SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methadone Mixture DTF (Sugar Free) 1mg inlml Oral Solution Physeptone Mixture SF

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains methadone hydrochloride 1mg.

Contains excipients Liquid Maltitol (E 965) 0.4 ml/ml and Sunset Yellow (E110) 0.008 mg/ml.

For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Oral solution

A clear, green oral solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The treatment of Opioid drug addiction as a narcotic abstinence syndrome suppressant.

4.2 Posology and method of administration

For oral use only.

The dose is adjusted according to the degree of dependence with the aim of gradual reduction.

Adults

Initially 10 - 20mg per day, increasing by 10 - 20mg daily until there is no sign of withdrawal or intoxication.

The elderly

In the case of the elderly or ill patients, repeated doses should be given with extreme caution.

Children

Not recommended (see section 4.3)

4.3 Contraindications

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

•    Acute alcoholism (See section 4.5)

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

•    Where there is a risk of paralytic ileus

•    Concurrent administration of MAOI drugs, including moclobemide, or for 2 weeks after stopping (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 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 (>100 mg/d). Methadone should be administered with caution to patients at risk for 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 CYP 3A4 inhibitors (see section 4.5).

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

4.5 Interaction with other medicinal products and other forms of interaction

• Alcohol - may induce serious respiratory depression and hypotension (see section 4.3)

• Analgesics

o Buprenorphine and pentazocine - rapidly precipitate withdrawal symptoms in patients addicted to methadone. o Other opioid analgesics - additive CNS depression, respiratory depression and/or hypotension.

• Antiarrhythmics

o Mexiletine - methadone may delay mexiletine absorption o See also Drugs affecting cardiac conduction below

• Antidepressants

o MAOIs including moclobemide (concurrent or within 2 weeks of discontinuation) are contraindicated (see section 4.3) - risk of CNS excitation or depression

o Fluvoxamine - possible increase in plasma concentrations of methadone.

o Tricyclics - additive CNS depression, respiratory depression and/or hypotension.

• Antivirals

o Nevirapine - may decrease plasma concentrations of methadone by increasing its hepatic metabolism with subsequent withdrawal symptoms. Patients on methadone who start nevirapine should be monitored for withdrawal reactions and the methadone dose adjusted accordingly.

o Efavirenz - similar reaction to nevirapine

o Nelfinavir , ritonavir and possibly abacavir - possible reduction in plasma concentrations of methadone

o Zidovudine - methadone may increase the plasma concentrations of zidovudine.

• Ciprofloxacin - may increase methadone levels by inhibiting its metabolism

• Cytochrome P450 3A4 inhibitors - methadone metabolism is mediated by the CYP 3A4 isoenzyme and therefore clearance is reduced when administered with drugs which inhibit CYP 3A4 activity such as o Some anti-HIV agents (see Antivirals above) o Macrolide antibiotics

o Cimetidine (also see Gastro-intestinal drugs below) o Azole antifungal agents

• Drugs affecting cardiac conduction and electrolyte balance - risk of cardiac events when taken concurrently with methadone.

• Carbamazepine - reduction in plasma concentrations of methadone

• CNS depressants such as anaesthetics, antipsychotics, anxiolytics, major and minor tranquillisers and sedatives - additive CNS depressant, respiratory depression and/or hypotension.

• Gastro-intestinal drugs

o Cimetidine - potentiation of opioid activity due to displacement of methadone from protein binding sites

o Metoclopramide and domperidone - GI effects antagonised by methadone

• Naloxone - antagonises the analgesic, CNS and respiratory depressant effects of methadone.

• Naltrexone - rapidly precipitates withdrawal symptoms in patients addicted to methadone

• Phenytoin - potentiation of opioid activity due to displacement of methadone from protein binding sites

• Rifampicin and other Rifamycins - reduce opiate effects due to increased metabolism

Urinary acidifiers - increase the rate of methadone excretion thus decreasing plasma concentrations

4.6    Fertility, pregnancy and lactation

There is no or inadequate evidence of safety in human pregnancy, but it has been in wide use for a considerable number of years without apparent ill consequence. Animal studies have not shown any evidence of hazard. It should not be used in labour as the prolonged duration of action increases the risk of neonatal depression. Methadone is excreted in breast milk. This may be permissible during maintenance dosage.

4.7    Effects on ability to drive and use machines

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.

4.8 Undesirable effects

Nausea, vomiting and dizziness may occur. Methadone has the potential to increase intracranial pressure, particularly where it is already raised. In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage.

Other undesirable effects that may occur after taking methadone are hallucinations, confusion, vertigo, mood changes, dysphoria, dependence, headache, drowsiness, sweating, postural hypotension, miosis, difficulty with micturition and hypothermia.

Bradycardia, palpitations, tachycardia, facial flushing, constipation, a dry mouth, ureteric or biliary spasm, an antidiuretic affect, decrease of libido or potency, urticaria, pruritis and rashes may also occur.

Cases of QT prolongation and torsade de pointes have been rarely reported.

4.9 Overdose

Symptoms

Serious overdosage is characterised by respiratory depression, extreme somnolence progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin and sometimes bradycardia and hypotension. In severe overdosage, particularly by the intravenous route, apnea, circulatory collapse, cardiac arrest and death may occur.

Treatment

A patent airway and assisted or controlled ventilation must be assured. Narcotic antagonists may be required but it should be remembered that methadone is a long acting depressant (36 - 48 hours), whereas antagonists act for 1 -3 hours, so that treatment with the latter must be repeated as needed. Observation and supportive measures must be continued for 36-48 hours.

An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression. Nalorphine (0.1mg/kg) or Levallorphan (0.02mg/kg) should be give intravenously as soon as possible and repeated, if necessary, every 15 minutes. Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. In a person physically dependant on narcotics, administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome: use of the antagonist in such a person should be avoided if possible, but if it must be used to treat serious respiratory depression, it should be administered with great care.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Methadone is a narcotic analgesic in the manner of morphine but has a less sedative effect. It acts on the CNS system and smooth muscle. This action is caused by the response of structurally and sterically specific opiate receptor sites in the brain, spinal cord and nervous system. Methadone depresses the cough and respiratory centre. In the treatment of opioid addiction the drug of abuse is replaced by methadone. In some situations the use of methadone can reduce or eliminate the effects of other opioids taken during the treatment period. This process is referred to as “narcotic blockade”.

5.2 Pharmacokinetic properties

Methadone is rapidly absorbed after oral administration. Protein binding: up to 90% but considerable inter-subject variation. About 15% is bound to immunoglobulin the remainder to albumin. Distribution in blood:

Plasma: Whole blood ratio; about 1:3.

Clearance: Plasma clearance about 2m1/min/kg.

Volume of distribution: approx. 5L/kg

Half life: single dose = 10-25 hours

Repeated dose = 13-55 hours

Therapeutic concentration: In plasma, usually in the range 0.05 - 1.0ug/ml.

During methadone maintenance treatment considerable fluctuations occur day to day.

Deposition in the body: Widely distributed in the tissues, with higher concentrations in the liver, lungs and kidneys than in the blood. The main metabolic reaction is N-demethylation resulting in a substance which spontaneously cyclises to form the major metabolites 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl-1-pyrolline (EMDP), neither of which are active. Hydroxylation to methadol followed by N-demethylation to Normethadol also occurs to some extent.

Other metabolic reactions occur and there are at least eight known metabolites. In subjects on methadone maintenance, about 20-60% of a dose is excreted in the urine in 24 hours, with up to about 33% of the dose is unchanged drug and up to about 43% as EDDP, EMDP accounts for about 5 to 10% of the dose. The ratio of EDDP to unchanged methadone is usually very much higher in the urine of patients on methadone maintenance treatment than in simple overdose cases. Urinary excretion of unchanged drug is pH dependent, being increased in acid urine. Up to 30% of a dose may be eliminated in the Faeces, but this appears to decrease with increasing dosage. About 75% of the total excreted material is unconjugated.

5.3 Preclinical safety data

None stated.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Liquid maltitol (E965), Potassium Sorbate (E202), Green S (E142), Sunset Yellow (E110), Quinoline Yellow (E104), Hydrochloric acid or sodium hydroxide (for pH-adjustment) and Purified Water.

6.2    Incompatibilities

No major incompatibilities known

6.3    Shelf life

12 months

Use within 28 days of opening

6.4    Special precautions for storage

Do not Store above 25 °C.

6.5 Nature and contents of container

30ml, 50ml, 100ml and 500ml of the oral solution in Type III amber glass bottles fitted with child resistant closures. Contact material: Polypropylene. Not all pack sizes are marketed.

6.6 Special precautions for disposal

None stated.

7 MARKETING AUTHORISATION HOLDER

Martindale Pharmaceuticals Ltd Bampton Road,

Harold Hill,

Romford,

RM3 8UG,

UK.

8    MARKETING AUTHORISATION NUMBER(S)

PL 0156/0030

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

First Authorised: 21 March 1996

10 DATE OF REVISION OF THE TEXT

14/04/2008