Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Macarthys Laboratories Ltd, T/A Martindale Pharma, Bampton Road, Harold Hill, Romford, Essex, RM3 8UG, United Kingdom
In the treatment of opioid addiction, the following are contraindicated:
Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2).
Methadone has a long half life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.
Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). 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 continuing opioid substitution therapy should be reviewed regularly.
Tolerance and dependence may occur as with morphine.
Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.
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. The decision to maintain a patient on a longterm opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).
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.
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.
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).
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.
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)
Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management. Methadone should not be withdrawn abruptly and infants will require careful monitoring for signs of respiratory depressions and/or opioid withdrawal.
Special care should be taken with patients with severe liver damage, as there is a risk that methadone might precipitate porto-systemic encephalopathy or precipitate coma.
Reduce doses to avoid increased and prolonged effect, increased cerebral sensitivity
Cases of QT interval prolongation and torsade 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 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 100 mg/d and at seven days after titration.
Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries.
Methadone, as with other opiates, has the potential to increase intracranial pressure especially where it is already raised.
Children (under 16 years): Even at low doses methadone is a special hazard to children if ingested accidentally. Children under 6 months, particularly neonates may be more sensitive to respiratory depression than adults
Methadone should be used with caution in elderly or debilitated patients due to its long half-life.
Use with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, biliary tract disorders, inflammatory or obstructive bowel disorders or myasthenia gravis.
Local injection site reactions can occur therefore injection sites should be inspected regularly. Injections may be painful.
Methadone 50mg/ml Solution for injection 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 Physeptone 50mg/ml Solution for injection
Methadone 50mg/ml Solution for injection 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).
Methadone is metabolised by the liver cytochrome P450 isoenzymes including CYP 3A4. CYP 1A and CYP 2D6. Interactions are likely with enzyme inhibitors or inducers.
Methadone clearance is decreased when co-administered with drugs which inhibit CYP3A4 activity, such as some anti-HIV agents, macrolide antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme). Please see further details of specific interactions with antiviral-HIV agents, erythromycin, cimetidine and fluconazole/ketoconazole/voriconazole given later in this section.
The concurrent use of MAOIs is contra-indicated (see also section 4.3 Contra-indications) as they may prolong and enhance the respiratory depressant effects of methadone. Severe CNS excitation, delirium, hyperpyrexia, convulsions or respiratory depression is possible with concurrent use of opiates and MAOIs. With moclobemide, either CNS excitation or depression (hypertension or hypotension) is possible.
Concomitant use of pethidine and other opioid agonist analgesics is not advised because of the potential for additive effects on CNS depression, respiratory depression and hypotension.
Naloxone and naltrexone antagonise 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.
Concomitant use of other CNS depressants is not advised. Hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole) and anxiolytics may increase the general depressant effects of methadone. Antipsychotics may enhance the sedative and hypotensive effects of methadone. The plasma concentration of methadone may be increased by fluvoxamine and to a lesser extent, fluoxetine and theoretically other SSRIs due to decreased methadone metabolism. There may be increased sedation with tricylic antidepressants.
There is an increased risk of ventricular arrhythmias when methadone is given with the CNS stimulant,atomoxetine.
Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.
Plasma concentrations of methadone may be reduced by the nucleoside reverse transcriptase inhibitor abacavir, and, the protease inhibitors nelfinavir and ritonavir (which are metabolised by cytochrome P450 enzyme systems) and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine, which may interact with a number of drugs metabolised in the liver. Methadone may increase the plasma concentration of the nucleoside reverse transcriptase inhibitor zidovudine.
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. Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to the inhibition of CYP1A2 and CYP3A4. Reduced serum concentrations of ciprofloxacin may occur. Erythromycin theoretically may increase methadone levels due to decreased methadone metabolism. Rifabutin may decrease methadone levels due to increased metabolism.
Phenytoin and carbamazepine increase the metabolism of methadone. Adjustment of the dose of methadone should be considered.
May stimulate hepatic enzymes that increase methadone metabolism, reducing methadone levels. There may be increased sedation and additive CNS depression.
May have additive psychoactive effects; antimuscarinic effects at high doses.
May raise methadone levels, due to decreased methadone metabolism.
Reducing the dose of methadone should be considered.
There are several anecdotal reports of raised methadone levels due to decreased methadone metabolism.
Retards oxidative hepatic drug metabolism by binding to microsomal cytochrome P450. The metabolism of methadone may be inhibited leading to increased plasma concentration and opiate action.
Concomitant antimuscarinics (e.g. atropine and synthetic anticholinergics) may increase the risk of severe constipation and/or urinary retention.
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/metoclopromide on gastro-intestinal activity.
Drugs that acidify (e.g. ascorbic acid) or alkalinise (e.g. sodium bicarbonate) the urine may have an effect on clearance of methadone as it is increased at acidic pH, and decreased at alkaline pH.
Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal motility.
Methadone may delay the absorption of the antiarrhythmic mexiletine. Methadone may increase desipramine levels by up to a factor of two.
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.
The hypnotic effect of sodium oxybate may be enhanced by opioid analgesics; concomitant use should be avoided.
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 inadequate evidence of safety in human pregnancy.
Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management.
A careful risk/benefit assessment should be made before administration to pregnant women because of possible adverse effects on the foetus and neonate include respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths.
In labour there is a greater risk of gastric stasis and inhalation pneumonia in the mother.
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.
Specialised care from obstetric and paediatric staff with experience in such management is required.
Patients should not drive or use machines whilst taking methadone.
Methadone may cause drowsiness and reduce alertness and the ability to drive. after the administration of methadone.
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:
Methadone is associated with undesirable effects similar to other opioid analgesics. There are no modern clinical studies available that can be used to determine the frequency of undesirable effects. Therefore, all the undesirable effects listed are classed as “frequency unknown”.
Endocrine Disorders: Hyperprolactinaemia.
Psychiatric Disorders: Confusion, mood change including euphoria and dysphoria, hallucinations, restlessness, sleep disturbances. Drug dependence (see section 4.4).
Nervous System Disorders: Drowsiness, dizziness, vertigo.
Eye Disorders: Dry eyes, visual disturbances such as miosis.
Cardiac Disorders: Bradycardia, tachycardia, palpitations, QT prolongation, torsades de pointes.
Vascular Disorders: Orthostatic hypotension.
Respiratory, Thoracic & Mediastinal Disorders: Respiratory depression (see also section 4.9 overdose), dry nose.
Gastrointestinal Disorders: Nausea, vomiting (particularly at the start of treatement), constipation, biliary spasm, dry mouth.
Skin & Subcutaneous tissue Disorders: Sweating, facial flushing, rashes (urticaria, pruritus), oedema.
Musculoskeletal, Connective Tissue & Bone Disorders: Muscle rigidity
Renal & Urinary Disorders: Micturition difficulties, urinary retention, ureteric spasm
Reproductive System & Breast Disorders: Decreased libido, dysmenorrhoea, amenorrhoea, sexual dysfunction
Metabolism and nutrition disorders SOC: Hypoglycaemia (frequency not known).
General & Administration Site Disorders: Hypothermia, drug withdrawal syndrome.
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, but do not mix with other medicinal products.
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