Consumer medicine information

Methadone-AFT

Methadone hydrochloride

BRAND INFORMATION

Brand name

Methadone-AFT

Active ingredient

Methadone hydrochloride

Schedule

S8

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Methadone-AFT.

SUMMARY CMI

Methadone-AFT

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 Methadone-AFT?

Methadone-AFT contains the active ingredient methadone. Methadone-AFT is used for the relief of chronic, moderate to severe pain.

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

2. What should I know before I use Methadone-AFT?

Do not use if you have ever had an allergic reaction to methadone 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 Methadone-AFT? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Methadone-AFT 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 Methadone-AFT?

  • The usual dose for adults is one tablet (5 mg or 10 mg) taken 2 to 3 times a day, but this dosage may be adjusted by your doctor.
  • Methadone-AFT tablets are not recommended for use in children. The doctor may prescribe a smaller dose in elderly patients.

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

5. What should I know while using Methadone-AFT?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using Methadone-AFT.
  • Tell your doctor if, for any reason, you have not taken your medicine exactly as directed.
Things you should not do
  • Do not stop using this medicine suddenly.
  • Do not use Methadone-AFT to treat any other complaints unless your doctor says to.
Driving or using machinesMethadone-AFT tablets may cause drowsiness. It is recommended that you don't drive, use machinery or undertake any activities where alertness is required.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • You must not drink alcohol while taking Methadone-AFT tablets.
Looking after your medicineKeep Methadone-AFT tablets in a cool, dry place, where the temperature stays below 25°C.
Keep Methadone-AFT tablets where children cannot reach them.

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

6. Are there any side effects?

Common and less serious side effects of Methadone-AFT include nausea, vomiting, constipation, dizziness, confusion, dry mouth, sweating and problems with urine flow. Serious side effects include difficulty in breathing, hayfever, hives, fainting and swelling in lips/ mouth.

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

Methadone-AFT tablets should only be used when your doctor decides that other treatment options are not able to effectively manage your pain or you cannot tolerate them.

Hazardous and harmful use

Methadone-AFT tablets poses risks of abuse, misuse and addiction which can lead to overdose and death. Your doctor will monitor you regularly during treatment.

Life threatening respiratory depression

Methadone-AFT tablets can cause life-threatening or fatal breathing problems (slow, shallow, unusual or no breathing) even when used as recommended. These problems can occur at any time during use, but the risk is higher when first starting Methadone-AFT tablets and after a dose increase, if you are older, or have an existing problem with your lungs. Your doctor will monitor you and change the dose as appropriate.

Use of other medicines while taking Methadone-AFT tablets

Taking Methadone-AFT tablets with other medicines that can make you feel drowsy such as sleeping tablets (e.g. benzodiazepines), other pain relievers, antihistamines, antidepressants, antipsychotics, gabapentin, 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 taking Methadone-AFT tablets.



FULL CMI

Methadone-AFT

Active ingredient: Methadone hydrochloride

Consumer Medicine Information (CMI)

This leaflet provides important information about using Methadone-AFT. 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 Methadone-AFT.

Where to find information in this leaflet:

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

1. Why am I using Methadone-AFT?

Methadone-AFT contains the active ingredient methadone hydrochloride which belongs to a group of medicines called opioid analgesics.

Methadone-AFT is used for the relief of chronic, moderate to severe pain.

2. What should I know before I use Methadone-AFT?

Warnings

Addiction

You can become addicted to Methadone-AFT tablets even if you take it exactly as prescribed. Methadone-AFT tablets may become habit forming causing mental and physical dependence. If abused, it may become less able to reduce pain.

Dependence

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

Tolerance

Tolerance to Methadone-AFT tablets may develop, which means that the effect of the medicine may decrease. If this happens, more may be needed to maintain the same effect.

Withdrawal

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

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

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

Methadone-AFT tablets 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 Methadone-AFT has been prescribed for you.

Your doctor may have prescribed it for another reason.

Do not use Methadone-AFT if:

  • you have ever had an allergic reaction to methadone hydrochloride (the active ingredient in Methadone-AFT tablets); any other opioid drug; or any of the ingredients listed at the end of this leaflet.
  • 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)
  • 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:

  • you are allergic to foods, dyes, preservatives or any other medicines
  • you are pregnant, or become pregnant while taking Methadone-AFT, are about to give birth, or are breastfeeding
  • you have any other medical condition including:
    - hormone problems
    - 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 while taking Methadone-AFT.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines may interfere with Methadone-AFT and affect how it works.

Extreme caution is necessary if Methadone-AFT is prescribed with any drug known to have the potential to prolong the QT interval. 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.

Medicines that may increase the metabolism of methadone include 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 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 re-uptake inhibitors (SSRIs), particularly fluvoxamine. This may increase the likelihood of methadone toxicity.

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.

The general depressant effects of methadone may be enhanced by other centrally-acting agents such as other opioids, alcohol, antihistamines, antipsychotics, barbiturates, benzodiazepines, cannabis, centrally-acting anti-emetics, gabapentinoids, hypnotics, neuromuscular blocking agents, phenothiazines, sedatives, tricyclic antidepressants, tranquillisers and other CNS depressants

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

4. How do I use Methadone-AFT?

How much to take

  • The usual dose for adults is one tablet (5 mg or 10 mg) taken 2 to 3 times a day, but this dosage may be adjusted by your doctor.
  • Methadone-AFT tablets are not recommended for use in children. The doctor may prescribe a smaller dose in elderly patients.
  • Follow all the instructions provided to you by your doctor and pharmacist. Do not take more than the recommended dose. Do not stop taking Methadone-AFT or change the dose without first checking with your doctor.

How to take it

Swallow the tablet with a glass of water

If you forget to take Methadone-AFT

Methadone-AFT should be used as instructed by your doctor or pharmacist. 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 tablets more often than recommended by your doctor.

If you use too much Methadone-AFT

If you think that you have used too much Methadone-AFT, 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.

If you or someone else receive too much (overdose) and experience one or more of the symptoms below, immediately call 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 taken Methadone-AFT tablets that was prescribed for you. If someone takes an overdose they may experience one or more of the following symptoms:

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

When seeking medical attention, take this information and remaining medicine with you to show the doctor. Also tell them about any other medicines or alcohol which you have been taken.

5. What should I know while using Methadone-AFT?

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.

Seek medical help immediately if Methadone-AFT is accidentally taken by a child.

Things you should not do

  • Do not stop using this medicine 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 Methadone-AFT to treat any other complaints unless your doctor says to

Things to be careful of

Particular care should be taken when starting treatment with Methadone-AFT or increasing the dose. The medicine 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

Methadone-AFT tablets may cause drowsiness. It is recommended that you don't drive, use machinery or undertake any activities where alertness is required.

Drinking alcohol

Tell your doctor if you drink alcohol.

You must not drink alcohol while taking Methadone-AFT tablets.

Looking after your medicine

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

Keep it where young children cannot reach it.

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

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

Heat and dampness can destroy some medicines.

Keep it in the blister pack until it is time to take them.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to your pharmacist or 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 think you are experiencing any side effects or allergic reactions due to taking Methadone-AFT tablets, even if the problem is not listed below.

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
Stomach and digestion related:
  • Vomiting
  • Constipation
Alertness related:
  • Drowsiness
  • Dizziness
  • Light-headedness
  • Confusion
Body as a whole:
  • Nausea
  • Dry mouth
  • Sweating
  • Problems with urine flow
  • Tolerance and dependence
Speak to your doctor if you have any of these less serious side effects and they worry you.
These side effects are common.
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 withdrawal symptoms.

Serious side effects

Serious side effectsWhat to do
Breathing related:
  • Difficulty in breathing
  • Wheezing
Allergy related:
  • Hayfever
  • Lumpy rash (hives)
Body as a whole:
  • Fainting
  • Swelling in the lips/ mouth
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.
These could be a symptom of an allergic reaction.

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.

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 Methadone-AFT contains

Active ingredient
(main ingredient)		Methadone hydrochloride
Other ingredients
(inactive ingredients)		Lactose monohydrate
Starch pregelatinized
Magnesium stearate
Potential allergensLactose monohydrate

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

What Methadone-AFT looks like

5 mg: Methadone-AFT tablets are white coloured round tablets with 5 on one side and scored on the other side (Aust R 380311).

10 mg: Methadone-AFT tablets are white coloured round tablets with 10 on one side and scored on the other side (Aust R 380312).

Who distributes Methadone-AFT

AFT Pharmaceuticals Pty Ltd.
113 Wicks Road, North Ryde, NSW 2113
Email: [email protected]

This leaflet was prepared in February 2023.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Methadone-AFT

Active ingredient

Methadone hydrochloride

Schedule

S8

 

1 Name of Medicine

Methadone hydrochloride.

2 Qualitative and Quantitative Composition

Methadone hydrochloride is a synthetic opioid analgesic with the general properties of morphine.

5 mg tablets.

Methadone-AFT tablets contain methadone hydrochloride 5 mg.

10 mg tablets.

Methadone-AFT tablets contain methadone hydrochloride 10 mg.

Excipients with known effect.

Lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

5 mg.

Methadone-AFT 5 mg tablets are white to almost white coloured round-shaped tablets debossed with "5" on one side and scored on the other side.

10 mg.

Methadone-AFT 10 mg tablets are white to almost white coloured round-shaped tablets debossed with "10" on one side and scored on the other side.

4 Clinical Particulars

4.1 Therapeutic Indications

Methadone-AFT 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.
Methadone-AFT is not indicated for use in chronic non-cancer pain other than in exceptional circumstances.
Methadone-AFT is not indicated as an as-needed (PRN) analgesia.
Methadone-AFT is not recommended for use in ambulant patients.

4.2 Dose and Method of Administration

Adults.

Usual single dose 5-10 mg by mouth.
Owing to its long plasma half-life, caution with repeated dosage should be observed 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-AFT 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 for the control of pain associated with a chronic condition, it is wise to restrict the dose to the smallest amount which adequately controls the symptoms.
Methadone has less hypnotic effect than morphine. If it is necessary to give a patient a potent analgesic for a prolonged period, some increase in dose may be necessary.

Children and adolescents less than 18 years of age.

Methadone-AFT 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.

4.3 Contraindications

Methadone-AFT, like other opioids, is contraindicated in patients with severe respiratory disease, acute respiratory disease and respiratory depression, especially in the presence of cyanosis and excessive bronchial secretions, and obstructive airways disease.
Methadone-AFT should not be given during an attack of bronchial asthma.
Concurrent administration with monoamine oxidase inhibitors, or within 2 weeks of discontinuation of treatment with them.
Obstetric use is not recommended.
Methadone-AFT is contraindicated in individuals who are hypersensitive to methadone.
Methadone-AFT is contraindicated in the presence of acute alcoholism, head injury and raised intracranial pressure.
Methadone-AFT, as with other opioids, is contraindicated in patients with ulcerative colitis, since it may precipitate toxic dilatation or spasm of the colon.
As with all narcotic analgesics, Methadone-AFT should not be administered to patients with severe hepatic impairment as it may precipitate hepatic encephalopathy.
At the recommended dosages, Methadone-AFT 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.

Methadone-AFT contains the opioid methadone and is a potential drug of abuse, misuse and addiction. Addiction can occur in patients appropriately prescribed Methadone-AFT at recommended doses. The possibility of addiction cannot be excluded and patients should be reminded of the necessity of adhering to the prescribed dosage. However, when used for pain relief in terminal care, the risk of dependence is of limited concern.
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 Methadone-AFT.
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 Methadone-AFT with anyone else.

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 Methadone-AFT 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.
Children are very sensitive to the depressant effects of methadone.

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 Methadone-AFT 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).

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 Methadone-AFT with CNS depressant medicines, such as other opioid analgesics, benzodiazepines, gabapentinoids, cannabis, sedatives, hypnotics, tricyclic antidepressants, antipsychotics, antihistamines, centrally-active antiemetics and other CNS depressants, should be reserved for patients for whom other treatment options are not possible. If a decision is made to prescribe Methadone-AFT 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 Methadone-AFT.

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

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

Accidental ingestion/ exposure.

Accidental ingestion or exposure of Methadone-AFT, 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 Methadone-AFT (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.
Methadone-AFT should be used with caution in the presence of the following: hypothyroidism, adrenocortical insufficiency, hypopituitarism, prostatic hypertrophy, shock, diabetes mellitus.
Extreme caution should be exercised when administering Methadone-AFT to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.
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.

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).

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 Adverse Effects (Undesirable Effects); Section 4.9 Overdose).

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 patient 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.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Methadone is metabolised by various cytochrome P450 (CYP450) enzymes. Therefore, co-administration of drugs known to interfere with CYP450 enzymes may affect its clinical activity.
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 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 re-uptake 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.
The general depressant effects of methadone may be enhanced by other centrally-acting agents such as other opioids, alcohol, antihistamines, antipsychotics, barbiturates, benzodiazepines, cannabis, centrally-acting anti-emetics, gabapentinoids, hypnotics, neuromuscular blocking agents, phenothiazines, sedatives, tricyclic antidepressants, tranquillisers 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 co-administered.

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 these products should 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 treatment 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 treatment have been reported to have smaller birth weights when compared to infants of non-drug exposed mothers. The infants born to mothers on methadone treatment 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 breastfeeding.
Breastfeeding 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, breastfeeding 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.
From theoretical considerations methadone is likely to be excreted in breast milk. Withdrawal symptoms can occur in the infant. Assays of breast milk from methadone maintained mothers showed methadone concentrations of 0.17 to 5.6 microgram/mL.

4.7 Effects on Ability to Drive and Use Machines

In common with other opioids, Methadone-AFT 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)

*Adverse reactions denoted with an asterisk appear to be more common in ambulatory patients and in those receiving oral therapy (methadone 10 mg/mL injection vials are available from other brands).

Respiratory.

The major side effect of methadone is respiratory depression.

Gastrointestinal.

Reported events include nausea*, vomiting*, dry mouth* and constipation. Nausea and vomiting appear to be more frequent after oral administration than after injection. Methadone, in common with other opioids may cause spasm of the biliary tract (see Section 4.3 Contraindications).

Neurological.

Reported events include dizziness*, drowsiness*, light-headedness*, sweating* and confusion*. Euphoria has been reported at higher doses in tolerant patients. Methadone is reported to produce less euphoria than morphine.

Cardiovascular.

Hypotension, collapse, and generalised oedema have occasionally been reported. ECG changes including QT prolongation and Torsade 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). In rare cases a hypersensitive subject may react with a sudden transient fall in blood pressure; this is short-lived and self-terminating.

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.

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.
Side effects are more common and more severe in ambulant patients.

Metabolism and nutrition disorders.

Frequency (not known): hypoglycaemia.

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

Symptoms.

Toxic doses of methadone cause unconsciousness, pin-point pupils, slow shallow respiration, cyanosis and weak pulse, profound respiratory depression, hypotension, circulatory failure and pulmonary oedema, coma and death. Mydriasis may replace miosis as asphyxia intervenes. Drowsiness, floppiness, pin-point pupils and apnoea have been reported in children. Often there is a 2-3 hour delay between ingestion and the appearance of symptoms. Hypoglycaemia has been reported. These symptoms and signs of overdosage parallel those for other opioids.

Treatment.

General supportive measures, including ECG monitoring, should be employed as required. Lavage, dialysis and CNS stimulation are contraindicated. The specific opioid antagonist naloxone is the treatment of choice for the reversal of coma and the restoration of spontaneous respiration. Intravenous naloxone should be given and repeated at 5-10 minute intervals to attain full benefit. 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.
Acidification of the urine will increase the rate of elimination of the drug via the kidney.
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.
Methadone is not dialysable by either peritoneal or haemodialysis.
For information on the management of an overdose, contact the Poisons Information Centre on 131126 (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.

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.
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 auto-induction of hepatic microsomal enzymes.

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.

Metabolism to the major metabolite 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine and the minor metabolite 2-ethyl-3,3-diphenyl-5-methylpyrrolidine, both of them inactive, occurs in the liver. These metabolites are excreted in the faeces and urine together with unchanged methadone. Other metabolites, including methadol and normethadol (reported to be pharmacologically active), have also been described but account for a small proportion of the dose. The liver may also serve as a major storage site of unchanged methadone which is taken up, bound non-specifically by the liver and released again mainly unchanged.

Excretion.

Methadone has a half-life of about 15 hours after a single dose in nontolerant subjects. After chronic administration the half-life is about 22 hours. However, 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.

5.3 Preclinical Safety Data

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 pre-implantation deaths and chromosomal aberrations of sperm cells when compared with controls.

Genotoxicity/carcinogenicity.

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

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.

6 Pharmaceutical Particulars

6.1 List of Excipients

Lactose monohydrate, pregelatinized maize starch, magnesium stearate.

6.2 Incompatibilities

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

6.3 Shelf Life

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

6.4 Special Precautions for Storage

Store below 25°C.

6.5 Nature and Contents of Container

5 mg.

Blister (Al/PVC/PVDC) pack of 20 tablets.

10 mg.

Blister (Al/PVC/PVDC) pack of 10 tablets and 20 tablets.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

Methadone is a racemic mixture and levo-methadone is the active isomer. Methadone 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.
The chemical name for methadone hydrochloride is 6-dimethylamino-4,4- diphenyl-3-heptanone hydrochloride. Molecular formula: C21H27NO.HCl. Relative molecular mass: 345.9.

Chemical structure.


CAS number.

1095-90-5.

7 Medicine Schedule (Poisons Standard)

Schedule 8 (S8) - Controlled drug.