Methadone Linctus BP

Methadone Hydrochloride BP 0.04% w/v

Oral Solution

For the suppression of cough in terminal disease.

Oral

Not recommended for use in children under 12 years.

• Hypersensitivity to methadone or to any of the excipients.

• Respiratory depression, obstructive airways disease, and during an asthma attack.

• Risk of paralytic ileus.

• Acute alcoholism.

• Avoid in raised intracranial pressure or head injury (in addition to interfering with respiration, affects pupillary responses vital for neurological assessment).

• Use during labour (prolonged duration of action increases the risk of neonatal depression).

• Contra-indicated in patients taking monoamine oxidase inhibitors (including moclobemide) or within 14 days of stopping such treatment.

Tolerance and dependence of the morphine type may occur. Methadone should be given with caution to patients with asthma (see Section 4.3), convulsive disorders, depressed respiratory reserve, hypotension, shock, prostatic hyperplasia, adrenocortical insufficiency, inflammatory or obstructive bowel disorders, myasthenia gravis or hypothyroidism. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.

Dosage should be reduced in elderly and debilitated patients and those with a history of drug abuse.

Children are very sensitive to the depressant effects.

Cases of QT interval prolongation and torsade de pointes have been reported during treatment with methadone, particularly at high doses (>100mg/d). Methadone should be administered with caution to patients at risk of 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 treatments with drugs that have a potential for QT-prolongation,

-concomitant treatment with drugs which may cause electrolyte abnormalities,

-concominant treatment with cytochrome P450 CYP 3A4 inhibitors (see section 4.5).

In patients with recognised risk factors of 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.

Interactions potentiating the effects of methadone;

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, ciprofloxacin and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

Cimetidine and phenytoin – may lead to potentiation of opioid activity due to displacement of methadone from protein binding sites. However, as phenytoin is also a hepatic enzyme inducer, it may lower plasma methadone levels (see below).

Fluvoxamine may increase plasma concentrations of methadone.

The depressant effects of methadone are likely to be enhanced by depressants of the CNS, such as other opioid analgesics, alcohol (see section 4.3), anaesthetics, antipsychotics, anxiolytics, hypnotics and sedatives, major and minor tranquilisers and phenothiazines. As well as CNS depression, there may be respiratory depression and/or hypotension. Tricyclic antidepressants may exert a similar effect.

Interactions reducing the effects of methadone;

The opioids antagonists, naloxone and naltrexone, will precipitate an acute withdrawal syndrome in methadone-dependent individuals. Naloxone will also antagonise the analgesic, CNS and respiratory depressant effects of methadone.

Buprenorphine and pentazocine may also rapidly precipitate withdrawal symptoms in patients addicted to methadone.

The hepatic enzyme-inducing drugs, nevirapine, rifampicin (and other rifamycins), phenytoin, phenobarbital and carbamazepine may lower plasma methadone levels and produce symptoms of withdrawal in methadone dependent patients. Similar effects have been reported with efavirenz nelfinavir, ritonavir and possibly abacavir.

Urinary acidifiers: Acidification of the urine will increase the rate of elimination of methadone by the kidney thereby reducing plasma concentrations.

Effects of methadone on other drugs;

Methadone may increase plasma desipramine levels and increase desipramine side-effects when given concurrently.

Zidovudine – methadone may increase the plasma concentrations of zidovudine.

Mexiletine – methadone may delay mexiletine absorption.

Metoclopramide and domperidone – the gastrointestinal effects may be antagonised by methadone.

Methadone treatment has been found to decrease the rate of absorption and decrease the bioavailability of the nucleoside reverse transcriptase inhibitors didanosine and to a lesser extent stavudine.

Other important interactions;

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.

As serious and sometimes fatal reactions have occurred following administration of pethidine to patients receiving MAOIs, other drugs related to pethidine are contraindicated in patients taking MAOI's (including moclobemide) or within 14 days of stopping such treatment, (see section 4.3) as there is a risk of CNS excitation or depression.

Cross tolerance and cross dependence can be expected between other opioids acting at the same receptors.

Pregnancy;

There is no or inadequate evidence of safety in human pregnancy, but the drug has been widely used for many years without apparent ill consequence and animal studies have not shown any hazard.

Opioid analgesics taken in pregnancy may depress neonatal respiration and cause withdrawal effects in neonates of dependent mothers. May cause gastric stasis and risk of inhalation pneumonia in mothers during labour.

Lactation;

Methadone is excreted in breast milk. A decision must be made whether to discontinue breastfeeding or discontinue the methadone therapy.

Taken during breastfeeding may cause withdrawal symptoms in the infant.

A maintenance dose may be acceptable during breastfeeding, but the dose should be kept to a minimum and the baby should be monitored to avoid sedation.

May cause drowsiness and or dizziness. If affected do not drive or operate machinery.

Blood and lymphatic system disorders

Lymphocytosis

Endocrine disorders

Increased prolactin concentrations

Psychiatric disorders

Dependence, hallucinations, confusion, mood changes including dysphoria, decreased libido, restlessness

Nervous system disorders

Raised intracranial pressure occurs in some patients. Dizziness, headache, drowsiness

Eye disorders

Miosis

Ear and labyrinth disorders

Vertigo

Cardiac disorders

Cases of QT prolongation and torsade de pointes have been rarely reported. Bradycardia, palpitations, tachycardia

Vascular disorders

Hypotension, facial flushing

Respiratory, thoracic and mediastinal disorders

Respiratory depression, Exacerbation of existing asthma

Gastrointestinal disorders

Nausea, vomiting, constipation, dry mouth

Hepatobiliary disorders

Biliary spasm

Skin and subcutaneous tissue disorders

Rashes, pruritus, urticaria, sweating

Renal and urinary disorders

Difficulty in micturation, ureteric spasm, antidiuretic effect

Reproductive system and breast disorders

Erectile dysfunction

General disorders and administration site conditions

Hypothermia.

Investigations

Globulins increased, blood albumin increased

Symptoms of overdosage with opiods include respiratory depression, pinpoint pupils, pulmonary odema and coma. Hypotension may occur and rhabdomyolysis progressing to renal failure has been reported. The presence of signs of drug abuse supports the diagnosis. In children methadone overdose produces drowsiness, floppiness, pinpoint pupils and apnoea.

Treatment consists of the establishment of a patent airway together with supportive measures, and the administration of a specific opioid antagonist, preferably naloxone given as per local guidance. Reversal of coma and respiratory depression is seen within 2 minutes of naloxone administration. Repeated treatment with naloxone may be required to prevent recurrence of coma because the duration of action of naloxone is shorter than that of methadone. Patients should be monitored for signs of relapse for at least 48 hours.

Methadone hydrochloride is a potent analgesic with action similar to that of morphine, but having a less marked sedative effect. It has a depressant action on the cough centre and is given to control non-productive coughing of intractable disorders, such as lung cancer. It is also used as part of the treatment of dependence on opioid drugs. It is readily absorbed from the gastro-intestinal tract. It is widely distributed in the tissues and diffuses across the placenta. It is extensively protein bound. It is metabolised in the liver, mainly by n-demethylation and cyclisation and the metabolites are excreted in the bile and urine.

The analgesic effect begins about 45 minutes after administration by mouth (about 15 minutes after subcutaneous injection) and the effect lasts about 4 hours. It has a prolonged half life. As accumulation occurs following repeated doses the effects become more prolonged.

None.

Glycerol, tolu flavour solution, purified water, tartrazine compound solution, syrup.

None known.

500ml : 24 months unopened.

This product is subject to the Controlled Drugs Regulations. Store in an authorised location.

500ml: Plain amber glass bottle with plastic cap and viskring.

None.

Thornton & Ross Ltd

Linthwaite Laboratories

Huddersfield

HD7 5QH

00240/6420R

15.01.81 /16.07.98

16.04.2010