Consumer medicine information

Aspen Methadone Syrup

Methadone hydrochloride

BRAND INFORMATION

Brand name

Aspen Methadone Syrup

Active ingredient

Methadone hydrochloride

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Aspen Methadone Syrup.

SUMMARY CMI

ASPEN METHADONE SYRUP

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 ASPEN METHADONE SYRUP?

ASPEN METHADONE SYRUP contains the active ingredient methadone hydrochloride. ASPEN METHADONE SYRUP is used for the treatment of severe pain and for the treatment of dependence on opioid drugs.

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

2. What should I know before I use ASPEN METHADONE SYRUP?

Do not use if you have ever had an allergic reaction to methadone hydrochloride or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use ASPEN METHADONE SYRUP? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ASPEN METHADONE SYRUP 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 ASPEN METHADONE SYRUP?

  • The usual dosage for adults is 1 to 2 mL, taken 3 to 4 times a day, but this dosage may be adjusted by your doctor.
  • Do not take more than the recommended dose.

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

5. What should I know while using ASPEN METHADONE SYRUP?

Things you should do
  • Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.
  • Seek medical help immediately if ASPEN METHADONE SYRUP is accidentally taken by a child.
Things you should not do
  • Do not give this medicine to anyone else, even if their symptoms seem similar to yours.
Driving or using machines
  • This medicine may cause drowsiness. It is recommended that you don't drive, use machinery or undertake any activities where alertness is required.
Drinking alcohol
  • Do not drink alcohol while taking ASPEN METHADONE SYRUP.
Looking after your medicine
  • Store ASPEN METHADONE SYRUP in a cool, dry place where it stays below 25°C. Protect from light.
  • Keep this medicine where children cannot reach it.

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

6. Are there any side effects?

Common side effects include drowsiness, dizziness, vomiting and sweating. Serious side effects include symptoms of an allergic reaction such as wheezing, swelling of the lips/mouth, difficulty in breathing and fainting.

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
ASPEN METHADONE SYRUP 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
ASPEN METHADONE SYRUP poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor your regularly during treatment.

Life threatening respiratory depression
ASPEN METHADONE SYRUP 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 ASPEN METHADONE SYRUP 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 ASPEN METHADONE SYRUP
Using ASPEN METHADONE SYRUP 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 ASPEN METHADONE SYRUP.



FULL CMI

ASPEN METHADONE SYRUP

Active ingredient: methadone hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using ASPEN METHADONE SYRUP. 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 ASPEN METHADONE SYRUP.

Where to find information in this leaflet:

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

1. Why am I using ASPEN METHADONE SYRUP?

ASPEN METHADONE SYRUP contains the active ingredient methadone hydrochloride. It belongs to a group of medicines called opioid analgesics.

ASPEN METHADONE SYRUP is used for the treatment of severe pain and for the treatment of dependence on opioid drugs.

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

Tolerance
Tolerance to ASPEN METHADONE SYRUP may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

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

If you stop having this medicine suddenly, your pain may worsen and you may experience some or all of the following withdrawal symptoms:

  • nervousness, restlessness, agitation, trouble sleeping or anxiety
  • body aches, weakness or stomach cramps
  • loss of appetite, nausea, vomiting or diarrhoea
  • increased heart rate, breathing rate or pupil size
  • watery eyes, runny nose, chills or yawning
  • increased sweating.

ASPEN METHADONE SYRUP given to the mother during labour can cause breathing problems and signs of withdrawal in the newborn.

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

Your doctor may have prescribed it for another reason.

ASPEN METHADONE SYRUP is only available with a doctor's prescription.

2. What should I know before I use ASPEN METHADONE SYRUP?

Warnings

Do not use ASPEN METHADONE SYRUP if:

  • you have ever had an allergic reaction to methadone hydrochloride, any other opioid drug or any of the ingredients listed toward the end of this leaflet. Symptoms of an allergic reaction may include shortness of breath, wheezing or difficulty in breathing; swelling of the face, lips, tongue or any other parts of the body; rash, itching or hives on the skin.
  • you have any other medical condition including:
    - suffering from a lung disorder such as asthma, or any illness causing difficulty in breathing, especially if there is excessive phlegm or skin is bluish in colour
    - a recent head injury or increased pressure in the head
    - a bowel condition known as ulcerative colitis
    - certain liver or kidney conditions
    - certain heart conditions
    - alcoholism.
  • you are taking or have recently taken antidepressants of the type called monoamine oxidase inhibitors (MAOIs) or selective serotonin re-uptake inhibitors (SSRIs).
  • you suffer from biliary and renal tract spasm
  • the expiry date (EXP) printed on the pack has passed
  • the packaging is torn or shows signs of tampering.

Check with your doctor if you:

  • are under 18 years of age
  • are allergic to foods, dyes, preservatives or any other medicines
  • are pregnant or become pregnant while taking it
  • are about to give birth or are breastfeeding
  • have any other medical condition including:
    - hormone problems
    - an underactive thyroid gland
    - diabetes
    - prostate disease
    - phaeochromocytoma (a rare tumour of the adrenal gland).
    Symptoms include bouts of anxiety and headaches. There may be palpitations (banging of the heart felt in the chest), dizziness, weakness, nausea, vomiting, diarrhoea, dilated pupils, blurry vision, stomach pains and raised blood pressure.
  • you intend to drink alcohol, particularly large amounts, while you are taking ASPEN METHADONE SYRUP.

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?

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 of the medicines that may interfere with this medicine include:

  • St John's wort
  • rifampicin, an antibiotic
  • medicines to treat epilepsy
  • medicines to treat HIV infections
  • fluconazole, an antifungal
  • selective serotonin re-uptake inhibitors (SSRIs) which are medicines to treat depression or obsessive compulsive disorders e.g. fluvoxamine
  • any other medicines to treat depression
  • medicines to treat mental illness
  • medicines to treat heart conditions
  • other pain relievers, muscle relaxants or tranquilisers
  • fluid or water tablets
  • laxatives
  • fludrocortisone, a medicine used in certain hormone conditions.

You may need to take different amounts of your medicine or you may need to take different medicines. Your doctor or pharmacist has a more complete list of medicines to avoid while taking this medicine.

Use in children and elderly patients

ASPEN METHADONE SYRUP is not recommended for use in children under 18 years of age.

The doctor may prescribe a smaller dose in elderly patients.

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

4. How do I use ASPEN METHADONE SYRUP?

How much to take

Take this medicine as directed by your doctor or pharmacist.
The usual dosage for adults is 1 to 2 mL, taken 3 to 4 times a day, but this dosage may be adjusted by your doctor.

Do not take more than the recommended dose.
It can result in low blood sugar.

How to take ASPEN METHADONE SYRUP

ASPEN METHADONE SYRUP is designed specifically to be taken by mouth only.

It is NOT SUITABLE for injection. Injecting this medicine can be extremely hazardous.

How long to take it for

Do not stop taking this medicine or change the dose without first checking with your doctor.

Your doctor may want to gradually reduce the amount you are taking before stopping completely in order to lessen the chance of possible withdrawal side effects.

If you use too much ASPEN METHADONE SYRUP

You will usually take your dose under the supervision of your pharmacist or doctor who has calculated the appropriate amount for you. Therefore, overdosage should not normally occur. Take home doses have also been calculated specifically for you and should not result in an overdosage.

If you or someone else receive too much (overdose) and experience one or more of the symptoms below, immediately call triple zero (000) for an ambulance. Keep the person awake by talking to them or gently shaking them every now and then. You should follow the above steps even if someone other than you have accidentally used ASPEN METHADONE SYRUP that was prescribed for you.

If someone takes an overdose they may experience one or more of the following symptoms:

  • slow, unusual or difficult breathing
  • drowsiness, dizziness or unconsciousness
  • slow or weak heartbeat
  • nausea or vomiting
  • convulsions or fits.

If you think that you have used too much ASPEN METHADONE SYRUP, 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 ASPEN METHADONE SYRUP?

Things you should do

Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.

Otherwise your doctor may think that it was not working as it should and change your treatment unnecessarily.

If you forget to take a dose, take it as soon as you remember and then go on as before, but remember not to take the medicine more often than recommended by your doctor.

Seek medical help immediately if ASPEN METHADONE SYRUP is accidentally taken by a child.

Things you should not do

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

Do not use it to treat any other complaints unless your doctor says to.

Things to be careful of

Particular care should be taken when starting this medicine or increasing the dose. Methadone can decrease heart and breathing rates, which if severe, may lead to death.

Speak to your doctor immediately if you have any concerns.

Driving or using machines

ASPEN METHADONE SYRUP may cause dizziness in some people. It is recommended that you don't drive, use machinery or undertake any activities where alertness is required.

Drinking alcohol

Do not drink alcohol while taking ASPEN METHADONE SYRUP.

Looking after your medicine

Store ASPEN METHADONE SYRUP in a cool, dry place where it stays below 25°C. Protect from light.

Keep this medicine where children cannot reach it.

A locked cupboard at least one-and-a-half metres above the ground is a good place to store medicines.

Getting rid of any unwanted medicine

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

Do not use this medicine after the expiry date.

6. Are there any side effects?

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

With prolonged use, the dose may have to be increased to achieve the same benefit, whilst a sudden decrease in dose or interruption of therapy may give rise to possible withdrawal symptoms.

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
  • fatigue
  • weakness
  • dizziness
  • light-headedness
  • nausea
  • vomiting
  • dry mouth
  • sweating
  • confusion
  • constipation
  • problems with urine flow
  • lack of appetite
  • low blood pressure
  • tolerance and dependence.
Speak to your doctor or pharmacist if you have any of these less serious, common side effects and they worry you.
  • decreased libido
  • impotence
  • absence of menstruation.
Speak to your doctor if you have any of these side effects that may be associated with long-term use.

Serious side effects

Serious side effectsWhat to do
Allergic reaction including:
  • wheezing
  • swelling of the lips/mouth
  • difficulty in breathing
  • hayfever
  • lumpy rash (hives)
  • fainting.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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

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

Reporting side effects

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

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

7. Product details

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

What ASPEN METHADONE SYRUP contains

Active ingredient
(main ingredient)		methadone hydrochloride 5 mg/mL
Other ingredients
(inactive ingredients)
  • sodium benzoate
  • ethanol
  • sorbitol solution 70% (non-crystallising)
  • glycerol
  • sunset yellow FCF
  • anise spice SC491233
  • purified water.
Potential allergens
  • benzoate
  • alcohol
    Contains 4.4% v/v ethanol.
  • sorbitol.
    Contains 6.2 g of sorbitol per recommended maximum daily dose. Products containing sorbitol may have a laxative effect or cause diarrhoea.

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

ASPEN METHADONE SYRUP is lactose, sucrose and gluten free.

What ASPEN METHADONE SYRUP looks like

ASPEN METHADONE SYRUP is a bright, amber-coloured syrup, with an aromatic odour. It is available in 200 mL or 1 L brown HDPE bottles with a child-resistant cap (AUST R 49372).

Who distributes ASPEN METHADONE SYRUP

Aspen Pharmacare Australia Pty Ltd
34-36 Chandos Street
St Leonards NSW 2065
Australia

This leaflet was revised in December 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Aspen Methadone Syrup

Active ingredient

Methadone hydrochloride

Schedule

S8

 

1 Name of Medicine

Methadone hydrochloride.

2 Qualitative and Quantitative Composition

Aspen Methadone Syrup is an oral solution of 5 mg/mL methadone hydrochloride.

List of excipients with known effect.

Sodium benzoate, ethanol and sorbitol solution (70%) (non-crystallising). For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

A bright amber coloured syrup with an aromatic odour.

4 Clinical Particulars

4.1 Therapeutic Indications

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

4.2 Dose and Method of Administration

Aspen Methadone Syrup must not be used parenterally.
Dose initiation, titration and duration should be individualised, taking into account the pharmacodynamic and pharmacokinetic properties of methadone and the need for close observation of the patient for cumulative toxicity. This should be based on a careful evaluation of subjective and objective patient data, bearing in mind clinical status, including hepatic or renal function of the patient.
Care needs to be taken with methadone to avoid toxicity because the time to reach steady-state concentrations following a change in dosage may be up to 12 days. Dose conversion ratios from other opioids are not static, but are a function of previous opioid exposure. Incomplete cross tolerance between mu-opioid agonists makes determination of dosing during opioid conversion complex.
It is recommended that use of this drug should only be undertaken by prescribers familiar with its use.

Treatment of dependence on opioid drugs.

A dose of 10 to 20 mg by mouth may be given initially and increased as necessary by 5 to 10 mg daily. The dose must not be increased by more than 5 to 10 mg daily, and by no more than 30 mg in any seven day period. After stabilisation, which can often be achieved with a daily dose of 30 to 50 mg daily (up to a maximum of 80 mg daily), the dose of methadone is gradually decreased until total withdrawal is achieved. Some treatment schedules for opioid dependence involved prolonged maintenance therapy with methadone where the daily dose is adjusted carefully for the individual.

Treatment of severe pain.

Adults.

Usual single dose 5-10 mg by mouth.
Owing to its long plasma half-life, caution with repeated dosage should be observed in all patients, particularly in the very ill or elderly. The usual initial dose should be 5-10 mg 6-8 hourly, later adjusted to the degree of pain relief obtained. Doses administered more frequently than 6- to 8-hourly are liable to cause accumulation with increasing sedation and respiratory depression. In chronic use, methadone should not be administered more than twice daily.
Methadone may be used in combination with non-narcotic analgesics to provide additive analgesia.
Where the drug is given orally for longer duration, it is wise to restrict the dose to the smallest amount which controls the symptoms.

Children and adolescents aged less than 18 years.

Methadone is not recommended for use in this age group, since documented clinical experience has been insufficient to establish a suitable dosage regimen; furthermore, children are particularly sensitive to the respiratory and central nervous system depressant effects of methadone.

Elderly.

Methadone has a long plasma half-life which may lead to accumulation, particularly if renal function is impaired (see Section 4.4 Special Warnings and Precautions for Use; Section 5 Pharmacological Properties).
In common with other opioids, methadone may cause confusion in this age group; therefore, careful monitoring is advised.

Renal impairment.

Methadone should be used with caution in patients with renal dysfunction; the dosage interval should be increased to a minimum of eight hourly when the glomerular filtration rate (GFR) is 10 to 50 mL/minute and to a minimum of 12 hourly when the GFR is below 10 mL/minute.

Hepatic impairment.

Particular care should be taken when methadone is to be used in patients with hepatic impairment as these patients metabolise methadone more slowly than normal patients. Where not contraindicated, methadone should be given at less than the normal recommended dose and the patient's response used as a guide to further dosage requirements (see Section 4.3 Contraindications).

Cardiac repolarisation disorders.

Methadone should be administered with particular caution to patients at risk of development of prolonged QT interval (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).

4.3 Contraindications

Aspen Methadone Syrup is contraindicated in individuals who are hypersensitive to methadone or other components of the oral liquid.
Like other opioids, methadone is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression, especially in the presence of cyanosis and excessive bronchial secretions.
Methadone should not be given during an attack of bronchial asthma.
Methadone is contraindicated in the presence of acute alcoholism, head injury and raised intracranial pressure.
Methadone is contraindicated in individuals receiving monoamine oxidase inhibitors or within 14 days of stopping such treatment.
As with other opioids, methadone is contraindicated in patients with ulcerative colitis, since it may precipitate toxic dilation or spasm of the colon.
As with all narcotic analgesics, methadone should not be administered to patients with severe hepatic impairment as it may precipitate hepatic encephalopathy (see Section 4.4 Special Warnings and Precautions for Use).
Methadone is contraindicated in biliary and renal tract spasm.
Methadone is contraindicated in individuals with existing QT prolongation, including those with congenital long QT syndrome (see Section 4.4 Special Warnings and Precautions for Use).

4.4 Special Warnings and Precautions for Use

Hazardous and harmful use.

Aspen Methadone Syrup contains the opioid methadone and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Aspen Methadone Syrup at recommended doses. The possibility of addiction cannot be excluded and patients should be reminded of the necessity of adhering to the prescribed dosage.
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 Aspen Methadone Syrup.
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 Aspen Methadone Syrup with anyone else.
However, when used for pain relief in terminal care, the risk of dependence is of limited concern. Discontinuation of therapy with methadone should be carried out gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms (see Section 4.8 Adverse Effects (Undesirable Effects)).

Respiratory depression.

Deaths due to cardiac arrhythmias and respiratory depression may occur, particularly in patients receiving methadone for analgesia during treatment initiation or conversion from other opioids.
Serious, life-threatening or fatal respiratory depression can occur with the use of opioids even when used as recommended. The peak depressive effects persist longer than peak analgesic effects, especially during the initial dosing period. It can occur at any time during the use of Aspen Methadone Syrup but the risk is greatest during initiation of therapy or following an increase in dose. Patients should be monitored closely for respiratory depression at these times.
The risk of life-threatening respiratory depression is also higher in elderly, frail, or debilitated patients, in patients with existing impairment of respiratory function (e.g. chronic obstructive pulmonary disease; asthma) and in patients with hepatic or hepatic impairment (see Use in hepatic impairment and Use in renal impairment). Opioids should be used with caution and with close monitoring in these patients (see Section 4.2 Dose and Method of Administration). The use of opioids is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression (see Section 4.3 Contraindications).
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 naive patients. Initiation of opioid treatment should be at the lower end of the dosage recommendations with careful titration of doses to achieve effective pain relief. Careful calculation of equianalgesic doses is required when changing opioids or switching from immediate release to modified release formulations, together with consideration of pharmacological differences between opioids. Consider starting the new opioid at a reduced dose to account for individual variation in response.

Cardiac repolarisation.

In vivo and in vitro studies have demonstrated that methadone inhibits cardiac potassium channels and prolongs cardiac repolarisation (i.e. prolongs the QT interval). QT interval prolongation and serious arrhythmia (Torsade de Pointes) have been observed during treatment with methadone and appear to be more common with higher doses. Particular caution and careful monitoring is recommended in patients at risk of prolonged QT interval (e.g. cardiac hypertrophy, concomitant diuretic use, hypokalaemia, hypomagnesaemia), patients with a previous history of cardiac repolarisation prolongation, those taking medications affecting cardiac repolarisation or methadone metabolism, and in patients with an increased risk of arrhythmia (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients developing QT prolongation while on methadone treatment should be evaluated for modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism.

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 Aspen Methadone Syrup 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 Aspen Methadone Syrup 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 Aspen Methadone Syrup.

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

Opioid analgesics have an established role in the treatment of acute pain, cancer pain and palliative and end-of-life care. Current evidence does not generally support opioid analgesics in improving pain and function for most patients with chronic non-cancer pain. The development of tolerance and physical dependence and risks of adverse effects, including hazardous and harmful use, increase with the length of time a patient takes an opioid. The use of opioids for long-term treatment of CNCP is not recommended.
The use of an opioid to treat CNCP should only be considered after maximised non-pharmacological and non-opioid treatments have been tried and found ineffective, not tolerated or otherwise inadequate to provide sufficient management of pain. Opioids should only be prescribed as a component of comprehensive multidisciplinary and multimodal pain management.
Opioid therapy for CNCP should be initiated as a trial in accordance with clinical guidelines and after a comprehensive biopsychosocial assessment has established a cause for the pain and the appropriateness of opioid therapy for the patient (see Hazardous and harmful use, above). The expected outcome of therapy (pain reduction rather than complete abolition of pain, improved function and quality of life) should be discussed with the patient before commencing opioid treatment, with agreement to discontinue treatment if these objectives are not met.
Owing to the varied response to opioids between individuals, it is recommended that all patients be started at the lowest appropriate dose and titrated to achieve an adequate level of analgesia and functional improvement with minimum adverse reactions. Immediate-release products should not be used to treat chronic pain, but may be used for a short period in opioid-naïve patients to develop a level of tolerance before switching to a modified-release formulation. Careful and regular assessment and monitoring is required to establish the clinical need for ongoing treatment. Discontinue opioid therapy if there is no improvement of pain and/or function during the trial period or if there is any evidence of misuse or abuse. Treatment should only continue if the trial has demonstrated that the pain is opioid responsive and there has been functional improvement. The patient's condition should be reviewed regularly and the dose tapered off slowly if opioid treatment is no longer appropriate (see Ceasing opioids).

Tolerance, dependence and withdrawal.

Neuroadaptation of the opioid receptors to repeated administration of opioids can produce tolerance and physical dependence. Tolerance is the need for increasing doses to maintain analgesia. Tolerance may occur to both the desired and undesired effects of the opioid.
Physical dependence, which can occur after several days to weeks of continued opioid usage, results in withdrawal symptoms if the opioid is ceased abruptly or the dose is significantly reduced. Withdrawal symptoms can also occur following the administration of an opioid antagonist (e.g. naloxone) or partial agonist (e.g. buprenorphine). Withdrawal can result in some or all of the following symptoms: dysphoria, restlessness/agitation, lacrimation, rhinorrhoea, yawning, sweating, chills, myalgia, mydriasis, irritability, anxiety, increasing pain, backache, joint pain, weakness, abdominal cramps, insomnia, nausea, anorexia, vomiting, diarrhoea, increased blood pressure, increased respiratory rate and increased heart rate.
When discontinuing Aspen Methadone Syrup in a person who may be physically-dependent, the drug should not be ceased abruptly but withdrawn by tapering the dose gradually (see Ceasing opioids; see Section 4.2 Dose and Method of Administration).

Accidental ingestion/exposure.

Accidental ingestion or exposure of Aspen Methadone Syrup, especially by children, can result in a fatal overdose of methadone. Patients and their caregivers should be given information on safe storage and disposal of unused Aspen Methadone Syrup (see Section 6.4 Special Precautions for Storage; Section 6.6 Special Precautions for Disposal).

Hyperalgesia.

Hyperalgesia may occur with the use of opioids, particularly at high doses. Hyperalgesia may manifest as an unexplained increase in pain, increased levels of pain with increasing opioid dosages or diffuse sensitivity not associated with the original pain. Hyperalgesia should not be confused with tolerance (see Tolerance, dependence and withdrawal). If opioid induced hyperalgesia is suspected, the dose should be reduced and tapered off if possible. A change to a different opioid may be required.

Ceasing opioids.

Abrupt discontinuation or rapid decreasing of the dose in a person physically dependent on an opioid may result in serious withdrawal symptoms and uncontrolled pain (see Tolerance, dependence and withdrawal). Such symptoms may lead the patient to seek other sources of licit or illicit opioids. Opioids should not be ceased abruptly in a patient who is physically dependent but withdrawn by tapering the dose slowly. Factors to take into account when deciding how to discontinue or decrease therapy include the dose and duration of the opioid the patient has been taking, the type of pain being treated and the physical and psychological attributes of the patient. A multimodal approach to pain management should be in place before initiating an opioid analgesic taper. During tapering, patients require regular review and support to manage any increase in pain, psychological distress and withdrawal symptoms.
There are no standard tapering schedules suitable for all patients and an individualised plan is necessary. In general, tapering should involve a dose reduction of no more than 10 percent to 25 percent every 2 to 4 weeks (see Section 4.2 Dose and Method of Administration). If the patient is experiencing increased pain or serious withdrawal symptoms, it may be necessary to go back to the previous dose until stable before proceeding with a more gradual taper.
When ceasing opioids in a patient who has a suspected opioid use disorder, the need for medication assisted treatment and/or referral to a specialist should be considered.

Phaeochromocytoma.

Extreme caution should be exercised when administering methadone to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.
Methadone should be used with caution in the presence of: hypothyroidism, adrenocortical insufficiency, hypopituitarism, prostatic hypertrophy, shock, diabetes mellitus.
Aspen Methadone Syrup is not suitable for administration by injection.
Aspen Methadone Syrup is for oral use only.

Hypoglycaemia.

Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see Section 4.8; Section 4.9).

Adrenal insufficiency.

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness or low blood pressure.

Decreased sex hormone and increased prolactin.

Long term use of opioid analgesics maybe associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.

Use in hepatic impairment.

Particular care should be taken when methadone is to be used in patients with hepatic impairment as these patients metabolise methadone more slowly than normal patients. Where not contraindicated methadone should be given at less than the normal recommended dose and the patient's response used as a guide to further dosage requirements (see Section 4.3 Contraindications).

Use in renal impairment.

Methadone should be used with caution in patients with renal dysfunction. The dosage interval should be increased to a minimum of 8-hourly when the glomerular filtration rate (GFR) is 10 to 50 mL/minute and to a minimum of 12-hourly when the GFR is below 10 mL/minute.

Use in the elderly.

Methadone has a long plasma half life which may lead to accumulation, particularly if renal function is impaired (see Use in renal impairment).
In common with other opioids, methadone may cause confusion in this age group, therefore careful monitoring is advised.

Paediatric use.

Methadone is not recommended for use in children less than 18 years of age since documented clinical experience has been insufficient to establish a suitable dosage regimen; furthermore, children are particularly sensitive to the respiratory and central nervous system effects of methadone.

Effects on laboratory tests.

The serum BSP retention test may be increased (hepatotoxic effect or spasm of sphincter of Oddi). Plasma cortisol may be increased in response to cold to an extent not seen in controls. An increase in the serum albumin, prolactin and immunoglobulin IgG levels may be seen as a response to chronic administration. A significant decrease in serum indocyanine green level has been observed in a small series of patients with normal liver function tests. PCO2 may be increased due to decreased pulmonary ventilation. False positive urine pregnancy tests have occurred, mainly with the Gravindex test. Physiological changes in thyroid hormones may be seen - decrease in serum thyroxine (T4), a decrease in free thyroxine and an increase in tri-iodothyronine (T3).

4.5 Interactions with Other Medicines and Other Forms of Interactions

Methadone is metabolised by various cytochrome P450 (CYP450) enzymes. Therefore, coadministration of drugs known to interfere with CYP450 enzymes may affect its clinical activity (see Section 5 Pharmacological Properties).
Some compounds may increase the metabolism of methadone, e.g. rifampicin, phenytoin, carbamazepine, St John's wort and antiretroviral agents used in the treatment of HIV infection (particularly nevirapine, efavirenz and some protease inhibitors). This has the potential to result in withdrawal symptoms.
Patients on methadone maintenance who are also taking enzyme inducers, such as carbamazepine, may require higher than typical doses of methadone.
Some compounds may decrease the metabolism of methadone, e.g. fluconazole and some selective serotonin reuptake inhibitors (SSRIs), particularly fluvoxamine. This may increase the likelihood of methadone toxicity.
In addition to compounds that may decrease the metabolism of methadone, extreme caution is necessary when any drug known to have the potential to prolong the QT interval is prescribed in conjunction with methadone (see Section 4.4 Special Warnings and Precautions for Use). Interactions may occur with methadone and potentially arrhythmogenic agents such as class I and III antiarrhythmics, some neuroleptics and tricyclic antidepressants and calcium channel blockers. Caution should also be exercised when prescribing concomitant drugs capable of inducing electrolyte disturbances that may prolong the QT interval (hypomagnesaemia, hypokalaemia). These include diuretics, laxatives and, in rare cases, mineralocorticoid hormones.
Methadone can also affect the metabolism of other drugs. Plasma concentrations of some drugs may be increased, e.g. nelfinavir, zidovudine, fluconazole and desipramine, whereas concentrations of others may be decreased, e.g. abacavir and amprenavir.
Monoamine oxidase inhibitors (MAOIs) may prolong and enhance the respiratory depressant effects of methadone. Opioids and MAOIs used together may cause fatal hypotension and coma.

Central nervous system depressants.

The general depressant effects of methadone may be enhanced by other centrally-acting agents such as other opioids, alcohol, anti-histamines, antipsychotics, barbiturates, benzodiazepines, cannabis, centrally-acting anti-emetics, gabapentinoids, hypnotics, neuromuscular blocking agents, phenothiazines, sedatives, tricyclic antidepressants, tranquilisers and other CNS depressants (see Section 4.4 Special Warnings and Precautions for Use, Risks from concomitant use of benzodiazepines or other CNS depressants, including alcohol). Some psychotropic drugs, however, may potentiate the analgesic effects of methadone.
Propranolol has been reported to enhance the lethality of toxic doses of opioids in animals. Although the significance of this finding is not known for man, caution should be exercised when such drugs are coadministered.

Cardiac repolarisation disorders.

Methadone should be administered with particular caution to patients at risk for development of prolonged QT interval (see Section 4.4 Special Warnings and Precautions for Use; Section 4.3 Contraindications).
Opioid analgesics may antagonise the effects of agents that stimulate gastrointestinal motility (metoclopramide, domperidone, cisapride).
Anticholinergics increase the risk of constipation, urinary retention and so on.
Antihypertensives may aggravate the hypotensive effects of opioid analgesics.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Methadone does not appear to impair human female fertility.
Studies in men on methadone maintenance programs have shown that methadone reduces serum testosterone and markedly depresses the ejaculate volume and sperm motility. The sperm counts of methadone subjects were twice that of controls but this reflected the lack of dilution from seminal secretions. A reduction in libido has been reported as well as impotence, delayed and/or failed ejaculation.
(Category C)
There is insufficient evidence on which to determine the safety profile of methadone in pregnancy, therefore, it should only be used if the potential benefit outweighs the potential risk.
Narcotic analgesics may cause respiratory depression in the newborn infant. During the last 2-3 hours before expected delivery narcotic analgesics should therefore only be used after weighing the needs of the mother against the risk to the foetus. Methadone is not recommended for use during labour because its prolonged duration of action increases the risk of respiratory depression in the neonate.
Like other opiates, methadone crosses the placenta during pregnancy, and most neonates born to mothers on methadone maintenance will suffer from withdrawal if left untreated.
Withdrawal symptoms may be observed in infants born to mothers receiving methadone maintenance consisting of central nervous system, gastrointestinal, and respiratory disturbances. Abstinence syndrome may not occur in the neonate for some days after birth. Therefore, in addition to initial monitoring of respiratory depression, neonates should undergo prolonged monitoring for signs and symptoms of withdrawal.
Infants born to mothers on methadone maintenance have been reported to have smaller birthweights when compared to infants of nondrug exposed mothers. The infants born to mothers on methadone maintenance were not small for gestational age, and by six months of age, these infants did not exhibit any general development sequelae.
 Caution should be exercised when methadone is administered to a nursing woman due to the risks of sedation and respiratory depression in the infant. Serious harm, including death, has been reported in infants following exposure to methadone through breast feeding.
Breast feeding is permissible in mothers receiving methadone for maintenance therapy but specialist care from obstetric and paediatric staff with experience in such management is required. The baby should be monitored to avoid sedation. Therefore breast feeding mothers should be counselled on how to identify respiratory depression and sedation in their babies and when it may be necessary to seek immediate medical care. The dose of methadone should be as low as possible.
Methadone is distributed into breast milk, with a mean ratio of milk to plasma concentration of 0.44. However, doses of methadone to the infant via breast milk are low, estimated at 3% of maternal doses, on average, and insufficient to prevent neonatal abstinence syndrome in infants born to mothers on methadone maintenance.

4.7 Effects on Ability to Drive and Use Machines

Ambulatory patients.

In common with other opioids, methadone may produce orthostatic hypotension and drowsiness in ambulatory patients. They should be cautioned, therefore, against driving vehicles, operating machinery or other activities requiring vigilance.

4.8 Adverse Effects (Undesirable Effects)

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.

Respiratory.

The major side effect of methadone is respiratory depression.

Gastrointestinal.

Reported events include nausea*, vomiting*, dry mouth*, loss of appetite and constipation. Less common reactions include stomach cramps or pain. Methadone, in common with other opioids may cause spasm of the biliary tract (see Section 4.3 Contraindications).

Neurological.

Reported events include dizziness*, drowsiness*, lightheadedness*, sweating*, confusion*, weakness, fatigue and low blood pressure. Less common reaction includes blurred vision. Euphoria has been reported at higher doses in tolerant patients.

Cardiovascular.

Hypotension, collapse and generalised oedema have occasionally been reported. Less common reactions include bradycardia, tachycardia and palpitations. ECG changes including QT prolongation and torsades de pointes have occurred very rarely, usually in patients with risk factors or receiving high doses of methadone (see Section 4.4 Special Warnings and Precautions for Use).

Renal.

Methadone, in common with other opioids, may cause spasm of the renal tract (see Section 4.3 Contraindications). It also possesses antidiuretic properties, and urinary retention or hesitancy has been reported.

Endocrine.

Prolonged use of methadone in men has been reported to be associated with the development of gynaecomastia. Long term use may also cause decreased libido, impotence and amenorrhea.

Withdrawal (abstinence) syndrome.

Chronic use of opioid analgesics may be associated with the development of physical dependence. 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 and unexplained fever. With appropriate dose adjustments and gradual withdrawal these symptoms are usually mild.
In known drug addicts, methadone has produced withdrawal symptoms but these are mild. Tolerance and dependence of the morphine type may occur.
* These adverse reactions appear to be more common in ambulatory patients and in those receiving oral therapy.

Metabolism and nutrition disorders.

Frequency (not known): Hypoglycaemia.

4.9 Overdose

Symptoms and signs.

The symptoms and signs of overdosage with methadone parallel those for other opioids, namely profound respiratory depression, pinpoint pupils, hypotension, circulatory failure and pulmonary oedema, coma and death. Hypoglycaemia has been reported.
Mydriasis may replace miosis as asphyxia intervenes. Drowsiness, floppiness, pinpoint pupils and apnoea have been reported in children.

Treatment.

General supportive measures, including ECG monitoring, should be employed as required. Lavage, dialysis and CNS stimulation are contraindicated. The specific opioid antagonist naloxone can be used for the reversal of coma and the restoration of spontaneous respiration. Intravenous infusion is the preferred route of administration in the management of methadone overdose because of the short half-life of naloxone relative to the long half-life of methadone, continuous infusion reduces the possibility of prolonged respiratory depression and the risk of relapse, which can occur suddenly. It should be noted that QT prolongation will not be reversed by naloxone.
In opioid dependent patients the administration of the usual dose of an opioid antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. The use of an opioid antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent person the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
Patients should be monitored closely for at least 48 hours after apparent recovery in case of relapse, since the duration of action of the antagonist may be substantially shorter than that of methadone.
The use of other respiratory or central stimulants is not recommended.
Acidification of the urine will enhance urinary excretion of methadone.
Methadone is not dialysable by either peritoneal or haemodialysis.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

The pharmacological actions of methadone are qualitatively similar to those of morphine. Significant quantitative differences are its effective analgesic activity after administration by the oral route and its tendency to show persistent effects with repeated administration.

Pharmacodynamic effects.

The combination of opioid agonism and N-methyl-d-aspartate (NMDA) antagonism by methadone produces an additive analgesic response while limiting opioid tolerance.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Absorption.

Methadone hydrochloride is readily absorbed after administration by mouth and has high oral bioavailability. Peak plasma concentrations have been reported 1 to 5 hours after oral administration of a single dose in tablet form.

Distribution.

Methadone undergoes considerable tissue distribution and protein binding is reported to be 60 to 90% with α1-acid glycoprotein being the main binding protein in plasma.

Metabolism.

Methadone undergoes N-demethylation to 2-ethylidene-1,5-dimethyl- 3,3-diphenylpyrrilidine (EDDP) with CYP3A4 being the main enzyme responsible. However, other CYP450 enzymes, including CYP2D6, are also likely to be involved in methadone's metabolism.

Excretion.

Elimination of methadone occurs principally by metabolism, followed by urinary and faecal excretion of the metabolites, though there is some renal excretion of unchanged methadone. Marked interindividual variations in kinetics have been observed with methadone. Elimination half-lives vary considerably (a range of 15 to 60 hours has been reported) and careful adjustment of dosage is necessary with repeated administration.
Plasma concentrations have been found to vary widely during methadone maintenance therapy with large differences between patients and wide fluctuations in individual patients. Declining concentrations have been reported during methadone maintenance suggesting that tolerance occurs, possibly as a result of autoinduction of hepatic microsomal enzymes.

Special patient populations.

Elderly.

Methadone clearance does not appear to be markedly affected by age, though a slight decrease has been observed over age 65.

Renal impairment.

Although methadone is mostly eliminated by metabolism, a significant proportion of the dose is excreted via the kidney.

5.3 Preclinical Safety Data

Genotoxicity.

Mutagenic potential.

Methadone did not exhibit demonstrable mutagenic activity in a wide range of standard in vitro and in vivo mutagenicity assays. However, in a Dominant Lethal assay in mice, treatment with methadone at doses between 1 and 6 mg/kg was associated with increased preimplantation deaths and chromosomal aberrations of sperm cells when compared with controls.

Teratogenic potential.

No teratogenic effects have been observed in standard teratogenicity studies in rats and rabbits given methadone at doses from ten to fifty times the average daily human maintenance dose. Developmental abnormalities of the central nervous system have been reported in hamsters and mice given high doses in early pregnancy.

Carcinogenicity.

Long-term carcinogenicity tests in rodents did not reveal any evidence of methadone related neoplasia.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sunset Yellow FCF, ethanol, glycerol, sodium benzoate, sorbitol solution (70%) (noncrystallising), purified water and anise spice SC491233.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Store below 25°C. Protect from light.

6.5 Nature and Contents of Container

Supplied in an amber glass or brown HDPE bottle with child-resistant closure. It is an oral liquid containing methadone hydrochloride 5 mg/mL. Pack sizes: 200 mL and 1 litre. (Note: Not all bottle types may be marketed).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Methadone hydrochloride is a synthetic opioid analgesic with the general properties of morphine. Methadone is a racemic mixture and levo-methadone is the active isomer. It occurs as odourless, colourless crystals or white crystalline powder. It is soluble in water, freely soluble in alcohol and chloroform; practically insoluble in ether and in glycerol.
Molecular formula: C21H27NO.HCl, relative molecular mass: 345.9. The chemical name for methadone hydrochloride is (6RS)6-(dimethylamino)-4,4-diphenylheptan-3-one hydrochloride.

Chemical structure.


CAS number.

1095-90-5.

7 Medicine Schedule (Poisons Standard)

S8 - Controlled Drug.

Summary Table of Changes