SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Methadone Mixture 1 mg/ml.

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Methadone Hydrochloride 1 mg/ml.

For the full list of excipients, see section 6.1

3.    PHARMACEUTICAL FORM Oral Solution.

4.    CLINICAL PARTICULARS

4.1.    Therapeutic indications

For the treatment of dependence on opioid drugs.

4.2.    Posology and method of administration

Adults:

10 - 20mg (10 - 20ml) should be taken as an initial daily dose by oral administration. The dose should be increased cautiously by 10 - 20mg daily until no signs of withdrawal or intoxication occur. The usual dose for maintenance is 40 - 60mg daily. The dose can then be gradually decreased, when appropriate, until total withdrawal is achieved.

Elderly:

Methadone mixture should be used cautiously in elderly patients.

Children:

Not recommended for use in children.

4.3 Contraindications

•    Hypersensitivity to methadone or to any of the excipients.

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

•    Patients dependent on non-opioid drugs,

•    Concurrent administration with monoamine oxidase inhibitors (including moclobemide) or within 2 weeks of discontinuation of them.

•    Head injury and raised intracranial pressure (further rise in intracranial pressure - papillary response affected; see section 4.8).

•    Where there is a risk of paralytic ileus.

•    Acute alcoholism (see section 4.5).

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

•    Children (serious risk of toxicity).

4.4 Special warnings and precautions for use

In the case of elderly or ill patients, repeated doses should only be given with extreme caution. Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2).

Tolerance and dependence of the morphine type may occur. Methadone should be given with caution to patients with a history of 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.

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.

4.5 Interaction with other medicinal products and other forms of interaction

Interactions potentiating the effects of methadone;

Cytochrome P450 3A4 inhibitors: methadone clearance is decreased when coadministered 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 opioid 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.

4.6 Pregnancy and lactation

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.

Methadone should only be used in pregnancy if the physician considers that the potential benefits outweigh the risks. It should be used cautiously under the close supervision of a physician if the physician considers it essential to continue or initiate (in the case of an i.v. opioid user) methadone maintenance. It may be necessary to increase the dose of methadone if withdrawal symptoms develop as increased clearance and reduced plasma levels have been reported during pregnancy.

Infants of methadone-maintained mothers may experience symptoms of withdrawal in utero and following birth.

Methadone should not be used during labour as the prolonged duration of action increases the risk of neonatal depression.

Lactation:

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

4.7. Effects on ability to drive and use machines

Methadone may produce drowsiness and patients should be advised not to drive or operate machinery if affected. Once affected, the time after which such activities may be resumed is extremely variable between patients and should 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 medicine is likely to affect your ability to drive

•    Do not drive until you know how the medicine affects you

•    It is an offence to drive while under the influence of this medicine

•    However, you would not be committing an offence (called “statutory defence”) if:

o The medicine has been prescribed to treat a medical or dental problem and

o You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and o It was not affecting your ability to drive safely

4.8 Undesirable effects

Blood and lymphatic system disorders

Lymphocytosis

Endocrine disorders

Adrenal insufficiency, increased prolactin concentrations, decreased testosterone concentrations

Psychiatric disorders

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

Nervous system disorders

Methadone may increase intra-cranial pressure, particularly when it is already raised. 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, excessive sweating Renal and urinary disorders

Difficulty in micturation, ureteric spasm, antidiuretic effect Reproductive system and breast disorders

Erectile dysfunction, reductions in the ejaculate volume and seminal vesicular and prostatic secretions

General disorders and administration site conditions

Abrupt cessation or reduction of the dose of methadone will result in symptoms of withdrawal. In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage.

Hypothermia.

Investigations

Globulins increased, blood albumin increased Reporting of suspected adverse reactions

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.

4.9. Overdose

Symptoms

Overdosage of methadone is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pulmonary oedema, extreme somnolence, progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. The presence and signs of drug abuse supports the diagnosis.

In children, methadone overdose produces drowsiness, floppiness, constricted pupils and apnoea.

In severe overdosage, particularly by the intravenous route, apnoea, circulatory collapse, cardiac arrest and death may occur.

Emergency procedures

If ingestion is recent, gastric aspiration and lavage can be employed after acute poisoning.

Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Narcotic antagonists can be used to counteract the potentially lethal respiratory depression in a nontolerant individual, especially a child. Methadone is, however, a long-acting depressant (36-48 hours) whereas the antagonists act for much shorter periods (1-3 hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the respiratory depression is only due to overdosage with methadone, the use of other respiratory stimulants is not indicated.

An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists (naloxone, nalorphine or levallorphan) can be used to reverse signs of intoxication and should be given repeatedly until the patient’s status remains satisfactory.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.

In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will 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 narcotic 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 for signs of relapse for at least 48 hours.

PHARMACOLOGICAL PROPERTIES

5.1. Pharmacodynamic properties

Methadone is a p agonist with pharmacological properties similar to morphine.

Its long duration of action enables itto be used daily on a supervised basis in opioid dependent individuals.

5.2. Pharmacokinetic properties

Methadone is well absorbed from the gastrointestinal tract with peak plasma levels occurring 1-5 hours after a single dose. Wide variations in plasma levels occur during maintenance therapy. Plasma levels may decrease on long term maintenance suggesting tolerance to develop possibly as a result of autoinduction of hepatic microsomal enzymes.

Methadone is widely distributed in the tissues. It diffuses across the placenta and is excreted in breast milk. Plasma protein binding is 60-90%. After repeated administration, there is a gradual accumulation in the tissues and on discontinuation low concentrations in the plasma are maintained by slow release from extravascular binding sites accounting for the relatively mild but protracted withdrawal syndrome.

N-demethylation to the inactive major metabolite 2-ethylidine-1, 5-dimethyl-3, 3-diphenylpyrrolidine and other pyrrolidines and pyrroline occurs in the liver. These metabolites are excreted in the faeces and urine together with unchanged methadone. Urinary excretion is increased with an acidic urine. The elimination half-life is long and varies considerably with a range of 15-60 hours having been reported. Decreased excretion of methadone and its metabolites occur in liver dysfunction and urinary elimination is reduced in renal failure.

In methadone-maintained pregnant women, trough plasma levels have been found to be significantly lower and total or unbound methadone clearance greater during pregnancy than after delivery.

5.3. Preclinical safety data

No relevant data.

6.1. List of excipients

Benzoic acid solution Syrup

Green S dye E142 Tartrazine E102 Sunset yellow E110 Purified water

6.2. Incompatibilities

None reported.

6.3 Shelf life

3 years unopened

Use within 56 days of first opening

6.4. Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

500ml: Amber soda lime silica glass bottle with white polypropylene cap with polyethylene laminate wad or 28mm tamper evident plastic cap with polyethylene laminate wad.

500ml: Round high density polythene bottle with 28mm polypropylene cap with polyethylene laminate wad or 28mm tamper evident cap with polyethylene laminate wad.

1Lt, 2Lt and 5Lt high density polyethylene bottle with 38mm polypropylene, tamper evident cap with polyethylene laminate wad.

Instruction for use/handling

None.

7. MARKETING AUTHORISATION HOLDER

Thornton & Ross Ltd,

Linthwaite Laboratories,

Huddersfield,

HD7 5QH.

8. MARKETING AUTHORISATION NUMBER

PL 00240/0039

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

18 December 1995

10 DATE OF REVISION OF THE TEXT

31/03/2015