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.4.1 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.
