Opioids (opiates).

Generic - pain

Methadone 10mg/ml Solution for Injection

Solution for injection A clear and colourless solution

Methadone injection may be used in the management of opioid dependence; as an analgesic for moderate to severe pain as an alternative to morphine.

Opioid dependence: The use of injectable methadone for this indication must be initiated by physicians with adequate expertise and experience in addiction therapy.

The use of methadone in opiate addiction must be part of a broader treatment programme including regular treatment reviews and must be supervised by specialist services.

Method of Administration: by intramuscular or subcutaneous injection.

Management of opioid dependence:

The intramuscular route is preferred when repeated administration is required. Volumes greater than 2ml (20mg) may need to be given in divided doses at different sites.

To avoid the injection of large volumes of the product, higher strengths should be considered for patients requiring treatment with larger doses of methadone.

Adults:

Initially 10-20mg per day, increasing by 10-20mg per day until there are no signs of withdrawal or intoxication. The usual dose is 40 -60mg per day. After stabilisation, the dose is gradually decreased until total withdrawal is achieved.

The dose should be adjusted according to the individual needs of the patient with the aim of gradual reduction. Providing a dosage schedule is difficult as it is largely subjective based on the addict's reported drug use and a clinical assessment of their dependence. A cautious approach is usually adopted starting at a low dose and following with incremental increases as judged appropriate bearing in mind the general health of the patient. (See Sections 4.4 and 4.5 below).

Treatment of moderate to severe pain

Usually 5-10 mg at six to eight hours should be adjusted according to response. In prolonged use it should not be administered more than twice a day.

Hepatic impairment:

In patients with severe liver damage, the dose of methadone should be reduced and carefully controlled as there is a risk that methadone might precipitate porto-systemic encephalopathy.

Renal impairment:

The dose may need to be reduced in moderate or severe renal impairment

As methadone has not been adequately studied in children, it should not be used in children under the age of 16 years until further data become available.

Elderly and debilitated patients :

Reduce dose. If repeated doses are required, use with extreme caution due to the long plasma half-life. There may be a greater risk of respiratory depression, with or without any associated renal or hepatic impairment in this patient group.

Known hypersensitivity to methadone or any other ingredients contained in the product.

Respiratory depression and obstructive airways disease. Use during an acute asthma attack is not advisable.

Methadone should not be administered to patients with head injuries or raised intracranial pressure as there is a risk of respiratory depression which may lead to a further elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient.

Monoamine oxidase inhibitor drugs given concurrently or within two weeks of discontinuation.

Acute alcoholism.

Phaeochromocytoma.

Risk of paralytic ileus.

Obstetric use is not recommended because of the increased risk of neonatal depression due to the long duration of action.

Use in children under 16 years.

Addiction/tolerance/dependence

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, especially in elderly or debilitated patients. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.

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.

Withdrawal

Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.

Even at low doses methadone is a special hazard to children if ingested accidentally.

Respiratory depression

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two and may exacerbate asthma due to histamine release. Use with caution or reduce dose in patients with asthma or decreased respiratory reserve.

Hepatic disorders

Caution as methadone may precipitate porto-systemic encephalopathy in patients with severe liver damage.

Pregnancy and risks to the neonate:

Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management. Babies born to mothers receiving methadone may suffer withdrawal symptoms. Methadone should not be withdrawn abruptly and infants will require careful monitoring for signs of respiratory depression and/or opioid withdrawal.

Further warnings

Methadone should be used with great caution in patients with convulsive disorders.

In the case of elderly or ill patients the drug should be used with caution due to its long half-life.

Risk benefit should be assessed and methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, hypotension, shock, biliary tract disorders, inflammatory or obstructive bowel disorders or myasthenia gravis.

Local reactions at the site of injection can occur therefore these sites should be inspected regularly.

Even at low doses methadone is a special hazard to children if ingested accidentally.

Cases of QT interval prolongation and torsades de ponites 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:

-history of cardiac conduction abnormalities,

- advanced heart disease or ischaemic heart disease,

- liver disease,

- family history of sudden death,

- electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia,

- concomitant treatment with drugs that have a potential for QT-prolongation,

- concomitant treatment with drugs which may cause electrolyte abnormalities,

- concomitant treatment with cytochrome P450 CYP3A4 inhibitors.

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.

Methadone is metabolised in the liver by cytochrome P450 isoenzymes, including CYP3A4, CYP1A and CYP2D6. Interactions are likely with enzyme inhibitors or inducers; for example, cimetidine may enhance the effects of methadone, while phenytoin may increase its metabolism; Similarly, an increase in its urinary excretion has been reported with rifampicin.

MAOIs

The current use of Monoamine oxidase inhibitors (MAOIs) is contraindicated as they may prolong and enhance the respiratory depressant effects of methadone. Severe CNS excitation, delirium, convulsions or respiratory depression is possible with concurrent use of opiates and MAOIs. Hyperpyrexia and CNS toxicity has been reported when selegiline was coadministered with opioid analgesics.

CNS depressants

Concomitant use with other central nervous system depressants is not advised. Anaesthetics, hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole), anxiolytics and barbiturates may increase the general depressant effects of methadone. Antipsychotics may enhance the sedative effects 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 tricyclic antidepressants.

Alcohol

Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.

Opioid agonist

Additive effects on CNS depression, respiratory depression and hypotension can occur with concomitant use of pethidine and other opioid agonist analgesics

Opioid antagonists

Naloxone and naltrexone antagonise the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms. Similarly buprenorphine and pentazocine may precipitate withdrawal symptoms.

Anticonvulsants

Phenytoin and carbamazepine increase methadone metabolism. Adjustment of the dose of methadone should be considered.

Histamine H₂ antagonists

Histamine H₂ antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action.

pH of urine

Drugs that acidify or alkalinise the urine may affect methadone clearance as it is increased at acidic pH and decreased at alkaline pH.

Antiviral drugs used in HIV

Plasma concentrations of methadone may be reduced by the nucleoside reverse transcriptase inhibitor, abacavir, 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 interact with a number of drugs metabolised in the liver. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly. Methadone maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Methadone may increase the plasma concentration of the nucleoside reverse transcriptase inhibitor, zidovudine.

Antibacterials

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 inhibition of CYP 1A2 and CYP 3A4. Reduced serum concentrations of ciprofloxacin may occur. Co-administration of ciprofloxacin with methadone may result in profound sedation, confusion and respiratory depression. This combination should be avoided.

Erythromycin theoretically may increase methadone levels due to decreased methadone metabolism.

Rifabutin may decrease methadone levels due to increased metabolism.

Cyclizine and other sedating antihistamines

May have additive psychoactive effects; antimuscarinic effects at high doses.

Fluconazole and ketoconazole

May raise methadone levels, due to decreased methadone metabolism.

Grapefruit juice

There are several anecdotal reports of raised methadone levels due to decreased methadone metabolism.

Antimuscarinics

Concomitant antimuscarinics (e.g. atropine and synthetic anticholinergics) may increase the risk of severe constipation and/or urinary retention.

Drugs affecting gastric emptying

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 gastro-intestinal activity.

Antiarrhythmics

Methadone delays the absorption of mexiletine.

Other drugs

Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal motility.

Methadone may increase desimipramine levels by up to a factor of two.

Cytochrome P450 3A4 inhibitors

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).

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.

Pregnancy Tests

Methadone may interfere with the urine testing for pregnancy.

Methadone is associated with undesirable effects common to other opioid analgesics. The most common side are nausea, vomiting, drowsiness, constipation, confusion and euphoria, but the most serious hazard is respiratory depression.

Respiratory Disorders

Respiratory depression particularly with larger doses

Gastrointestinal Disorders

Nausea and vomiting (particularly at the start of treatment), constipation and dry mouth

CNS Disorders

Dependence, drowsiness, dizziness, vertigo, headache, confusion, restlessness can occur. Changes of mood, including euphoria, and hallucinations are occasionally reported.

Renal and Urinary Disorders

Less commonly micturition difficulties are observed.

Cardiovascular Disorders

Bradycardia, palpitation and orthostatic hypotension can occur. Cases of QT prolongation and torsades de pointes have been rarely reported.

Skin Disorders

Sweating, rashes.

Other Undesirable Effects

Other side effects which occur more commonly in ambulant patients, include pruritus, urticaria, facial flushing, hypothermia, dry eyes and nose, decreased libido, dysmenorrhoea and amenorrhoea, and miosis can also occur. Raised intracranial pressure and muscle rigidity have been reported.

Methadone causes pain at injection sites. Local irritation has been observed at the injection site and induration may occur with repeated subcutaneous injection

Wockhardt UK Ltd

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