Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: T/A Martindale Pharma, Bampton Road, Harold Hill, Romford, RM3 8UG, United Kingdom
Tolerance and dependence of the morphine type may occur, though it is said that methadone has a greater respiratory depressive effect and a lesser sedative effect than an equianalgesic dose of morphine. Toxic doses are highly variable, regular usage giving tolerance. Pulmonary oedema is a frequent corollary of overdosage whilst the dose-related histamine-releasing property of methadone may account for at least some of the urticaria and pruritis associated with methadone administration. Methadone may lead to an increase in intracranial pressure.
Adverse effects occurring more rarely in patients being treated for opioid addiction are as follows:
(a) A number of heroin patients have been reported to die within a few days of starting a methadone maintenance programme. Evidence of chronic persistent hepatitis was detected in ten heroin patients, who died within 2-6 days of starting methadone treatment. The mean prescribed dose at the time of death was about 60mg. It has been suggested that these sudden deaths may have arisen as a result of accumulation of methadone over several days resulting in death from complications such as cardiac arrhythmias or cardiovascular collapse as methadone, like dextropropoxyphene, has membrane stabilising activity and can block nerve conduction.
In view of the possibility of reduced clearance and raised plasma levels it is recommended that liver function tests and urine tests be carried out prior to maintenance and that lower starting doses of methadone be used.
(b) Evidence of hypoadrenalism has been found in chronic methadone patients. Findings consistent with both deficient ACTH production and subsequent secondary hypoadrenalism and methadone induced primary adrenal cortical hypofunction have been reported.
© Choreic movements involving the upper limbs, torso and speech mechanisms have been reported in a 25-year-old man receiving methadone hydrochloride maintenance therapy (45-60 mg/day) for 2 years. Discontinuation of methadone resulted in complete alleviation of the abnormal movements with no recurrence during the subsequent eight months.
(d) The function of the secondary sex organs was found to be markedly impaired in 29 male participants in a methadone maintenance programme. The ejaculate volume and seminal vesicular and prostatic secretions in subjects maintained on methadone (mean daily dose 66.9 mg) were reduced by over 50% compared to 16 heroin patients and 43 opioid-free controls. Serum testosterone levels were also approximately 43% lower in those on methadone. Whilst the sperm counts of the methadone users were more than twice the control level, reflecting a lack of sperm dilution by secondary sex organ secretion, the sperm motility of these subjects was markedly lower than normal.
Methadone should be given with caution to patients with asthma, convulsive disorders, depressed respiratory reserve, hypotension, hypothyroidism or prostatic hypertrophy. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.
For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression).
Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.
A comprehensive patient history should be taken to document concomitant medications, including overthe- counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.
Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.
Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.
Patients should be closely monitored for signs of misuse, abuse, or addiction.
The clinical need for analgesic treatment should be reviewed regularly.
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with methadone.
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their new-born infants will experience neonatal withdrawal syndrome.
Cases of QT interval prolongation and torsades de pointes have been reported during treatment with methadone, particularly at high doses (> 100 mg/d). Methadone should be administered with caution to patients at risk for the development of prolonged QT interval, e.g. in case of:
In patients with recognised risk factors for QT-prolongation, or in case of concomitant treatment with drugs that have a potential for QT-prolongation, ECG monitoring is recommended prior to methadone treatment, with a further ECG test at dose stabilisation.
ECG monitoring is recommended, in patients without recognised risk factors for QT prolongation, before dose titration above 100mg/d and at seven days after titration.
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 and section 4.9).
Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.
Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.
Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.
Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two. Asthma may be exacerbated due to histamine release.
Concomitant treatment with other agents with CNS depressant activity is not advised due to the potential for CNS and respiratory depression (see also section 4.5 Interactions).Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of methadone and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe methadone concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
Children are more sensitive than adults and intoxication may follow a low dose intake of methadone. To avoid such intoxication following dose administration by mistake, methadone should be kept in a safe place out of reach by children when located at home
This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The concurrent use of MAOI’s is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone.
Anaesthetics, hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole), anxiolytics, sedatives, barbiturates, phenothiazines, some other major tranquillizers and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly. (See 4.4 Special warnings and precautions for use).
Antipsychotics may enhance the sedative effects and hypotensive effects of methadone.
Methadone may increase desimipramine levels by up to a factor of two.
There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.
Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.
Histamine H2 antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action
Rifampicin: Reduced plasma levels and increased urinary excretion of methadone can occur with concurrent administration of rifampicin. Adjustment of the dose of methadone may be necessary.
Ciprofloxacin: Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to inhibition of CYP 1A2 and CYP 3A4. Reduced serum concentrations of ciprofloxacin may occur. Concomitant use may lead to sedation, confusion and respiratory depression.
Erythromycin: Theoretically this may increase methadone levels due to decreased methadone metabolism.
Antifungals: e.g. Fluconazole ,voricanozole and ketoconazole: May raise methadone levels, due to decreased methadone metabolism.
Induces the metabolism of methadone and there may be a risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.
Drugs that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH.
Additive CNS depression, respiratory depression and hypotension
Naloxone and naltrexone antagonises the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms (See Section 4.9 Overdose). Similarly buprenorphine and pentazocine may precipitate withdrawal symptoms.
Based on the known metabolism of methadone, these agents may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Methadone may increase the plasma concentration of zidovudine. Narcotic withdrawal syndrome has been reported in patients treated with some retroviral agents and methadone concomitantly.
Methadone maintained patients beginning antiretroviral therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.
May have additive psychoactive effects; antimuscarinic effects at high doses.
Methadone may have an effect on other drugs as a consequence of reduced gastrointestinal motility.
Methadone may interfere with the urine testing for pregnancy.
Methadone clearance is decreased when coadministered with drugs which inhibit CYP3A4 activity, such as some antiHIV agents, macrolide antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).
May lower plasma concentrations of methadone.
There are several anecdotal reports of raised methadone levels due to decreased methadone metabolism.
Domperidone and metoclopramide may increase the speed of onset but not the extent of methadone absorption by reversing the delayed gastric emptying associated with opioids. Conversely, methadone may antagonise the effect of domperidone/metoclopramide on gastrointestinal activity.
Methadone delays the absorption of mexiletine.
In patients taking drugs affecting cardiac conduction, or drugs which may affect electrolyte balance there is a risk of cardiac events when methadone is taken concurrently. Please refer to Section 4.4.
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
Serotonergic syndrome may occur with concomitant administration of methadone with pethidine, monoamine oxidase (MAO) inhibitors and serotonin agents such as Selective Serotonin Re-uptake Inhibitor (SSRI), Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) and tricyclic antidepressants (TCAs). The symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
There is no evidence of safety in human pregnancy. A careful risk/benefit assessment should be made before administration to pregnant women because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, methadone has not been associated with congenital malformations.
It may be necessary to increase the dose of methadone if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy.
During labour there is a risk of gastric stasis and inhalation pneumonia in the mother and foetal distress. Methadone should not be used in labour (see 4.3 Contraindications).
Methadone is excreted in breastmilk at low levels. The decision to recommend breast-feeding should take into account clinical specialist advice and consideration should be given to whether the woman is on a stable maintenance dose of methadone and any continued use of illicit substances. If breastfeeding is considered, the dose of methadone should be as low as possible. Prescribers should advise breastfeeding women to monitor the infant for sedation and breathing difficulties and to seek immediate medical care if this occurs. Although the amount of methadone excreted in breast milk is not sufficient to fully suppress withdrawal symptoms in breast-fed infants, it may attenuate the severity of neonatal abstinence syndrome. If it is necessary to discontinue breastfeeding it should be done gradually, as abrupt weaning could increase withdrawal symptoms in the infant.
Specialist care for obstetric and paediatric staff with experience in such management is required. If breast feeding is considered, the dose of methadone should be as low as possible and the infant monitored to avoid sedation. Breastfed infants may develop physical dependence and exhibit withdrawal symptoms.
Reports of visual disorders have been reported in neonates following exposure to methadone during pregnancy. However, other factors have also been present and a definitive causal link to methadone has not been established (see section 4.4).
The ability to drive or operate machinery may be severely effected during and after treatment with methadone. The time after which such activities can be safely resumed is extremely patient dependant and must be decided by the physician.
This medicine can impair cognitive function and can affect a patient’s ability to drive safely. This class of medicine is in the list of drugs included in regulations under 5a of the Road Traffic Act 1988. When prescribing this medicine, patients should be told:
The adverse effects of methadone are generally the same as with other opioids, most commonly nausea and vomiting, which are observed in approximately 20% of the patients who undergo methadone outpatient treatment, where the medicinal control is often unsatisfactory.
The most serious adverse effect of methadone is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest have occurred.
Adverse reactions listed below are classified according to frequency and system organ class. These reactions are more frequently observed in non opioid tolerant individuals. Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
Not known: Hyperprolactinaemia
Common: Euphoria, hallucinations
Uncommon: Dysphoria, dependence, agitation, insomnia, disorientation, reduced libido
Unknown: Drug dependence (see section 4.4)
Common: Sedation
Uncommon: Headache, syncope
Common: Blurred vision, miosis, dry eyes
Not Known: Nystagmus
Common: Vertigo
Rare: Bradycardia, palpitations, cases of prolonged QT interval and torsade de pointes have been reported, especially with high doses of methadone.
Uncommon: Facial flush, hypotension
Uncommon: Pulmonary oedema, exacerbation of asthma, dry nose, respiratory depression particularly with large doses
Very common: Nausea, vomiting
Common: Constipation
Uncommon: Xerostomia, glossitis
Uncommon: Bile duct dyskinesia
Common: Transient rash, sweating
Uncommon: Pruritis, urticaria, other rash and in very uncommon cases bleeding urticaria
Uncommon: Urinary retention, antidiuretic effect
Uncommon: Reduced potency, galactorrhoea, dysmenorrhoea and amenorrhoea
Common: Fatigue, drowsiness
Uncommon: Oedema of the lower extremities, asthenia, oedema, hypothermia, drug withdrawal syndrome
Common: Weight increase
Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
No major incompatibilities known.
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