets must not be chewed or crushed and the mouth should be rinsed to ensure that all pellets have been swallowed.
The pellets may be administered through a 16 French gastrostomy tube:
flush the gastrostomy tube with water to ensure that it is wet;
sprinkle the Kapanol pellets into 10 mL of water;
use a swirling motion to pour the pellets and water into the gastrostomy tube through a funnel;
rinse the beaker with a further 10 mL of water and pour this into the funnel;
repeat rinsing until no pellets remain in the beaker.
The administration of Kapanol pellets through a nasogastric tube should not be attempted.

Dose conversion for management of severe pain.

For patients currently receiving opioids, the following dosing recommendations should be considered.
Conversion from other oral morphine formulations to Kapanol for management of severe pain. Patients on other oral morphine formulations may be converted to Kapanol by administering one half of the patient's total daily morphine dose as Kapanol capsules on an every 12 hours dosing regimen or the patient's total daily morphine dose as Kapanol capsules on an every 24 hours dosing regimen. Dose is then adjusted as needed.
Conversion from parenteral morphine or other parenteral or oral opioids to Kapanol for management of severe pain. Kapanol can be administered as the initial oral morphine drug product. However, in this case, particular care must be exercised in the conversion process. Because of uncertainty about and inter-subject variation in relative estimates of opioid potency and cross tolerance, initial dosing regimens should be conservative, that is, an underestimation of the 24 hour oral morphine requirement is preferred to an overestimate. To this end, initial individual doses of Kapanol should be estimated conservatively.
Estimates of the relative potency of opioids are only approximate and are influenced by route of administration, individual patient differences, and possibly, by an individual's medical condition.
Consequently, it is difficult to recommend any fixed rule for converting a patient to Kapanol directly. The following general points should be considered:

Parenteral to oral morphine ratio.

Estimates of the oral to parenteral potency of morphine vary. Some authorities suggest that a dose of oral morphine only three times the daily parenteral morphine requirement may be sufficient in chronic use settings.

Other parenteral or oral opioids to oral morphine.

Because there are no data on these types of analgesic substitutions, specific recommendations are not possible. Physicians are advised to refer to published relative potency data, keeping in mind that such ratios are only approximate (see Table 1). In general, it is safer to underestimate the daily dose of Kapanol required and rely upon ad hoc supplementation to deal with inadequate analgesia.
Conversion from Kapanol to other controlled release oral morphine formulations for management of severe pain. Although for a given dose the same amount of morphine is available from Kapanol as from morphine solution or controlled-release morphine tablets (i.e. AUC is the same), Kapanol results in reduced fluctuation in dose adjusted plasma morphine levels. Conversion from Kapanol to the same daily dose of other morphine preparations may lead to an initial change in the clinical status of the patient and close observation is recommended.
Conversion from Kapanol to parenteral morphine for management of severe pain. Based on single dose studies, 10 mg parenteral morphine is equipotent to 60 mg oral morphine. However, in chronic use this ratio may not apply and the ratio of 10 mg parenteral morphine to 30 mg oral morphine may be more appropriate. When converting from Kapanol to parenteral morphine, it is best to assume that the parenteral to oral potency is high and estimate the parenteral morphine dose per 24 hours based on the 1:6 ratio (parenteral:oral). The frequency of administration depends on the site and method of the parenteral administration. The dose should be adjusted based on the patient's clinical response.
Opioid analgesic agents do not effectively relieve dysesthetic pain, post-herpetic neuralgia, stabbing pains, activity-related pain, and some forms of headache. Patients suffering these types of severe pain should only be prescribed a short-term trial of opioid analgesics if other treatment options have failed, are contraindicated, not tolerated or are otherwise inappropriate to provide sufficient management of pain. Pain without nociception is usually not opioid-responsive.

Information for patients.

All patients.

A Consumer Medicine Information leaflet for Kapanol is available from your pharmacist. Medical practitioners should be familiar with the contents of this leaflet. If clinically advisable, patients receiving Kapanol should be given the following instructions by the medical practitioner.
1. The use of Kapanol should be determined by consultation with a medical practitioner.
2. Morphine may impair mental and/or physical ability required for the performance of potentially hazardous tasks (e.g. driving, operating machinery).
3. Morphine should not be taken with alcohol or other central nervous system (CNS) depressants (sleeping medications, tranquillisers) because additive effects including CNS depression may occur. A medical practitioner should be consulted if other prescription medications are currently being used or are prescribed for future use.
4. Morphine poses risks of opioid addiction, abuse and misuse. A medical practitioner should be consulted if patients have any further questions or concerns regarding abuse, addiction or physical dependence.
5. For women of childbearing potential who become or are planning to become pregnant, a medical practitioner should be consulted regarding analgesics and other drug use.
6. The pellets in Kapanol capsules must not be chewed or crushed as this may destroy their sustained-release properties.

For palliative use in chronic breathlessness.

Kapanol should only be commenced after a careful discussion of the risks and possible benefits of its use with the patient, and carer(s) where possible. The following additional information should be provided:
1. Kapanol will be trialled to see if it reduces the intensity of breathlessness.
2. A low dose of Kapanol will be started. Any increase in this dose will only occur in consultation with the prescribing medical practitioner and after consideration of therapeutic response and occurrence of adverse effects.
3. Kapanol may cause nausea, vomiting, constipation, drowsiness and confusion. Laxatives will be commenced at the same time to proactively manage constipation.
4. Kapanol may cause respiratory depression that has been associated with fatal outcome. This risk is increased if Kapanol is taken with alcohol or benzodiazepines or if the pellets in the Kapanol capsules are chewed or crushed.

4.3 Contraindications

Kapanol should not be given to patients with:
known hypersensitivity to morphine or other opioid analgesics, morphine salts or any of the capsule components;
acute respiratory disease, acute-on-chronic respiratory disease, respiratory depression, cor pulmonale;
severe respiratory disease unless related to use for the symptomatic reduction of chronic breathlessness in the palliative care setting (see Section 4.1 Therapeutic Indications);
acute alcoholism or delirium tremens; convulsive disorders, severe CNS depression; increased cerebrospinal or intracranial pressure; head injury; brain tumour; biliary colic; cardiac arrhythmias; gastrointestinal obstruction, particularly paralytic ileus; suspected surgical abdomen; severe liver disease; incipient hepatic encephalopathy; severe renal dysfunction;
concurrent MAO inhibitors or within 14 days of such therapy (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Kapanol should not be given to patients who have a prior history of substance or alcohol abuse.

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Kapanol contains the opioid morphine sulfate pentahydrate and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Kapanol 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 Kapanol.
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 Kapanol with anyone else.
In the absence of a clear indication for a strong opioid analgesic, drug-seeking behaviour must be suspected and resisted, particularly in individuals with a history of, or propensity for, drug abuse. Concerns about abuse, addiction, and diversion should not prevent the proper management of severe pain or chronic breathlessness. This is not a prime concern in the management of terminally ill patients with chronic breathlessness or patients in severe pain.

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 Kapanol 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, patients with hepatic insufficiency and significantly decreased renal function; (see Special risk groups) 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 when not related to use for the symptomatic reduction of chronic breathlessness in the palliative care setting, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
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 for severe pain should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of analgesic doses is required when changing opioids or switching from immediate release to modified release formulations (see Section 4.2 Dose and Method of Administration, Dose conversion for management of severe pain), together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.

Impaired respiration when treating chronic breathlessness.

Morphine should be used with extreme caution in patients with chronic obstructive pulmonary disease and in patients having a substantially decreased respiratory reserve, hypoxia, 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. In such patients, even usual therapeutic doses of morphine may increase airway resistance and decrease respiratory drive to the point of apnoea.
Kapanol treatment for chronic breathlessness should be commenced at 10 mg with careful titration to a maximum of 30 mg daily (see Section 4.2 Dose and Method of Administration, Symptom reduction of chronic breathlessness).
Reported use of Kapanol carefully titrated at doses up to 30 mg/day in people with severe COPD did not result in episodes of respiratory depression (see Section 5.1 Pharmacodynamic Properties, Clinical trials). However, observational studies have reported an increased risk of death with opioids in patients with severe COPD. Patients should be advised of this risk.

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 Kapanol 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 Kapanol 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 Kapanol.

Use of opioids in chronic (long-term) non-cancer pain (CNCP).

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised nonpharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation (see Section 4.2 Dose and Method of Administration). 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).
The prescription and monitoring of the patient's opioid use should be the responsibility of one doctor only.

Palliative use in chronic breathlessness.

The use of Kapanol for the reduction of chronic breathlessness should be restricted to situations where:
the approved treatments for the underlying cause(s) of the breathlessness and nonpharmacological measures are not effective; and
review by a respiratory, palliative care or other appropriate specialist has confirmed that treatment of the underlying cause(s) is optimal; and
the breathlessness is having a significant impact on the patient's quality of life, and the patient has been informed of the potential risks; and
there is no psychiatric contraindication or history of drug abuse.
The prescriber should be knowledgeable in the use of Kapanol for this indication and should consult appropriate clinical guidelines on the use of opioids for the symptomatic reduction of chronic breathlessness in palliative care. The prescription and monitoring of the patient's opioid use should be the responsibility of one doctor only.

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 Kapanol 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).
Tolerance has not been reported when regular, low dose Kapanol is used to reduce chronic breathlessness.
Infants born to mothers who are physically dependent on opioid analgesics may also be physically dependent and may exhibit withdrawal symptoms. These infants may have respiratory depression at birth (see Section 4.6 Fertility, Pregnancy and Lactation).

Accidental ingestion/exposure.

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

Opioid-induced hyperalgesia and allodynia.

Opioid-induce hyperalgesia (OIH) may occur with the use of opioids, particularly at high doses. OIH 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 (allodynia). OIH should not be confused with tolerance (see Tolerance, dependence and withdrawal). If OIH 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.
The patient should be informed that reducing and/or discontinuing opioids decreases their tolerance to these drugs. If treatment needs to be re-initiated, the patient must start at the lowest dose and titrate up to avoid overdose.
When treating patients with chronic breathlessness, opiate withdrawal symptoms have been reported after 2 weeks of treatment. Care should be taken during cessation and patients advised regarding the symptoms of opiate withdrawal.

Conversion between different morphine preparations.

Caution is needed when changing between different presentations of morphine, or other potent opioid analgesic preparations, and the patient should be re-titrated and clinically reassessed.

Serotonergic medicines.

Morphine must be administered with caution in patients taking serotonergic medicines (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hormonal changes.

Opioids, such as morphine, 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.

Seizure threshold.

Morphine may lower the seizure threshold in patients with a history of epilepsy.

Head injury and increased intracranial pressure.

The respiratory depressant effects of morphine with carbon dioxide retention and secondary elevation of cerebrospinal fluid pressure may be markedly exaggerated in the presence of head injury, other intracranial lesions, or a pre-existing increase in intracranial pressure. Morphine produces effects which may obscure neurological signs of further increases in pressure in patients with head injuries.

Hypotensive effect.

Kapanol, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or a concurrent administration of drugs such as phenothiazines or general anaesthetics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Kapanol may produce orthostatic hypotension in ambulatory patients.
Kapanol, like all opioid analgesics, should be administered with caution to patients in circulatory shock, as vasodilation produced by the drug may further reduce cardiac output and blood pressure.

Gastrointestinal motility.

As with any other oral dose morphine formulation, diarrhoea may reduce morphine absorption.

Abdominal conditions.

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

Biliary tract and sphincter of Oddi conditions.

Morphine may cause dysfunction and spasm of the sphincter of Oddi, thus raising intrabiliary pressure and increasing the risk of biliary tract symptoms and pancreatitis. Morphine should be used with caution in patients with diseases of the biliary tract 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 operations on the biliary tract and acute pancreatitis.

Acute ulcerative colitis and inflammatory bowel disorders.

Morphine may cause toxic dilatation in patients with acute ulcerative colitis.
Morphine should be used with caution in patients with inflammatory bowel disorders.

Cordotomy.

Severe pain antagonises the subjective and respiratory depressant actions of morphine. Should pain suddenly decrease, these effects may rapidly become manifest. Patients who are scheduled for cordotomy or other interruption of pain transmission pathways should not receive Kapanol 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 Kapanol capsules is indicated, the dosage should be adjusted to the new post-operative requirement.

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. 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.

Post-operatively.

Kapanol should not be used in the first 24 hours following surgery, and should be administered with caution thereafter, especially following abdominal surgery.

Special risk groups.

Kapanol should be administered with caution, and in reduced dosages in elderly or debilitated patients; patients with hepatic insufficiency; significantly decreased renal function; patients with adrenocortical insufficiency (e.g. Addison's disease); myxoedema; hypothyroidism; prostatic hypertrophy or urethral stricture, acute ulcerative colitis (due to the risk of toxic dilation).
Caution should also be exercised in the administration of Kapanol to patients with CNS depression; toxic psychosis; severe kyphoscoliosis; about to undergo biliary surgery and patients with acute pancreatitis secondary to biliary tract disease.

Oral P2Y12 inhibitor antiplatelet therapy.

Reduced efficacy of P2Y12 inhibitor treatment has been observed with co-administration of morphine and oral P2Y12 inhibitors (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Use in hepatic impairment.

See Special risk groups.

Use in renal impairment.

See Special risk groups.

Use in the elderly.

See Special risk groups.

Paediatric use.

The use of Kapanol in children has not been evaluated.

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.

CNS depressants.

Concomitant use of opioids with benzodiazepines or other CNS depressants, including alcohol should be avoided and may result in increased plasma levels and dangerous additive effects; profound sedation, respiratory depression, coma, other serious injuries or a potentially fatal overdose of morphine (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).
Morphine should be used with great caution and in reduced dosage with minimum duration during concomitant use of other CNS depressants including but 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 (e.g. gabapentin, pregabalin), cannabis, antihistamines, centrally-active antiemetics and alcohol, as they may enhance the depressant effects of morphine. Pyrazolidone antihistamines and 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.
Follow patients closely for signs and symptoms of respiratory depression and sedation. Reserve concomitant prescribing of Kapanol and benzodiazepines or other CNS depressants for use in patients for whom alternative treatment options are inadequate. When such combined therapy is contemplated, the dose of one or both agents should be reduced.

Muscle relaxants.

Morphine may enhance the neuromuscular blocking action of skeletal relaxants and produce an increased degree of respiratory depression.

Mixed agonist/antagonist opioid analgesics.

From a theoretical perspective, mixed agonist/antagonist opioid analgesics (e.g. pentazocine and buprenorphine) should not be administered to a patient who has received or is receiving a course of therapy with a pure opioid agonist analgesic. In these patients, mixed agonist/antagonist analgesics may reduce the analgesic effect or may precipitate withdrawal symptoms.

Monoamine oxidase inhibitors (MAOIs).

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

Serotonergic medicines.

Serotonin syndrome can occur during concomitant use of opioids with serotonergic drugs. This may occur within the recommended dose range. If concomitant use of morphine with a serotonergic drug is warranted, the patient should be observed for symptoms of serotonin syndrome, particularly during treatment initiation and dose increases. Treatment with the opioid and/or serotonergic medication should be discontinued if serotonin syndrome is suspected, and the patient should receive immediate medical attention.

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.

Cimetidine.

There is a report of confusion and severe respiratory depression when a haemodialysis patient was administered morphine and cimetidine. Although not reported with Kapanol, caution is advised when administering Kapanol with cimetidine.

Coumarin and other anticoagulants.

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

Ritonavir.

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

Propranolol.

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

Anticholinergics.

Medicinal products that block the action of acetylcholine, for example antihistamines, antiparkinsonians and antiemetics, may interact with morphine to potentiate anticholinergic adverse events (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Rifampicin.

Plasma concentrations of morphine may be reduced by rifampicin.

Diuretics.

Morphine reduces the efficacy of diuretics by inducing the release of antidiuretic hormone. Morphine may also lead to acute retention of urine by causing spasm of the sphincter of the bladder, particularly in men with prostatism. As Kapanol contains morphine it has the potential to cause similar effects.

P2Y12 inhibitors.

A delayed and decreased exposure to oral P2Y12 inhibitor antiplatelet therapy has been observed in patients with acute coronary syndrome treated with morphine. This interaction may be related to reduced gastrointestinal motility and apply to other opioids. The clinical relevance is unknown, but data indicate the potential for reduced P2Y12 inhibitor efficacy in patients co-administered morphine and an oral P2Y12 inhibitor (see Section 4.4 Special Warnings and Precautions for Use). In patients with acute coronary syndrome, in whom morphine cannot be withheld and fast P2Y12 inhibition is deemed crucial, the use of a parenteral P2Y12 inhibitor may be considered.

Alcohol.

In vitro data have shown that the presence of alcohol leads to an increased rate of release of morphine from the sustained-release pellets in the capsule.
Patients should be advised against co-administration of morphine sustained-release capsules with alcohol as this may lead to a rapid release and absorption of a potentially toxic dose of morphine (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol).

Food.

The bioavailability of Kapanol is not significantly affected by food.

St. John's wort.

In vitro data suggest that St. John's wort (Hypericum perforatum) may induce cytochrome P450 3A4. There is a theoretical possibility therefore, that plasma levels of morphine may be decreased during concomitant administration and increased upon withdrawal of St. John's wort.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Conventional animal reproduction studies have not been performed using morphine. However, there is evidence of reproductive toxicity in animals from other studies (see Use in pregnancy). It is not known whether morphine can cause foetal damage when administered throughout pregnancy or if it can affect reproductive capacity in humans. 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.
(Category C)
Treatment of laboratory animals with high doses of morphine during pregnancy has been associated with foetal and neonatal death, foetal growth retardation, exencephaly, skeletal effects, and alterations in behaviour and CNS development in offspring. Some of these findings were attributed to the hypoxic effects of large doses of morphine.
Morphine is not recommended for use in pregnant women. Pregnant women should only be given Kapanol when the benefits clearly outweigh potential risks to the foetus. Morphine crosses the placental barrier. Long-term use of opioids in pregnancy may result in a neonatal opioid withdrawal state.
Kapanol is not recommended for use in women during and immediately before labour. The effects of opioid analgesics are unpredictable. They may prolong labour by temporarily reducing the strength, duration and frequency of uterine contractions, or conversely they may tend to shorten labour by increasing the rate of cervical dilatation. Infants born to mothers receiving opioid analgesics during labour should be observed closely for signs of respiratory depression. In such infants, a specific opioid antagonist, naloxone hydrochloride, should be available for reversal of opioid-induced respiratory depression.
 Morphine is excreted in human milk and breast-feeding is not recommended while a patient is receiving Kapanol. Withdrawal symptoms have been observed in breast-fed infants when maternal administration of morphine is stopped.

4.7 Effects on Ability to Drive and Use Machines

Morphine may impair the mental and/or physical abilities needed to perform potentially hazardous activities such as driving a car or operating machinery (see Section 4.8 Adverse Effects (Undesirable Effects)). Patients must be cautioned accordingly.
Patients should also be warned about the potential combined effects of morphine with other CNS depressants, including other opioids, phenothiazines, sedatives/hypnotics, benzodiazepines, alcohol and illicit drugs (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
This medication may cause drowsiness and may increase the effects of alcohol. If affected do not drive a vehicle or operate machinery.

4.8 Adverse Effects (Undesirable Effects)

The adverse reactions caused by morphine are essentially the same as those observed with other oral and parenteral opioids. They include the following major hazards: respiratory depression, apnoea and to a lesser degree circulatory depression, respiratory arrest, shock and cardiac arrest.

Most common adverse effects.

Constipation, light-headedness, dizziness, headache, sedation, nausea, vomiting, sweating, dysphoria and euphoria.

Sedation.

Most patients receiving morphine will experience initial drowsiness. This usually disappears in three to five days and is not a cause for concern unless it is excessive, or accompanied with unsteadiness or confusion. Excessive or persistent sedation should be investigated. Factors to be considered should include: concurrent sedative medications, the presence of hepatic or renal insufficiency, exacerbated respiratory failure, tolerance to the dose used especially in older patients, disease severity and the patient's general condition. If the dose of Kapanol has been reduced and pain is not adequately controlled, the dose may be carefully increased again after a few days.

Dizziness and unsteadiness.

Dizziness and unsteadiness may be associated with morphine-induced postural hypotension, particularly in elderly or debilitated patients. The dosage should be adjusted according to individual needs but, because of reduced clearance, dosage may be lower in patients over 50 years of age.

Nausea and vomiting.

Nausea and vomiting are common after single doses of morphine or as an early undesirable effect of regular opioid therapy. The prescription of a suitable antiemetic should be considered. The frequency of nausea and vomiting usually decreases within a week or so but may persist due to opioid-induced gastric stasis. Metoclopramide is often useful in such patients.

Constipation.

Virtually all patients experience constipation while taking opioids on a chronic basis. Some patients, particularly elderly, debilitated or bedridden patients may experience impacted faeces. Patients must be cautioned accordingly and laxatives, softeners and other appropriate treatments should be initiated at the beginning of opioid therapy.

Other adverse reactions include.

Allergic.

Pruritus, urticaria, other skin rashes and oedema.

Cardiovascular.

Flushing of the face, chills, tachycardia, bradycardia, palpitations, faintness, syncope, hypotension and hypertension.

Central nervous system (CNS).

Euphoria, dysphoria, weakness, insomnia, dizziness, confusional symptoms and occasionally hallucinations.

Endocrine.

A syndrome of inappropriate antidiuretic hormone secretion characterised by hyponatraemia secondary to decreased free-water excretion may occur (monitoring of electrolytes may be necessary).

Gastrointestinal.

Dry mouth, anorexia, constipation, laryngospasm, colic, taste alterations and biliary colic, pancreatitis.

Genitourinary.

Urinary retention or hesitancy, reduced libido or potency.

Hepatobiliary.

Spasm of sphincter of Oddi.

Immune system.

Hypersensitivity.

Respiratory.

Central sleep apnoea syndrome.

Skin and subcutaneous tissue.

Acute generalised exanthematous pustulosis (AGEP).

Visual disturbances.

Blurred vision, nystagmus, diplopia and miosis.

Drug dependence.

Repeated use of opioid analgesics 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.

An abstinence syndrome may be precipitated when opioid administration is suddenly discontinued or opioid antagonists administered.
Withdrawal symptoms that may be observed after discontinuation of opioid use include: body aches, diarrhoea, piloerection, anorexia, nervousness or restlessness, rhinorrhoea, sneezing, tremors or shivering, abdominal colic, nausea, sleep disturbance, unusual increase in sweating and yawning, weakness, tachycardia or unexplained fever. With appropriate dose adjustments and gradual withdrawal, these symptoms are usually mild.

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

Contact the Poisons Information Centre on 13 11 26 (Australia) for advice on overdose management.

Symptoms.

Acute overdosage with morphine is manifested by respiratory depression, somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, constricted pupils, and sometimes bradycardia and hypotension.

Treatment.

Primary attention should be given to the establishment of a patent airway and institution of assisted or controlled ventilation. The pure opioid antagonist, naloxone hydrochloride, is a specific antidote against respiratory depression which results from opioid overdose. Naloxone (usually 0.4 to 2.0 mg) should be administered intravenously. However, because its duration of action is relatively short, the patient must be carefully monitored until spontaneous respiration is reliably re-established. Kapanol will continue to release and add to the morphine load for up to 24 hours after administration and the management of morphine overdosage should be modified accordingly. If the response to naloxone is sub-optimal or not sustained, additional naloxone may be administered as needed, or given by continuous intravenous infusion to maintain alertness and respiratory function. There is no information available about the cumulative dose of naloxone that may be safely administered.
Naloxone should not be administered in the absence of clinically significant respiratory or circulatory depression secondary to morphine overdosage. Naloxone should be administered cautiously to persons who are known or suspected to be physically dependent on Kapanol. In such cases, an abrupt or complete reversal of opioid effects may precipitate an acute withdrawal syndrome. The severity of the withdrawal syndrome produced will depend on the degree of physical dependence and the dose of the antagonist administered. If it is necessary to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
Supportive measures (including oxygen, vasopressors) should be employed in the management of circulatory shock and pulmonary oedema accompanying overdose as indicated. Cardiac arrest or arrhythmias may require cardiac massage or defibrillation.
Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected.
Morphine toxicity may be a result of overdosage but because of the large inter-individual variation in sensitivity to opioids it is difficult to assess the exact dose of any opioid that is toxic or lethal. The toxic effects of morphine tend to be overshadowed by the presence of pain or tolerance. Patients having chronic morphine therapy have been known to take in excess of 3,000 mg/day with no apparent toxic effects being present.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Morphine is an opioid analgesic which exerts an agonist effect at specific, saturable opioid receptors in the CNS and other tissues. Morphine produces diverse pharmacological effects in man, including analgesia, suppression of the cough reflex, respiratory depression due to a reduction in the responsiveness of the respiratory centre to carbon dioxide, nausea and emesis through direct stimulation of the chemoreceptor trigger-zone (CTZ), mood changes including euphoria and dysphoria, sedation, mental clouding, alterations in both the endocrine and autonomic nervous systems, and a decrease in gastrointestinal motility leading to constipation.

Clinical trials.

Management of severe pain.

Cancer related pain.

A total of 94 healthy subjects and 224 patients with cancer pain participated in a total of 8 studies (6 pharmacokinetic and 3 clinical; one study reported both pharmacokinetic and clinical data). Of these individuals, 94 healthy subjects and 171 patients received Kapanol. In the controlled clinical studies patients were followed for a median duration of 7 days.
Kapanol was compared to oral morphine solution and to MS Contin using trial designs that followed the clinical and pharmacokinetic performance of each treatment in cancer patients receiving chronic opioid therapy.
In one double-blind, controlled study, patients with moderate to severe cancer pain were titrated with immediate-release morphine (IRM) solution to a stable total daily dose of morphine for at least three consecutive days, then randomised to Kapanol once daily, Kapanol twice daily or MS Contin twice daily for seven days of observation. Kapanol given once a day proved similar to the same total dose of morphine given in divided doses in a 12-hour dosage form, with respect to pain relief, use of rescue medication, patient and investigator global assessment, and quality of sleep. Individual patient differences in the pattern of pain control emphasise the need to individualise the dose (see Section 4.2 Dose and Method of Administration).

Non-cancer related pain.

One multi-centre, randomised, open-label, parallel study compared the efficacy and tolerability of 12-hourly Kapanol with morphine sulfate controlled-release tablets (MST). Patients with severe chronic pain (n=165) of various origins (73.5% non-malignant, 26.5% malignant) were randomised and titrated to adequate analgesia with Kapanol or MST, respectively. The median titrated doses of morphine necessary for analgesia in the initial phase of the study were 40 mg twice daily in the Kapanol group and 30 mg twice daily in the MST group. Once stabilised, patients started the 2-week study period. 112 patients completed the study: 69 patients on Kapanol and 43 on MST. 22 of 91 (24.2%) of patients on Kapanol and 31 of 74 (41.9%) on MST withdrew prematurely. Inadequate efficacy was the reason for premature termination in 5 patients in the Kapanol group and 13 patients in the MST group. Significantly more patients on Kapanol achieved adequate analgesia than with MST, based on the physician's final assessment (73% vs 55.5%, p = 0.02), quality of sleep (p = 0.05), and effect on mood (p < 0.05). Inadequate efficacy was reported in 20% of patients on Kapanol and 21.5% of patients on MST.
Symptom reduction of chronic breathlessness.

Clinical trial 1.

282 opioid-naïve participants with modified Medical Research Council (mMRC) breathlessness scores 2-4 despite optimal treatment of the underlying cause(s) were randomised to double-blinded placebo or 20 mg Kapanol daily for 7 days. The primary outcome was reduction in breathlessness now intensity as measured on a 0-100 mm visual analogue scale (VAS) - no significant difference was found between the use of Kapanol and placebo for this measure. However, the study was confounded by the use of immediate release morphine as rescue medication in both arms.
A sub-group analysis for participants with more severe breathlessness (mMRC 3 or 4) found that there was a significant reduction in worst breathlessness when compared to placebo.
There were no episodes of respiratory depression in the study. See Table 2.

Clinical trial 2.

48 opioid-naïve participants with chronic breathlessness secondary to advanced disease with no reversible components were randomised to receive 20 mg sustained release morphine for 4 days or placebo in a double blind, crossover trial. The mean age of participants was 76 (SD 5) years, 73% were men, 88% had a diagnosis of COPD and 71% were receiving supplemental oxygen; Eastern Co-operative Oncology Group functional status was 2 or 3. The primary outcome variable was the sensation of breathlessness as measured on a VAS in the evening on the final day of the period. This was significantly reduced with sustained release morphine compared to placebo with a difference of 9.5 mm (SD 19, 95% CI 3.0 to 16.1, P = 0.006). 21% of participants withdrew from the study.1

Clinical trial 3.

83 opioid-naïve adult outpatients with a palliative diagnosis and chronic breathlessness (mMRC 3-4) were enrolled in an open-label dose finding study of sustained release morphine. Of the participants, mean age was 75 years, 64% were male, 54% had a diagnosis of COPD, median Australia-modified Karnofsky Performance Status function was 60. The duration of participation in the study was a mean of 142 days (SD 190; median 29; range 2 to 665). There were 52 participants who were assessed as responding (with this defined as a 10% improvement over baseline in VAS Breathlessness score and with acceptable/minimal side effects). In these patients, the average improvement from their own baselines was 17.1 mm (SD 11.6) and 69.2% had had benefit at a daily dose of 10 mg, 23.1% at 20 mg, and 7.7% at 30 mg.2
The most recent meta-analysis of controlled clinical trials of morphine for the reduction of chronic breathlessness explored 12 trials with significant heterogeneity, 11 of which were cross-over studies. The findings were of a statistically and clinically meaningful reduction in breathlessness.3 Of these studies, two used extended release (ER) morphine (64 participants) and one of these studies was for up to six weeks of treatment.
A further systematic review and meta-analysis that brought together 67 clinical studies of opioids for breathlessness found no evidence of clinically relevant respiratory adverse effects of opioids for chronic breathlessness including changes in blood gases or respiratory depression. In this study, 84 participants in three studies were on ER morphine, two of which for longer than seven days.4
1 Abernethy AP, Currow DC, Frith P, Fazekas BS, McHugh A, Bui C. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327(7414):523-528.
2 Currow DC, McDonald C, Oaten S, et al. Once daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manage 2011;42:388-399.
3 Ekstrom, Bajwah S, Bland JM, Currow DC, Hussain J, Johnson MJ. One evidence base; three stories: do opioids relieve chronic breathlessness? Thorax. 2018 Jan;73(1):88-90.
4 Verberkt CA, van den Beuken-van Everdingen MHJ, Schols JMGA, Datla S, Dirksen CD, Johnson MJ, van Kuijk SMJ, Wouters EFM, Janssen DJA. Respiratory adverse effects of opioids for breathlessness: a systematic review and meta-analysis Eur Respir J. 2017; Nov 22;50(5).

5.2 Pharmacokinetic Properties

Absorption.

Morphine is rapidly absorbed from the gastrointestinal tract, nasal mucosa, lung and after subcutaneous (s.c.) and intramuscular (i.m.) injection.
Following oral administration, the dose normalised extent of absorption (AUC) of morphine from Kapanol is similar to that obtained from morphine solution or controlled-release tablets. However, the rate of absorption of morphine from Kapanol is significantly slower.
On a 12 hourly dosing schedule, Kapanol at steady state exhibits a lower mean peak plasma morphine concentration (Cmax) and higher mean trough plasma morphine concentration (Cmin) than the same total daily dose of morphine solution administered on a 4 hourly dosing regimen. Although there is no clear relationship between the analgesic effect or the incidence of adverse reactions and plasma morphine concentrations, the reduced fluctuation in blood morphine concentrations following administration of Kapanol may reduce adverse reactions and the incidence of breakthrough pain.
On a 24 hourly dosing schedule, Kapanol at steady state maintained higher dose-adjusted minimum plasma morphine concentrations (Cmin) and was associated with reduced fluctuation in dose-adjusted plasma morphine levels than controlled-release morphine tablets administered on a 12 hourly dosing regimen. Plasma morphine concentrations remained at or above 75% of the maximum plasma concentration for longer with Kapanol than for controlled-release morphine tablets. There was no significant difference in the dose-adjusted AUC, average concentration (Cave) or Cmax between these two treatments.

Distribution.

Once absorbed, morphine is distributed to skeletal muscle, kidneys, liver, intestinal tract, lungs, spleen and brain. It crosses the placental membranes and has been found in breast milk. About 30 to 35% of morphine is reversibly protein bound.
When Kapanol is given on a fixed dosing regimen, steady state is achieved within about two days.
Pharmacokinetic parameters of morphine show considerable inter-subject variation. The average volume of distribution (Vd) is approximately 4 L/kg.

Metabolism.

When administered orally it is subject to extensive but variable 'first-pass' metabolism and only about 40% of the administered dose reaches the central compartment.
Virtually all morphine is converted to glucuronide metabolites including morphine-3-glucuronide (M-3-G) (about 50%) and morphine-6-glucuronide (M-6-G) (5 to 15%). Morphine-6-glucuronide has been shown to be pharmacologically active. Because accumulation of this metabolite has been observed in patients with renal disease, caution should be exercised in patients with clinically significant impairment of renal function. There has been no evaluation of Kapanol in patients with impaired hepatic and renal function.

Excretion.

Morphine is excreted primarily in the urine as morphine-3-glucuronide and morphine-6-glucuronide. A small amount of the glucuronide metabolites is excreted in the bile and there is some minor enterohepatic cycling. Seven to 10% of administered morphine is excreted in the faeces. The terminal half-life of morphine is 2 to 4 hours.

5.3 Preclinical Safety Data

Genotoxicity.

Genotoxicity was either not assessed or not identified as part of the registration of this medicine.

Carcinogenicity.

Carcinogenicity was either not assessed or not identified as part of the registration of this medicine.

6 Pharmaceutical Particulars

6.1 List of Excipients

Kapanol inactive ingredients: sucrose, maize starch, hypromellose, ethylcellulose, methacrylic acid copolymer, macrogol 6000, diethyl phthalate, purified talc, purified water, gelatin, Tek Print* SW-9009 Black Ink.

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 the capsules below 30°C. Protect from light and moisture.

6.5 Nature and Contents of Container

Kapanol capsules are available in blister packs of 20, 28 or 60 capsules.
Not all strengths or pack sizes may be distributed in Australia.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Chemical structure.

Chemically, morphine sulfate pentahydrate is 7,8-didehydro-4,5(alpha)-epoxy-17-methyl-morphinan-3,6 (alpha) diol sulfate (2:1) (salt) pentahydrate and has the following structural formula:
Morphine sulfate pentahydrate is an odourless, white, crystalline powder or needlelike crystals with a bitter taste. It has a solubility of 1 in 21 of water and 1 in 1000 of alcohol, but it is practically insoluble in chloroform or ether.

CAS number.

57-27-2.

7 Medicine Schedule (Poisons Standard)

S8.

Summary Table of Changes