SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Methadone Mixture DTF 1mg/ml Physeptone Mixture

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Methadone Hydrochloride 1mg/ml Excipients with known effect:

Sunset yellow (E110) 0.008mg/ml, tartrazine (E102) 0.07mg/ml, sucrose 197.17mg/ml.

Contains less than 1mmol/ml sodium per maximum daily dose, i.e. essentially ‘sodium-free.’

For full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

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 administration.

Adults

Initially 10 - 20mg/day, increasing by 10 - 20mg/day until there is no sign of withdrawal or intoxication. The usual dose is 40 - 60mg/day. The dose is adjusted according to the degree of dependence, with the aim of gradual reduction.

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 points 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 after titration.

Sunset yellow (E110) and tartrazine (E102) may cause allergic reactions.

Contains 197.17mg/ml sucrose, i.e. 11.83g per maximum daily dose. This should be taken into account in patients with diabetes mellitus. May be harmful to the teeth.

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 contra-induicated (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 the drug has been widely used for many years without apparent ill consequence and animal studies have not shown any hazard. It should not be used during labour. 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.

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

Nausea, vomiting and dizziness may occur. Methadone has the potential to increase intracranial pressure, particularly where it is already raised.

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 overdose 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 overdose, 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 given 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.

5.1    Pharmacodynamic properties

ATC code: N07BC02

Therapeutic form: Drugs used in opioid dependence

Methadone is a narcotic analgesic and has central stimulant actions. It has less sedative action than morphine. It depresses the cough centre and respiratory centre.

5.2    Pharmacokinetic properties

Methadone is rapidly absorbed after oral administration. It has a plasma half life of 15 - 25 hours. It is widely distributed throughout the tissues but found in greater concentration in the liver, kidneys and lungs. About 70% of the total dose excreted is unconjugated. Small doses are mainly excreted in the faeces, but larger doses are mainly excreted in the urine. Excretion is increased in acid urine.

5.3    Preclinical safety data

No additional data of relevance to the prescriber.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Syrup (contains sucrose)

Glycerol (E422)

Green S (E142)

Tartrazine (E102)

Sunset yellow (E110)

Hydrochloric acid (E507)

Sodium Benzoate (E211)

Sodium hydroxide (pH adjustment)

Purified water

6.2    Incompatibilities

No major incompatibilities known.

6.3    Shelf life

48 months glass bottles.

24 months plastic bottles.

Use within 1 month of opening

6.4    Special precautions for storage

Store below 25°C, protect from light.

6.5    Nature and contents of container

Amber glass Winchester bottle with a tamper evident child proof lined cap. 500, 100, 50 and 30ml pack sizes are available. Or HDPE plastic bottle with lined cap. The plastic bottles come in four different sizes; the 1L and 500ml bottles are sealed with a tamper evident and child resistant cap whereas the 2.5 and 5 L bottles are sealed with a tamper evident cap or tamper evidence is provided with a tamper evident sticker.

The product is not supplied with a patient leaflet but patient leaflets are available to the prescriber and dispenser in a tear off pad format.

The material for the construction of the closures is a HDPE with an EP wad.

6.6    Special precautions for disposal

None

7    MARKETING AUTHORISATION HOLDER

Macarthys Laboratories Ltd T/A Martindale Pharmaceuticals Bampton Road, Harold Hill, Romford, RM3 8UG

8    MARKETING AUTHORISATION NUMBER(S)

PL 01883/0018

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

First Authorised:    20 January 1983

Date renewed:    08 March 2005

24/04/2014