SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Metharose Sugar Free Green 1mg/1ml Oral Solution Methadone Hydrochloride Sugar Free 1mg/1ml Oral Solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Methadone Hydrochloride Ph.Eur 1mg/1ml

3 PHARMACEUTICAL FORM

Green solution for oral administration.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

For use in the treatment of opioid drug addictions (as a narcotic abstinence syndrome suppressant).

For use as an analgesic for moderate to severe pain.

4.2 Posology and method of administration

For oral administration only.

Addiction:

Adults:    Initially 10 - 20mg per day, increasing by 10 - 20mg per day until there

are no signs of withdrawal or intoxication. The usual dose is 40 -60mg per day. The dose is adjusted according to the degree of dependence with the aim of gradual reduction.

Elderly:    In the case of elderly or ill patients repeated doses should only be given

with extreme caution.

Children:    Not recommended for children.

Pain:

Adults:    Usual single dose, 5 to 10mg orally. Owing to its long plasma half

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

Elderly:    Use caution with repeated dosage in elderly and ill patients.

Children:    Not suitable.

4.3 Contraindications

Respiratory depression, obstructive airways disease. Use during an acute asthma attack is not recommended.

Concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them.

Patients dependent on non-opioid drugs.

Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression.

Methadone is not suitable for children.

Known hypersensitivity to methadone or any ingredients in the medicine.

Raised intracranial pressure or head injury.

Phaeochromocytoma.

Risk of paralytic ileus (including drug induced gastrointestinal hypotonia).

4.4. Special warnings and precautions for use

Caution should be exercised in patients with hepatic dysfunction or renal dysfunction, hypothyroidism or prostatic hypertrophy.

In the case of the elderly or ill patients repeated dose 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). It 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 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.

Neonates/children

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 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.

Methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.

Cases of QT interval prolongation and torsades 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 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.

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

Excipient Warnings

This medicine contains parahydroxybenzoates. These may cause allergic reactions (possibly delayed).

Liquid maltitol - patients with a rare hereditary problem of fructose intolerance should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

MAPI's:

The concurrent use of MAPI’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 ^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.

Fluconazole 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.

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 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).

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 gastro-intestinal 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. Breast-fed 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

This may be severely affected during and after treatment with methadone as it may cause drowsiness and reduce alertness. The time after which such activities may be safely resumed is extremely patient dependent 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:

-    The medicine has been prescribed to treat a medical or dental problem and

-    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

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 out-patient 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
Blood and lymphatic system disorders	Not known	Reversible thrombocytopenia has been reported in opioid-dependent patients with chronic hepatitis.
Metabolism and nutrition disorders	Common	Fluid retention
	Not known	Anorexia, hypokalaemia, hypomagnesaemia
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
Endocrine disorders	Not known	Raised prolactin levels with long-term administration

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

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, apnoea, circulatory collapse, cardiac arrest and death may occur.

Treatments: 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 to 48 hours), whereas antagonists act for 1 to 3 hours, so that treatment with the latter must be repeated as needed. An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression. The administration of Naloxone is advised.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. In a person physically dependent 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 strong opioid agonist with actions predominantly at the p receptor. The analgesic activity of the racemate is almost entirely due to the l-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 5 opiate receptors.

These cough actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect of 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 antiantagonism of Morphine. Like many basic drugs Methadone enters most 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 fairly extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in the lung, liver and kidneys being much higher than in blood. The pharmacokinetics of Methadone are unusual, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. With an intramuscular dose of 10mg, a peak plasma of 75pg/L is reached in one hour. With regular oral doses of 100 - l20mg daily, plasma concentrations rise from trough levels of approximately 500 pg/L to a peak of about 900pg/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 in sweat and found in saliva and in high concentrations 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 hours (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 life of elimination.

5.3 Preclinical safety data

Not applicable.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene Glycol	Ph.	Eur
Methyl Hydroxybenzoate	Ph.	Eur
Propyl Hydroxybenzoate	Ph.	Eur
Liquid Maltitol	Ph.	Eur
Caramel E150
Patent Blue V (E131)
Purified Water	Ph.	Eur

6.2 Incompatibilities

None known.

6.3. Shelf life

Amber (type III) glass bottle: 24 months

HDPE bottle: 24 months unopened; 1 month opened

6.4 Special precautions for storage

Store at or below 25°C. Protect from light.

6.5 Nature and contents of container

Glass bottle pack

Bottle:    Amber (type III) glass

Capacities:    50ml, 100ml and 500ml

Closure:    HDPE, EPE wadded, tamper evident, child resistant closure

Plastic bottle pack

Bottle:    HDPE

Capacities:    500ml, 2500ml and 5000ml

Closures:    HDPE, EPE wadded, tamper evident, child resistant closure

(for 500ml)

HDPE, LDPE wadded, tamper evident closure (for 2500ml and 5000ml bottles)

Not all pack sizes may be marketed.

6.6 Instructions for use/handling

Keep out of the reach of children.

7 MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8    MARKETING AUTHORISATION NUMBER(S)

PL 00427/0113

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

3 June 1998

10 DATE OF REVISION OF THE TEXT

17/03/2016