SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Physeptone Tablets Methadone Tablets BP 5 mg

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Methadone Hydrochloride PhEur 5.0mg/tablet

3    PHARMACEUTICAL FORM

Tablet

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For oral use as an analgesic for moderate to severe pain.

4.2    Posology and method of administration

ADULTS: Usual adult dose 5-10 mg.

Owing to its long plasrna half-life caution with repeated dosage should be observed in the very ill or elderly. The usual initial dose should be 5-10 mg, 6-8 hourly, later adjusted to the degree of pain relief obtained.

CHILDREN: Not suitable

USE IN THE ELDERLY: Use caution with repeated dosage in elderly and ill patients.

4.3    Contraindications

Respiratory depression, obstructive airways disease, in cases of acute alcoholism, head injury or raised intracranial pressure. It is not recommended during an asthma attack or where there is a risk of paralytic ileus. Concurrent administration with monoamine oxidase inhibitors (including moclobemide), or within 2 weeks of discontinuation of treatment with them. Obstetric use is not recommended.

4.4 Special warnings and precautions for use

Tolerance and dependence of the morphine type may occur. Methadone should be given with caution to patients with asthma, convulsive disorders, depressed respiratory reserve, hypotension, hypothyroidism or prostatic hypertrophy. 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 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 (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 100mg/d and at seven days after titration.

4.5 Interaction with other medicinal products and other forms of interaction

Monoamine oxidase inhibitors (MAOIs) (including moclobemide) may prolong and enhance the respiratory depressant effects of methadone.

The general depressant effects of methadone may be enhanced by other agents with central nervous system depressant activity such as alcohol, phenothiazines, tricyclic antidepressants, barbiturates, antipsychotics, anxiolytics and hypnotics. Antidepressants such as fluvoxamine may increase the plasma concentrations of methadone.

Rifampicin has been reported to reduce circulating levels of methadone and to increase its urinary excretion.

Antiepileptics such as carbamazepine decrease the effect of methadone and phenytoin has been reported to enhance the metabolism of methadone.

Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. 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. A similar interaction has occurred when efavirenz has been taken concomitantly with methadone. Other antivirals such as nelfinavir, ritonavir and possibly abacavir may reduce the plasma concentration of methadone. Methadone may increase the plasma concentrations of zidovudine.

Ciprofloxacin may increase levels of methadone by inhibiting its metabolism. With anti-arrhythmics there may be a delayed absorption of mexiletine.

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.

4.6 Pregnancy and lactation

Pregnancy and lactation: There is 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. From theoretical considerations methadone is likely to be excreted in breast milk.

4.7 Effects on ability to drive and use machines

Methadone can produce drowsiness and clouding of consciousness; patients should therefore be warned not to drive or use machines while taking the drug.

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 particularly in ambulant patients. Nausea and vomiting appear to be more frequent after oral administration than after injection.

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.

4.9 Overdose

The cardinal signs of methadone overdose are coma, depressed respiration, pinpoint pupils, hypotension and pulmonary oedema. 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 other supportive measures, and the administration of a specific opioid antagonist preferably naloxone given in a dose of 0.4 mg by intravenous injection repeated 2 or 3 times after 2 to 3 minutes. Reversal of coma and respiratory depression is seen within 2 minutes of naloxone administration. Naloxone should be administered to children in doses of 5 to10 microgram per kilogram body weight and to neonates in doses of 10 microgram per kilogram body weight. 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.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

The principal properties of methadone are its effective analgesic activity, its efficacy by the oral route, its extended duration of action in supporting withdrawal symptoms in physically dependant individuals, and its tendency to show persistent effects on repeated dosing. After parenteral administration to man, a single dose of methadone is an effective analgesic equal in potency and duration of action to morphine. However, miotic and respiratory depressant effects can be detected for more than 24 hours and on repeated administration sedation is seen in some patients. Effects on coughing and the secretion of pituitary hormones are qualitatively similar to those of morphine. Methadone increases intestinal tone, diminishes the amplitude of contraction and produces a marked decrease in propulsive activity. It is constipating and causes biliary tract spasm.

5.2    Pharmacokinetic properties

Appreciable concentrations of methadone can be found in the plasma within 10 minutes after its subcutaneous injection. It is also well absorbed from the gastrointestinal tract, being detected in plasma within 30 minutes and reaching peak concentrations at about 4 hours after oral ingestion. At therapeutic doses, methadone is approximately 90% bound to plasma proteins. Peak concentrations occur in the brain within 1 or 2 hours after subcutaneous or intramuscular administration, and this correlates well with the intensity and duration of analgesia.

Methadone undergoes extensive biotransformation in the liver. The major metabolites, the results of n-demethylation and cyclization to form pyrrolidines and pyrroline, are excreted in the urine and the bile along with small amounts of unchanged drug. The amount of methadone excreted in the urine is increased when the urine is acidified. The half life of methadone is about 1 to 1.5 days.

Methadone appears to be firmly bound to protein in various tissues, including brain. After repeated administration there is gradual accumulation in tissues. When administration is discontinued, low concentrations are maintained in plasma by slow release from extravascular binding sites. This process probably accounts for the relatively mild but protracted withdrawal syndrome.

5.3    Preclinical safety data

There are no preclinical data of relevance to the prescriber which are additional to that in other sections of the SmPC.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Lactose EP Starches EP Gelatin BP Glycerol EP

Magnesium stearate EP

6.2    Incompatibilities

None known

6.3    Shelf life

5 years

6.4    Special precautions for storage

Store below 25°C.

6.5    Nature and contents of container

Amber glass bottles with low density polyethylene snap-fit closures (pack size 100).

PVC/Aluminium foil blister packs (pack size 50).

6.6    Special precautions for disposal

No special instructions.

7    MARKETING AUTHORISATION HOLDER

Macarthys Laboratories Ltd

Trading style: Martindale Pharmaceuticals

Bampton Road

Harold Hill

Romford RM3 8UG

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 01883/0062

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

12/03/2009

10 DATE OF REVISION OF THE TEXT

30/04/2014