SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Physeptone 50mg/ml Injection Methadone 50mg/ml Injection

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Methadone Hydrochloride 50mg/ml (50mg in 1ml)

For excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for injection.

Clear colourless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of opioid drug addiction as a narcotic abstinence syndrome suppressant.

The use of injectable methadone for this indication must be initiated by physicians with adequate expertise and experience in addiction therapy.

The use of methadone in opiate addiction must be part of a broader treatment programme, including regular treatment reviews, supervised by specialist services.

4.2    Posology and method of administration

Method of administration: intramuscular, subcutaneous or intravenous injection.

Volumes greater than 2ml given intramuscularly may need to be administered in divided doses at different sites.

Adults

Initially 10-20mg per day, increasing by 10-20mg per day, until there are no signs of withdrawal or intoxication.

Treatment must be managed by physicians with suitable experience.

The initial dose, safe dosage increments and the establishment of a dose that prevents withdrawal symptoms needs to be individualised. The degree of tolerance or neuroadaptation, additional consumption of oral methadone or other opiates, the cumulative potential of methadone treatment (as opposed to shorter acting opiates) and the general health of the patient must be taken into account. Typical doses for heavily-addicted users can be fatal to those without such neuroadaptation.

The usual dose of injectable methadone, when the addict is stabilised, may need to exceed 100mg daily to prevent symptoms of opiate withdrawal.

The aims of treatment should include reducing criminality and to improve patient’s health and social productivity.

Elderly and debilitated patients:

If repeated doses are required, use with caution due to the long plasma halflife.

There may be a greater risk of respiratory depression, with or without any associated renal or hepatic impairment, in this age group.

Children:

As methadone has not been studied in children it should not be used in children under the age of 16 years.

Liver disease:

In patients with severe liver damage the dose of methadone should be carefully controlled as there is a risk that methadone might precipitate porto-systemic encephalopathy.

Renal Impairment:

The dose may need to be reduced in moderate or severe renal impairment.

4.3 Contraindications

In the treatment of opioid addiction, the following are contraindicated:

Patients not already receiving methadone (on account of the high methadone concentration).

Known hypersensitivity to methadone.

Acute respiratory depression and obstructive airways disease.

Use during an acute asthma attack.

Concurrent administration with monoamine oxidase inhibitors, or within 2 weeks of discontinuation of treatment with them.

4.4 Special warnings and precautions for use

Addiction/tolerance/dependence:

Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2).

Methadone has a long half life and can therefore accumulate. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.

Tolerance and dependence may occur as with morphine.

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.

Withdrawal:

Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.

Respiratory depression:

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two. Asthma may be exacerbated due to histamine release. Concomitant treatment with other agents with CNS depressant activity is not advised due to the potential for CNS and respiratory depression (see also section 4.5 Interactions).

Pregnancy and risks to the neonate (see also section 4.6 Pregnancy and Lactation):

Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management. Methadone should not be withdrawn abruptly and infants will require careful monitoring for signs of respiratory depressions and / or opioid withdrawal.

Hepatic disorders:

Special care should be taken with patients with severe liver damage, as there is a risk that methadone might precipitate porto-systemic encephalopathy.

QT Interval Prolongation / Torsade De Pointes

Cases of QT interval prolongation and torsade de pointes have been reported

during treatment with methadone, particularly at high doses (>200 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,

family history of sudden death,

low serum magnesium,

hypokalaemia,

concomitant treatment with drugs that have a potential for QT-prolongation,

concomitant treatment with drugs which might cause electrolyte abnormalities, concomitant treatment with cytochrome P450 CYP 3A4 inhibitors (see section 4.5).

An ECG check should be performed, before treatment initiation and during the treatment, in case of administration of high doses of methadone (>150 mg/d) in patients with risk factors for QT interval prolongation or in case of concomitant treatment with drugs that have a potential for QT-prolongation

Other warnings:

Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries.

Methadone, as with other opiates, has the potential to increase intracranial pressure especially where it is already raised.

Avoid use in phaeochromocytoma. Opiates may induce the release of endogenous histamine and stimulate catecholamine release.

Children (under 16 years): Even at low doses methadone is a special hazard to children if ingested accidentally. Children under 6 months, particularly neonates may be more sensitive to respiratory depression than adults

Methadone should be used with caution in elderly or debilitated patients due to its long half-life.

Use with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, biliary tract disorders, inflammatory or obstructive bowel disorders or myasthenia gravis.

Local injection site reactions can occur therefore injection sites should be inspected regularly. Injections may be painful.

4.5 Interaction with other medicinal products and other forms of interaction

Methadone is metabolised in the liver by cytochrome P450 isoenzymes, including CYP34A, CYP1A and CYP2D6. Interactions are likely with enzyme inhibitors or inducers.

Monoamine Oxidase Inhibitors:

The concurrent use of MAOIs is contra-indicated (see also section 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone. Severe CNS excitation, delirium, hyperpyrexia, convulsions or respiratory depression is possible with concurrent use of opiates and MAOIs.

Opioid agonists:

Concomitant use of pethidine and other opioid agonist analgesics is not advised because of the potential for additive effects on CNS depression, respiratory depression and hypotension.

Opioid antagonists:

Naloxone and naltrexone antagonise the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms (see section 4.9 Overdose). Similarly, buprenorphine and pentazocine may precipitate withdrawal symptoms.

CNS depressants:

Concomitant use of other CNS depressants is not advised. Hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole) and anxiolytics may increase the general depressant effects of methadone. Antipsychotics may enhance the sedative and hypotensive effects of methadone. The plasma concentration of methadone may be increased by fluvoxamine and to a lesser extent, fluoxetine and theoretically other SSRIs due to decreased methadone metabolism. There may be increased sedation with tricylic antidepressants.

Alcohol:

Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.

Antiviral Drugs used in HIV:

Plasma concentrations of methadone may be reduced by the nucleoside reverse transcriptase inhibitor abacavir, and, the protease inhibitors nelfinavir and ritonavir (which are metabolised by cytochrome P450 enzyme systems) and the non-nucleoside reverse transcriptase inhibitors efavirenz and nevirapine, which may interact with a number of drugs metabolised in the liver.

Methadone may increase the plasma concentration of the nucleoside reverse transcriptase inhibitor zidovudine.

Antibacterials:

Reduced plasma levels and increased urinary excretion of methadone can occur with concurrent administration of rifampicin. Adjustment of the dose of methadone may be necessary. Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to the inhibition of CYP1A2 and CYP3A4. Reduced serum concentrations of ciprofloxacin may occur. Erythromycin theoretically may increase methadone levels due to decreased methadone metabolism. Rifabutin may decrease methadone levels due to increased metabolism.

Anticonvulsants:

Phenytoin and carbamazepine increase the metabolism of methadone. Adjustment of the dose of methadone should be considered.

Barbiturates:

May stimulate hepatic enzymes that increase methadone metabolism, reducing methadone levels. There may be increased sedation and additive CNS depression.

Cyclizine and other sedating antihistamines:

May have additive psychoactive effects; antimuscarinic effects at high doses. Fluconazole and ketoconazole:

May raise methadone levels, due to decreased methadone metabolism. Grapefruit Juice:

There have been anecdotal reports of raised methadone levels due to decreased methadone metabolism.

Cimetidine:

Retards oxidative hepatic drug metabolism by binding to microsomal cytochrome P450. The metabolism of methadone may be inhibited leading to increased plasma concentration and opiate action.

Antimuscarinics:

Concomitant antimuscarinics (e.g. atropine and synthetic anticholinergics) may increase the risk of severe constipation and/or urinary retention.

Drugs affecting gastric emptying:

Domperidone and metoclopramide may increase the speed of onset but not the extent of methadone absorption by reversing the delayed gastric emptying associated with opioids. Conversely, methadone may antagonise the effect of domperidone / metoclopromide on gastro-intestinal activity.

Drugs affecting urinary pH:

Drugs that acidify (e.g. ascorbic acid) or alkalinise (e.g. sodium bicarbonate) the urine may have an effect on clearance of methadone as it is increased at acidic pH, and decreased at alkaline pH.

Other drugs:

Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal motility.

Methadone may delay the absorption of the antiarrhythmic mexiletine. Methadone may increase desipramine levels by up to a factor of two.

4.6 Fertility, pregnancy and lactation

Pregnancy:

There is inadequate evidence of safety in human pregnancy.

Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management.

A careful risk/benefit assessment should be made before administration to pregnant women. Possible adverse effects on the foetus and neonate include respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths.

During labour there is a risk of gastric stasis and inhalation pneumonia in the mother.

Lactation:

Methadone is excreted into breast milk. Specialised care from obstetric and paediatric staff with experience in such management is required. If breastfeeding is considered, the dose of methadone should be as low as possible and the infant monitored to avoid sedation. Breast-fed infants may develop physical dependence and exhibit withdrawal symptoms.

4.7. Effects on Ability to Drive and Use Machines

Patients should not drive or use machines whilst taking methadone.

Methadone may cause drowsiness and reduce alertness and the ability to drive.

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 It was not affecting your ability to drive safely

4.8 Undesirable effects

Methadone is associated with undesirable effects similar to other opioid analgesics. Common side effects are nausea, vomiting, drowsiness, constipation, dizziness and euphoria, but the most serious hazard is respiratory depression (see also section 4.9 Overdose).

CNS effects:

Respiratory depression (larger doses), dependence, drowsiness, confusion, nausea and vomiting (particularly at the start of treatment) can occur. Changes of mood, including euphoria, and hallucinations are occasionally reported.

Effects on the autonomic nervous system:

Constipation, dry mouth, eyes and nose, miosis and less commonly micturition difficulties are observed.

Cardiovascular effects:

Bradycardia, palpitations and orthostatic hypotension can occur. Rare cases of QT prolongation and torsade de pointes have been reported (see Section 4.4).

Other undesirable effects;

Sweating, facial flushing, vertigo, headache, hypothermia, restlessness, decreased libido, dysmenorrhoea and amenorrhoea and rashes can also occur.

4.9 Overdose

Signs:

Similar to those for morphine.

Respiratory depression, extreme somnolence progressing to stupor or coma, cyanosis, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, bradycardia and hypotension have been observed.

In cases of severe overdose apnoea, circulatory collapse, pulmonary oedema, cardiac arrest and death may occur.

Treatment:

Treatment is supportive. Patients should be kept conscious wherever possible.

A patent airway must be established with assisted or controlled ventilation. Narcotic antagonists may be required if there is evidence of significant respiratory or cardiovascular depression. However, treatment with these antagonists must be repeated as necessary because of the longer duration of depressant activity of methadone (36 to 48 hours) compared to the antagonists (1 to 3 hours). Nalorphine or Levallorphine should be given intravenously as soon as possible and repeated every 15 minutes if necessary. In a person addicted to narcotics, administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. In such cases, use of an antagonist should be avoided unless there is serious respiratory depression when they should be administered with great care.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diphenylpropylamine derivatives. ATC code N02A C02.

Methadone acts in the treatment of opioid addiction as an abstinence syndrome suppressant and/or by blocking the effects of other intravenous opiates (narcotic blockade). Methadone is a drug of addiction and repeated administration can result in dependence and tolerance. Cross-tolerance with other opioids can occur.

Methadone is a synthetic opioid, similar to morphine although less sedating. It acts on the CNS system and smooth muscle via the peripheral nervous system.

The analgesic effect of methadone usually occurs 10 - 20 minutes following parenteral administration.

Respiratory depression and miosis can occur for more than 24 hours after a single dose. Methadone can also reduce body temperature, heart rate and systemic blood pressure. Sedation may be seen in some patients receiving repeated doses. Sudden cessation of methadone treatment can result in withdrawal symptoms.

In common with morphine methadone has affects on bowel motility, cough suppression and pituitary hormone release. It can also cause allergic type reactions as a result the release of histamine from mast cells.

5.2 Pharmacokinetic properties

Methadone is rapidly absorbed following parenteral administration although there are wide inter-individual variations.

Methadone is widely distributed throughout the tissues with higher concentrations in the liver, lungs and kidneys than the blood. It diffuses across the placenta and is excreted in breast milk.

Up to 90% with considerable inter-subject variation. Approximately 15% is bound to immunoglobulin and the remainder to albumin. Plasma : Whole blood ratio about 1:3.

Plasma clearance about 2ml/min/kg

Approximately. 5L/kg

Single dose 10-25 hours

Repeated doses 13-55 hours

In plasma, usually in the range of 0.05-1.0pg/ml.

During methadone maintenance treatment

considerable fluctuations may occur day to day.

Methadone is metabolised in the liver by cytochrome P450 isoenzymes, including CYP34A, CYP1A and CYP2D6, to form inactive metabolites. The main metabolic reaction is N-demethylation but other metabolic reactions occur and there are at least eight known metabolites. The main routes of excretion are via the bile and urine. Urinary excretion is pH dependent and is increased at acidic pH and decreased at alkaline pH.

On account of the prolonged half-life methadone may accumulate with repeated administration.

5.3 Preclinical safety data

No additional data of relevance to the prescriber.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Water for Injections.

6.2    Incompatibilities

No major incompatibilities, but do not mix with other medicinal products.

6.3    Shelf life

36 months

6.4    Special precautions for storage

Do not store above 25°C.

Keep container in the outer carton.

6.5    Nature and contents of container

Clear, colourless Type I glass ampoules.

Pack size: 10 x 1ml ampoules in a cardboard carton.

6.6    Special precautions for disposal

None

7    MARKETING AUTHORISATION HOLDER

Macarthys Laboratories Ltd t/a Martindale Pharmaceuticals Bampton Road Harold Hill Romford

Essex, RM3 8UG United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 01883/0064

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/12/2010

10 DATE OF REVISION OF THE TEXT

08/05/2015