This information is intended for use by health professionals

1. Name of the medicinal product

Methadone Mixture DTF 1mg/ml

Physeptone Mixture

2. Qualitative and quantitative composition

Each ml contains methadone hydrochloride 1mg.

Excipients with known effect:

Sunset yellow (E110) 0.008mg/ml, tartrazine (E102) 0.07mg/ml, demineralised liquid sucrose 441.5mg/ml.

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

For the full list of excipients, see section 6.1.

3. Pharmaceutical form

A clear bright yellowish 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

Posology

Addiction:

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.

Elderly

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

Paediatric population

Not recommended (see section 4.3)

Method of administration

For oral administration.

4.3 Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.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 ( including drug induced gastrointestinal hypotonia).

• 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)

• Patients dependent on non-opioid drugs.

• Phaeochromocytoma

4.4 Special warnings and precautions for use

Caution should be exercised in patients with hepatic dysfunction or renal dysfunction.

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

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 possibly death.

Tolerance and dependence of the morphine type may occur.

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 and may exacerbate asthma due to histamine release

Hepatic disorders

Caution as methadone may precipitate porto-systemic encephalopathy in patients with severe liver damage.

As with other opioids, methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.

Biliary tract disorders.

Paediatric population

As there is a risk of greater respiratory depression in neonates and because there are currently insufficient published data on the use in children, methadone is not recommended in those under 16 (See sections 4.2, 5.2).

There are reports of neonates exposed to methadone during pregnancy developing visual disorders, in particular, nystagmus. The causal relationship to methadone in isolation has not been established as factors such as other drugs taken during pregnancy e.g. benzodiazepines, intake of alcohol, and drugs used to treat neonatal abstinence syndrome e.g. phenobarbital, could play a role in the adverse reactions seen.

Further warnings

Babies born to mothers receiving methadone may suffer withdrawal symptoms.

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

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.

Caution should be exercised in patients who are concurrently taking CNS depressants.

Excipient warnings;

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

Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrose-isomaltase insufficiency should not take this medicine. Contains 441.5mg/ml demineralised liquid sucrose, i.e. 26.49g 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

MAOI's:

The concurrent use of MAOI's is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone.

CNS depressants:

Anaesthetics, hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole), anxiolytics, sedatives, barbiturates, phenothiazines, some other major tranquillizers and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly. (See 4.4 Special warnings and precautions for use).

Antipsychotics may enhance the sedative effects and hypotensive effects of methadone.

Methadone may increase desimipramine levels by up to a factor of two.

There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.

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

Histamine H2 Antagonists:

Histamine H2 antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action

Antibacterials

Rifampicin: 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.

Ciprofloxacin: Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to inhibition of CYP 1A2 and CYP 3A4. Reduced serum concentrations of ciprofloxacin may occur. Concomitant use may lead to sedation, confusion and respiratory depression.

Erythromycin: Theoretically this may increase methadone levels due to decreased methadone metabolism.

Antifungals: e.g. Fluconazole ,voricanozole and ketoconazole: May raise methadone levels, due to decreased methadone metabolism.

Anticonvulsants (Phenytoin, Phenobarbital, Carbamazepine and Primidone):

Induces the metabolism of methadone and there may be a risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.

pH of urine:

Drugs that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH.

Opioid Agonist Analgesics:

Additive CNS depression, respiratory depression and hypotension

Opioid antagonists:

Naloxone and naltrexone antagonises 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.

Antiretroviral Agents such as Nevirapine, Efavirenz, Nelfinavir, Ritonavir, Abacavir:

Based on the known metabolism of methadone, these agents may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Methadone may increase the plasma concentration of zidovudine. Narcotic withdrawal syndrome has been reported in patients treated with some retroviral agents and methadone concomitantly.

Methadone maintained patients beginning antiretroviral therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly.

Cyclizine and other sedating antihistamines

May have additive psychoactive effects; antimuscarinic effects at high doses.

Other Drugs:

Methadone may have an effect on other drugs as a consequence of reduced gastrointestinal motility.

Pregnancy Tests:

Methadone may interfere with the urine testing for pregnancy.

Cytochrome P450 3A4 inhibitors:

Methadone clearance is decreased when coadministered with drugs which inhibit CYP3A4 activity, such as some antiHIV agents, macrolide antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

St. John's Wort:

May lower plasma concentrations of methadone.

Grapefruit Juice:

There are several anecdotal reports of raised methadone levels due to decreased methadone metabolism.

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/metoclopramide on gastrointestinal activity.

Antiarrhythmics:

Methadone delays the absorption of mexiletine.

Methadone and QT interval prolongation

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. Please refer to Section 4.4.

4.6 Fertility, pregnancy and lactation

There is no evidence of safety in human pregnancy. A careful risk/benefit assessment should be made before administration to pregnant women because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, methadone has not been associated with congenital malformations.

It may be necessary to increase the dose of methadone if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy.

During labour there is a risk of gastric stasis and inhalation pneumonia in the mother and foetal distress. Methadone should not be used in labour (see 4.3 Contraindications).

Lactation:

Methadone is excreted in breast milk. Specialist care for obstetric and paediatric staff with experience in such management is required. If breast feeding is considered, the dose of methadone should be as low as possible and the infant monitored to avoid sedation. Breastfed infants may develop physical dependence and exhibit withdrawal symptoms.

Reports of visual disorders have been reported in neonates following exposure to methadone during pregnancy. However, other factors have also been present and a definitive causal link to methadone has not been established (see section 4.4).

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

The adverse effects of methadone are generally the same as with other opioids, most commonly nausea and vomiting, which are observed in approximately 20% of the patients who undergo methadone outpatient treatment, where the medicinal control is often unsatisfactory.

The most serious adverse effect of methadone is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest have occurred.

Adverse reactions listed below are classified according to frequency and system organ class. These reactions are more frequently observed in non opioid tolerant individuals. Frequency groupings are defined according to the following convention: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

System organ class (MedDRA)

Frequency

Adverse event

Endocrine disorders

Not known

Hyperprolactinaemia

Psychiatric disorders

Common

Euphoria, hallucinations

Uncommon

Dysphoria, dependence, agitation, insomnia, disorientation, reduced libido

Nervous system disorders

Common

Sedation

Uncommon

Headache, syncope

Eye disorders

Common

Blurred vision, miosis, dry eyes

Not Known

Nystagmus

Ear and labyrinth disorders

Common

Vertigo

Cardiac disorders

Rare

Bradycardia, palpitations, cases of prolonged QT interval and torsade de pointes have been reported, especially with high doses of methadone.

Vascular disorders

Uncommon

Facial flush, hypotension

Respiratory, thoracic and

mediastinal disorders

Uncommon

Pulmonary oedema, exacerbation of asthma, dry nose, respiratory depression particularly with large doses,

Gastrointestinal disorders

Very common

Nausea, vomiting

Common

Constipation

Uncommon

Xerostomia, glossitis

Hepatobiliary disorders

Uncommon

Bile duct dyskinesia

Skin and subcutaneous tissue disorders

Common

Transient rash, sweating

Uncommon

Pruritis, urticaria, other rash and in very uncommon cases bleeding urticaria

Renal and urinary disorders

Uncommon

Urinary retention, antidiuretic effect

Reproductive system and breast disorders

Uncommon

Reduced potency, galactorrhoea, dysmenorrhoea and amenorrhoea

General disorders and administration site conditions

Common

Fatigue, drowsiness

Uncommon

Oedema of the lower extremities, asthenia, oedema, hypothermia

Investigations

Common

Weight increase

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

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. Pharmacological properties
5.1 Pharmacodynamic properties

ATC code: N07BC02

Pharmacotherapeutic group: (Nervous system, other nervous system drugs, drugs used in addictive disorders, methadone).

Methadone is a strong opioid agonist with actions predominantly at the µ receptor. The analgesic activity of the race mate is almost entirely due to the 1-isomer, which is at least 10 times more potent as an analgesic than the d- isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the K and δ opiate receptors. These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect on the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the oculomotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with pA2 value similar to its antagonism of morphine. Like many basic drugs, Methadone enters mast cells and releases histamine by a non-immunological mechanism. It causes a dependence syndrome of the morphine type

5.2 Pharmacokinetic properties

Methadone is one of the more lipid soluble opioids, and is well absorbed from the gastro-intestinal tract, but undergoes fairiy extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in lung, liver and kidneys being much higher than in blood. The phannacokinetics of Methadone are unusual, in that there is extensive binding to tissue proteins and fairiy slow transfer between some parts of this tissue reservoir and the plasma. With an intramuscular dose of 10 mg, a peak plasma concentration of 75 µg per litre is reached in one hour. With regular oral doses of 100-120 mg daily, plasma concentrations rise from trough levels of approximately 500 µg/L to a peak of about 900 µg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral Methadone, without any relation to symptoms. Methadone is secreted into sweat and found in saliva and in high concentration in gastric juice. The concentration in cord blood is about half the maternal level.

The half life after a single oral dose is 12-18 (mean 15) hours, partly reflecting distribution into tissue stores, as well as metabolic and renal clearance. With regular doses, the tissue reservoir is already partly filled, and so the half life is extended to 13-47 (mean 25) hours reflecting only clearance. In the first 96 hours after administration, 15-60% can be recovered from the urine, and as the dose is increased so a higher proportion of unchanged Methadone is found there. Acidification of the urine can increase the renal clearance by a factor of at least three and thus appreciably reduce the half time of elimination.

5.3 Preclinical safety data

There are no preclinical data of relevance to the prescriber, which are additional to those already included in other sections of the SmPC

6. Pharmaceutical particulars
6.1 List of excipients

Demineralised liquid 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.

Not all pack sizes may be marketed

6.6 Special precautions for disposal and other handling

Methadone is controlled under the Misuse of Drugs Act 1971 (Schedule 2).

Any unused product or waste material should be returned to the pharmacy or doctor for disposal.

7. Marketing authorisation holder

Macarthys Laboratories Ltd

T/A Martindale Pharma

Bampton Road,

Harold Hill,

Romford,

RM3 8UG

United Kingdom

8. Marketing authorisation number(s)

PL 01883/0018

9. Date of first authorisation/renewal of the authorisation

Date of first authorisation: 20 January 1983

10. Date of revision of the text

29/06/2017