INFORMATION FOR HEALTH PROFESSIONALS
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
Home | Consumers | Health Professionals | Regulatory | Other | Hot Topics | Search
A bright amber coloured syrup with an aromatic odour containing 5 mg/ml methadone hydrochloride.
Methadone hydrochloride is a synthetic opioid analgesic. Methadone is a racemic mixture and levo-methadone is the active isomer.
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.
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. It 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 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 methanol and nor-methadol (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.
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 auto-induction of hepatic microsomal enzymes.
Methadone is indicated for the treatment of dependence on opioid drugs. It is reported to produce less euphoria than morphine.
A dose of 10 to 20 mg by mouth may be given initially and increased as necessary by 5 to 10mg daily. The dose must not be increased by more than 5 to 10 mg daily, and by no more than 30 mg in any 7 day period. After stabilisation, which can often be achieved with a 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.
Methadone is contraindicated in individuals who are hypersensitive to methadone or other components in METHADONE Syrup.
Like other opioids, methadone is contraindicated in patients with 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 (see INTERACTIONS).
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 narcotics, methadone should not be administered to patients with severe hepatic impairment as it may precipitate hepatic encephalopathy (see WARNINGS and PRECAUTIONS).
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 Warnings and Precautions).
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.
Respiratory depression is the major hazard associated with methadone treatment. The peak depressive effects persist longer than peak analgesic effects, especially during the initial dosing period. Particular care should be taken during the dose initiation and adjustment period to minimise the risk of dose accumulation (see Dosage and Administration). In common with all opioids, prolonged use of methadone has the potential to produce dependence of the morphine type.
Methadone should be used with caution in the presence of hypothyroidism, adrenocortical insufficiency, hypopituitarism, prostatic hypertrophy, shock, diabetes mellitus.
Extreme caution should be exercised when administering methadone to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.
In common with other opioids, methadone may produce orthostatic hypotension and drowsiness in ambulatory patients. They should be cautioned, therefore, against driving a vehicle, operating machinery or other activities requiring vigilance.
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 of 1 to 6 mg/kg was associated with increased pre-implantation deaths and chromosomal aberrations of sperm cells, when compared with controls.
Long term carcinogenicity tests in rodents did not reveal any evidence of methadone-related neoplasia.
No teratogenic effects have been observed in standard teratogenicity studies in rats and rabbits given methadone at doses from 10 to 50 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.
Methadone does not appear to impair human female fertility.
Studies in men on methadone maintenance programmes 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, reflecting the lack of dilution through reduced seminal secretions.
There is inadequate evidence of the safety of methadone in human pregnancy although it has been in selected use for many years without apparent ill consequence. Autopsies on five infants who died in utero did not reveal any abnormality attributable to methadone use by their dependent mothers. Nevertheless, the use of methadone in pregnancy should be avoided unless there is no safer alternative.
Narcotics may cause respiratory depression in the newborn infant. During the last 2 to 3 hours before expected delivery, narcotics should therefore only be used after weighing the needs of the mother against the risk to the foetus.
Breast feeding is permissible in mothers receiving methadone for maintenance therapy but the baby should be monitored to avoid sedation. Withdrawal symptoms can occur in the infant. Assays of breast milk from methadone-maintained mothers showed methadone concentrations of 0.17 to 5.6 mcg/ml.
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.
Methadone has a long plasma half life which may lead to accumulation, particularly if renal function is impaired (see Renal Impairment).
In common with other opioids, methadone may cause confusion in this age group, therefore careful monitoring is advised.
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 CONTRAINDICATIONS).
Methadone should be used with caution in patients with renal dysfunction.
Methadone should be administered with particular caution to patients at risk for development of prolonged QT interval.
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 Contraindications and 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.
The following convention has been utilised for the classification of undesirable effects: very common ≥1/10, common ≥1/100, <1/10, uncommon ≥1/1000 and <1/100, rare ≥1/10,000 and <1/1000, very rare <1/10,000. For this product there is no modern clinical documentation which can be used as support for determining the frequency of adverse reactions.
Adverse reactions denoted by a hash (#) appear to be more common in ambulatory patients and in those receiving oral therapy.
Common: confusion#.
Euphoria has been reported at higher doses in tolerant subjects.
Very common: dizziness#, drowsiness#, light-headedness#.
Very rare: ECG changes including QT prolongation and Torsade de Pointes, usually in patients with risk factors or receiving high doses of methadone (see Warnings and Precautions).
Rare: hypotension and collapse.
Respiratory depression.
Very common: nausea#, vomiting#, dry mouth#, constipation.
Methadone, in common with other opioids may cause spasm of the biliary tract (see Contraindications).
Very common: sweating#.
Subcutaneous administration may cause local irritation.
Common: Urinary retention or hesitancy.
Methadone, in common with other opioids may cause spasm of the renal tracts (see Contraindications).
Prolonged use of methadone in men has been reported to be associated with the development of gynaecomastia and impaired fertility (see Pregnancy and Lactation).
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.
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 antriretroviral agents used in the treatment of HIV infection (particularly nevirapine, efavirenz and some protease inhibitors). This has the potential to result in withdrawal symptoms.
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 Warnings and Precautions). 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, alcohol, barbiturates, neuromuscular blocking agents, phenothiazines and tranquillisers. Some psychotropic drugs, however, may potentiate the analgesic effects of methadone.
The symptoms and signs of overdosage with methadone parallel those for other opioids, namely profound respiratory depression, pin-point pupils, 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.
General supportive measures, including ECG monitoring, should be employed as required. The specific opioid antagonist naloxone is the treatment of choice for the reversal of coma and the restoration of spontaneous respiration; the literature should be consulted for details of appropriate dosage. It should be noted that QT prolongation will not be reversed by naloxone.
In opioid dependent patients the administration of the recommended dose of an opioid antagonist may 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 a 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 patient 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 h 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.
Store below 25°C. Protect from light.
Controlled Drug B3.
200 ml of syrup 5 mg/ml.
Nil.
GlaxoSmithKline NZ Ltd
Quay Tower
Cnr Albert & Customs Streets
Private Bag 106600
Downtown
Auckland
NEW ZEALAND
Phone (09) 367 2900
Facsimile (09) 367 2506
29 March 2007
Issue: 5
METHADONE SYRUP™ is a trade mark of the GlaxoSmithKline group of companies.