Phymet DTF 1mg/ml Syrup

Package Leaflet Changes

2.          What you need to know before you use Phymet

Under the heading ‘Warnings and precautions’, added the subheading ‘Tolerance, dependence, and addiction‘, under which corresponding statements were added.

Added the new subheading ‘Sleep-related breathing disorders’, with the corresponding warning statements

Under ‘Other medicines and Phymet’, updated the statement regarding informing the doctor if taking the medicines in the following list, and added the following medicines to that list:

Medication to treat seizures (cannabidiol)

Medicines used to treat epilepsy, nerve pain or anxiety (gabapentin and pregabalin can increase the risk of opioid overdose, respiratory depression (breathing difficulties) and may be life-threatening).

3.          How to use Phymet

Added the following statements:

Always use this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

Before starting treatment and regularly during treatment, your doctor will discuss with you what you may expect from using Phymet DTF 1 mg/ml Syrup, when and how long you need to take it, when to contact your doctor, and when you need to stop it (see also if you stop taking Phymet DTF 1 mg/ml Syrup).

Under the subheading ‘If you take more Phymet than you should’, added the following statement ‘If you take too much Phymet you can experience brain disorder (known as toxic leukoencephalopathy)’

4.          Possible side effects

Updated the frequency category ‘Not known’ to ‘Frequency not known’, and added the following:

You can become dependent on Phymet (for more information see section 2 Warnings and Precautions)’ and ‘Sleep apnoea (breathing pauses during sleep)’

5.          How to store Phymet

Added the following:

Store this medicine in a safe and secure storage space, where other people cannot access it. It can cause serious harm and be fatal to people when it has not been prescribed for them

6 Contents of the pack & other information

Changed the date of revision from November 2020 to January 2022

SmPC Changes:

4.2        Posology and method of administration

Added the subheading ‘Treatment goals and discontinuation’ and added statements regarding consultation with the patient on the treatment strategies, durations and goals, the continued frequent contact between the physician and the patient for consideration of continued treatment, discontinuation or dose adjustment. Advice is included regarding the tapering off treatment when the patient no longer requires therapy with methadone. The following consideration was also added ‘In absence of adequate pain control, the possibility of tolerance and progression of underlying disease should be considered (see section 4.4)’.

4.4        Special warnings and special precautions for use

Removed the subheading ‘Addiction/Tolerance/Dependence’ and the statement ‘Tolerance and dependence may occur as with morphine’. These were replaced with the new subheading ‘Opioid Use Disorder (abuse and dependence)’ and statements were added regarding the tolerance, physical and/or psychological dependence that may develop upon repeated administration of methadone. Additional warnings were added regarding the agreement between the patient and physician on the treatment goals and discontinuation plan, the consequences and risk factors of Opioid Use Disorder and the mitigation that should be used to protect at risk of Opioid Use Disorder.

Added the subheading ‘Sleep-related breathing disorders’ with corresponding statements.

4.5        Interaction with other medicinal products and other forms of interaction

Added subheadings ‘Gabapentinoids’ and ‘Cannabidiol’, with respective warnings.

Added the subheading ‘Fluconazole and ketoconazole’ before the existing statement regarding these medicines.

4.8        Undesirable effects

Added ‘dependence’ with the frequency ‘not known’ under ‘Psychiatric disorders’.

Added ‘central sleep apnoea syndrome’ with the frequency ‘not known’ under ‘Respiratory, thoracic and mediastinal disorders’

4.9        Overdose

Added ‘Toxic leukoencephalopathy has been observed with methadone overdose.’

10 DATE OF REVISION OF THE TEXT

Changed from 16 December 2020 to 12 January 2023

Section 4.3:
• Introducing contraindications: obstructive airways disease, Phaeochromocytoma, patients dependent on non-opioid drugs and at risk of paralytic ileus
Section 4.4:
• Introducing warnings: hepatic and renal dysfunction
• Introducing warning: caution to be exercised in case elderly or ill patients in regard to repeated doses
• Introducing warning: exacerbation of asthma
• Introducing endocrinopathies warning
• Update to warning interaction with Grapefruit juice
• Introducing warnings: risks of respiratory depression and visual disturbances in neonates and children
Section 4.5
• Introducing warnings: interaction with phenobarbital, primidone, St John’s Wort, cyclizine and other sedating antihistamines, ciprofloxacin, rifampicin, erythromycin, fluconazole and ketoconazole. Inclusion of interactions with anaesthetics, hypnotics, anxiolytics, sedatives, tricyclic antidepressants, desimipramine and antidepressant drugs such as fluvoxamine and fluoxetine. Inclusion of warning for interaction with alcohol, Opioid Agonist Analgesics, Opioid antagonists and interference with pregnancy test.
• Inclusion of interaction with drugs affecting gastric emptying, antiarrhythmics and centrally acting alpha-adrenergic blockers
Section 4.6:
• Introducing potential risks in pregnancy including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. Addition of information about lack of association between methadone and congenital malformations. Addition of risk of gastric stasis, inhalation pneumonia in the mother and foetal distress during labour. Inclusion of statement regarding reports of visual disturbances in babies.
Section 4.7
• Addition of warning: reduction of alertness as an effect of methadone on ability to drive and use machines. Inclusion of information that physician must be the one who decides about time when such activities can be resumed
Section 4.8
• Introducing the following side effects
Common:
fluid retention, blurred vision, miosis (existing AE - moved from frequency not known), dry eyes, vertigo, transient rash, sweating (existing AE - moved from frequency very common), weight increase, euphoria (existing AE - moved from frequency not known), hallucinations
Uncommon:
dysphoria, dependence, agitation, insomnia, disorientation, reduced libido, headache, syncope (existing AE - moved from frequency not known), facial flush, hypotension (existing AE - moved from frequency rare), pulmonary oedema, exacerbation of asthma, dry nose, respiratory depression (existing AE - moved from frequency not known), glossitis, pruritis, urticaria, other rash and in very uncommon cases bleeding urticaria, oedema of the lower extremities, asthenia, oedema, hypothermia, drug withdrawal syndrome
Rare:
bradycardia, palpitations
Not known:
Reversible thrombocytopenia, anorexia, hypokalaemia, hypomagnesaemia, raised prolactin levels with long-term administration, hypoadrenalism, hypogonadism,
Section 4.9
• Update to section 4.9 Inclusion of serious symptoms of overdosage under symptoms section. Update to the treatment section and removal of treatment with naloxone.

Section 6.5 - minor update to the description of the replacement cap and deletion of the cap not in use.

Section 2:

• Addition of brilliant blue (E133), sodium benzoate (E211), glycerol and ethanol to the excipients with known effect.

Section 4.4:

• Inclusion of warning in relation to “coma and death” and instructions/ cautionary statement for caregivers in relation to the risk from concomitant use of sedative medicines such as benzodiazepines or related drugs.
• Update to warnings on adrenal insufficiency.
• Update to the warnings on decreased sex hormones.
• Addition of warning in relation to hypoglycaemia.
• Update to excipients warnings. Update to the maltitol and ethanol warnings. Addition of sodium benzoate, sodium and brilliant blue (E133) warnings.

Section 4.5

• Inclusion of CMDh recommended warning in relation to the concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs.
• Update to warnings on interaction between methadone and other serotonergic drugs. Update to section

Section 4.6

• Inclusion of warnings on the need for monitoring infants while breastfeeding.

Section 4.8

• Addition of hypoglycaemia as an AE under frequency not known
• Update to reporting of suspected adverse reactions section
   

Section 4.9

• Inclusion information about reported hypoglycaemia

Section 6.1

• Inclusion of information that Maltitol contains sorbitol
• Inclusion of information that Flavour spice contains ethanol

Section 4.2

·         Addition of sub section: Posology

·         Method of administration: text updated to ‘’for oral administration’’ instead of which may be administered orally

·         Addition of subsection – Method of administration

Section 4.3

·         Addition of ‘’MAOIs’’ for inhibitors

Section 4.4

·         Minor typo errors updated

·         Sub sections Opioids and CNS depressants, Serotonin syndrome & Adrenal insufficiency has been updated with minor changes.

·         Addition of warning regarding Grapefruit juice

Section 4.5

·         Addition of tranquillisers example and addition of Serotonergic drugs statement.

Section 4.6

·         Minor text has been updated in fertility section.

Section 4.8

·         Minor type errors updated and deletion of ‘’contraindications’’

Section 5.1

·         Addition of ‘’Pharmacotherapeutic group’’

Section 5.2

·         Older changed to Elderly

SPC 4.4 Special warnings and special precautions for use

·         Separated the sub-headings ‘Respiratory depression’ and ’Cardiac arrhythmias’ and added ‘Addiction/Tolerance’ to the subheading previously detailing ‘Dependence’.

·         Under the sub-heading ‘’Cardiac arrhythmias’, regarding the administration to patients at risk of development of prolonged QT interval, added warning that caution is required in cases of patients with hypokalaemia, patients with electrolyte imbalance or drugs likely to cause electrolyte imbalance, patients with family history of sudden death, patients who are taking other potentially arrythmogenic drugs, drugs that inhibit the cytochrome P450 isoenzyme CYP3A4, and added the advisory statement that ECG monitoring is recommended before starting methadone treatment in these patients, with a further test at dose stabilisation. ECG monitoring is also recommended before and at seven days after dose titration above 100 mg daily in patients without recognised risk factors.

·         Under the updated subheading ‘Addiction/Tolerance/Dependence’, updated the ‘dependence’ warning to include details of ‘Addiction’ and ‘Tolerance’.

·         Added the following circumstances that Methadone should be used with caution in the presence of hypotension, inflammatory or obstructive bowel disorders and/or myasthenia gravis.

SPC 4.5 Interaction with other medicinal products and other forms of interaction

·         Added interaction warnings regarding Histamine H2-antagonists, Ciprofloxacin, Drugs affecting gastrointestinal activity, Grapefuit juice and drugs that affect the pH of urine.

SPC 4.8 Undesirable effects

·         Added the side effects ‘syncope’ and ‘miosis’, with frequency ‘not known’.

·         Added the side effects ‘sexual dysfunction’, with frequency ‘not known’.

Minor editorial changes were made to SPC 4.2, 4.4, 4.5 and 4.8.

SPC #2:

Quantitatively listed the components of the excipient with known effect, maltitol solution.

SPC #4.2:

Updated dose instruction in the Opioid Addiction indication in line with best practice as defined in the Martindale methadone monograph – specifically recommending lower daily increases in methadone and sets a maximum weekly increase.

SPC #4.4:

Added excipient warning for maltitol solution and consolidated this in the same paragraph as the fructose intolerance warning.

SPC #4.7:

Added statement that ‘Phymet has moderate influence on the ability to drive and use machines’.

SPC #4.8:

Added the HPRA AE reporting details.

SPC #6.6:

Added the statement that ‘Any unused medicinal product or waste material should be disposed of in accordance with local requirements’.

4.4       Special Warnings and Special Precautions for Use

            Cardiac arrhythmias and respiratory depression

Deaths due to cardiac arrhythmias and respiratory depression may occur, particularly in patients receiving methadone for analgesia during treatment initiation or conversion from other opiods.

Respiratory depression is the major hazard associated with methadone treatment.  The peak depressive effects persist longer than peak analgesic effects, especially during the initial dosing period. Particular care should be taken during the dose initiation and adjustment period to minimise the risk of dose accumulation (see Section 4.2, Posology and Method of Administration).

Cases of QT interval prolongation and Torsade 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 of development of prolonged QT interval, e.g. in cases of:

·         Known history of QT prolongation,

·         Advanced heart disease,

·         Ischaemic heart disease and liver disease,

·         Concomitant treatment with drugs that have a potential for QT-prolongation.

Dependence

In common with all opioids, methadone has the potential to produce dependence of the morphine type.

Discontinuation of therapy

Discontinuation of therapy with opioid analgesics should be carried out gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms (see Section 4.8, Undesirable Effects).

Other

Methadone should be used with caution in the presence of the following:

·           hypothyroidism

·           adrenocortical insufficiency

·           hypopituitarism

·           prostatic hypertrophy

·           shock.

Extreme caution should be exercised when administering methadone to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.

Phymet DTF contains maltitol which may have a mild laxative effect and has a calorific value of 2.3kcal/g and glycerol which may cause headache, stomach upset and diarrhoea.

This medicine also contains small amounts of ethanol (alcohol), approximately 2mg/ml.

Fructose intolerance

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

Allergic Reactions

Changes in red

1.       TRADE NAME OF THE MEDICINAL PRODUCT

Phymet DTF 1mg/ml Syrup 1mg/ml

2.       QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains methadone hydrochloride 1mg.

Excipients: Sunset Yellow (E110) 0.0125 mg per ml

                  Methyl Parahydroxybenzoate (E218) 1.0 mg per ml

For a full list of excipients see section 6.1

4.2     Posology and Method of Administration

Adults

ANALGESIA

The usual initial dose is 5 to 10 mg methadone which may be administered orally. intramuscularly or subcutaneously.

Since rigid adherence to a dosage schedule may provide inadequate analgesia, subsequent doses should be adjusted according to individual patient response. However, doses administered more frequently than six to eight hourly are liable to cause accumulation with increasing sedation and respiratory depression. In chronic use methadone should not be administered more than twice daily.

Phymet DTF Syrup may be used in combination with non-narcotic analgesics to provide additive analgesia.

OPIOID ADDICTION

Dosing and duration should be individualised based on a careful evaluation of subjective and objective patient data, bearing in mind clinical status, including hepatic or renal function of the patient.

A daily dose of 10 to 20 mg of methadone hydrochloride by mouth may be given initially and increased as necessary by 10 to 20 mg daily until there are no signs of withdrawal or intoxication. After stabilisation, which can often be achieved with a daily dose of 40 to 60 mg, the dose of methadone is gradually decreased until total withdrawal is achieved. Some treatment schedules for opioid dependence involve prolonged maintenance therapy with methadone where the daily dose is adjusted carefully for the individual.

Children and adolescents aged less than 18 years

Phymet DTF Syrup is not recommended for use in this age group, since documented clinical experience has been insufficient to establish a suitable dosage regimen; furthermore, children are particularly sensitive to the respiratory and central nervous system depressant effects of methadone.

Elderly

Phymet DTF Syrup has a long plasma half life which may lead to accumulation, particularly if renal function is impaired (see Warnings and Precautions; Clinical Pharmacology).

In common with other opioids, methadone may cause confusion in this age group therefore, careful monitoring is advised (See section 4.4 and section 5.2).

Renal impairment

Phymet DTF Syrup should be used with caution in patients with renal dysfunction; the dosage interval should be increased to a minimum of eight hourly when the glomerular filtration rate (GFR) is 10 to 50 ml/minute and to a minimum of 12-hourly when the GFR is below 10 ml/minute.

Hepatic impairment

Particular care should be taken when Phymet DTF Syrup is to be used in patients with hepatic impairment as these patients metabolise methadone more slowly than normal patients.  Where not contraindicated, Phymet DTF Syrup should be given at less than the normal recommended dose and the patient's response used as a guide to further dosage requirements (see Contraindications section 4.3).

Cardiac repolarisation disorders

Methadone should be administered with particular caution to patients at risk of development of prolonged QT interval (see Contraindications and Warnings and Precautions section 4.4).

4.3     Contra-indications

Phymet DTF Syrup is contra-indicated in individuals who are hypersensitive to methadone or any of the excipients.

Phymet DTF Syrup, like other opioids, is contra-indicated in patients with respiratory depression, especially in the presence of cyanosis and excessive bronchial secretions.

Phymet DTF Syrup should not be given during an attack of bronchial asthma.

Phymet DTF Syrup is contra-indicated in the presence of acute alcoholism, head injury and raised intracranial pressure.

Phymet DTF Syrup is contra-indicated in individuals receiving monoamine oxidase inhibitors or within 14 days of stopping such treatment (see Interactions with Other Medicaments and Other Forms of Interaction section 4.5).

Phymet DTF Syrup, as with other opioids, is contra-indicated in patients with ulcerative colitis, since it may precipitate toxic dilatation or spasm of the colon.

As with all narcotic analgesics, Phymet DTF Syrup should not be administered to patients with severe hepatic impairment as it may precipitate hepatic encephalopathy (see Posology and Method of Administration section 4.2).

At the recommended dosages, Phymet DTF Syrup is contra-indicated in biliary and renal tract spasm.

Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression (see section 4.6).

Methadone is contraindicated in individuals with existing QT prolongation, including those with congenital long QT syndrome (see Warnings and Precautions).

4.4     Special Warnings and Special Precautions for Use

Deaths due to cardiac arrhythmias and respiratory depression may occur, particularly in patients receiving methadone for analgesia during treatment initiation or conversion from other opiods.

Respiratory depression is the major hazard associated with methadone treatment.  The peak depressive effects persist longer than peak analgesic effects, especially during the initial dosing period. Particular care should be taken during the dose initiation and adjustment period to minimise the risk of dose accumulation (see Section 4.2, Posology and Method of Administration).

In vivo and in vitro studies have demonstrated that methadone inhibits cardiac potassium channels and prolongs cardiac repolarisation (i.e. prolongs the QT interval).

Cases of QT interval prolongation and serious arrhythmia (Torsade de Pointes) have been observed reported during treatment with methadone and appear to be more common with higher doses. particularly at high doses (> 100 mg/d). Methadone should be administered with caution to patients at risk of development of prolonged QT interval, e.g. in cases of:

Methadone should be used with caution in the presence of the following:

·           hypothyroidism

·           adrenocortical insufficiency

·           hypopituitarism

·           prostatic hypertrophy

·           shock.

Extreme caution should be exercised when administering methadone to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.

Patients with rare hereditary problems of fructose intolerance should not take this medicine.

4.5     Interaction With Other Medicaments And Other Forms of Interaction

Methadone is metabolised by various cytochrome P450 (CYP450) enzymes.  Therefore, co-administration of drugs known to interfere with CYP450 enzymes may affect its clinical activity (see Clinical Pharmacology section 5.2).

Monoamine oxidase inhibitors (MAOIs) may prolong and enhance the respiratory depressant effects of methadone. Opioids and MAOIs used together may cause fatal hypotension and coma (see section 4.3).

Some compounds may increase the metabolism of methadone, e.g. rifampicin, phenytoin, carbamazepine, St John’s Wort, and antiretroviral agents used in the treatment of HIV infection (particularly nevirapine, efavirenz and some protease inhibitors).  This has the potential to result in withdrawal symptoms.

Some compounds may decrease the metabolism of methadone, e.g. fluconazole and some selective serotonin re-uptake  inhibitors (SSRIs), particularly fluvoxamine.  This may increase the likelihood of methadone toxicity.

Methadone clearance decreases in case of co-administration of methadone and drugs which inhibit CYP3A4 activity, such as some anti-HIV agents, macrolides antibiotics, cimetidine and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

methadone.

4.6     Pregnancy and Lactation

Pregnancy and Lactation

see Pre Clinical Safety Data

Fertility

Methadone does not appear to impair human female fertility.

Studies in men on methadone maintenance programmes have shown that methadone reduces serum testosterone and markedly depresses the ejaculate volume and sperm motility. The sperm counts of methadone subjects were twice that of controls but this reflected the lack of dilution from seminal secretions.

Pregnancy

There is insufficient evidence on which to determine the safety profile of methadone in pregnancy, therefore it should only be used where the benefits of a monitored methadone detoxification program outweigh the potential risks (see section 5.3).

Like other opiates, methadone crosses the placenta during pregnancy, and most neonates born to mothers on methadone maintenance will suffer from respiratory depression and neonatal abstinence syndrome if left untreated.

Abstinence syndrome may not occur in the neonate for some days after birth. Therefore in addition to initial monitoring for respiratory depression neonates should undergo prolonged monitoring for signs and symptoms of withdrawal.

Methadone is not recommended for use during labour because its prolonged duration of action increases the risk of respiratory depression in the neonate (see section 4.4).

Fertility

Methadone does not appear to impair human female fertility.

Studies in men on methadone maintenance programmes have shown that methadone reduces serum testosterone and markedly depresses the ejaculate volume and sperm motility. The sperm counts of methadone subjects were twice that of controls but this reflected the lack of dilution from seminal secretions.

4.8     Undesirable Effects

The following convention has been utilised for the classification of undesirable effects: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1000 and to <1/100); rare (≥1/10,000 and to <1/1000); very rare (≤ 1/10,000); not known (cannot be estimated from the available data).

Psychiatric disorders

Common: confusion#.

Not known: Euphoria has been reported at higher doses in tolerant subjects.

Cardiac Disorders

Very  Rare: ECG changes including QT prolongation and Torsade de Pointes. , usually in patients with risk factors or receiving high doses of methadone (see Warnings and Precautions).

Respiratory, thoracic and mediastinal disorders

Not known: Respiratory depression.

Hepatobiliary disorders

Not known: Methadone, in common with other opioids may cause spasm of the biliary tract (see Contraindications).

Skin and subcutaneous tissue disorders

Very common: sweating#.

Subcutaneous administration may cause local irritation.

Renal and urinary disorders

Common: Urinary retention or hesitancy.

Not known: Methadone, in common with other opioids may cause spasm of the renal tracts (see Contraindications).

Reproductive system and breast disorders

Not known: Prolonged use of methadone in men has been reported to be associated with the development of gynaecomastia and impaired fertility (see Pregnancy and Lactation).

6.       PHARMACEUTICAL PARTICULARS

6.1     List of Excipients

Glycerol

Methyl parahydroxybenzoate (E218)

Sodium benzoate (E211)

Lycasin 80/55

Flavour IFF 17.480.1831

Sunset yellow (E110)

Brilliant blue (E133)

Purified water

6.3     Shelf Life

24 months  2 years

6.5     Nature and Contents of Container

Bottle

Clear, 28 mm, type III, amber glass bottle with a nominal capacity of 500 ml.

Closure

28 mm, white Clic Loc, child resistant, Polypropylene closure with an .EPE/Saranex (LDPE/PVDC/LDPE) liner

or

28 mm, child-resistant, tamper evident, Polypropylene closure with an extruded foamed LDPE liner

Amber glass bottle with child-resistant cap.

Amber glass bottle with either a child resistant polypropylene cap with either a child resistant cap polypropylene cap with LDPE/PVDC/LDPE liner or a child-resistant, tamper evident, polypropylene cap with LDPE liner

Pack size: 500ml

4.4       Special Warnings and Special Precautions for Use

Deaths due to cardiac arrhythmias and respiratory depression may occur, particularly in patients receiving methadone for analgesia during treatment initiation or conversion from other opiods.

Respiratory depression is the major hazard associated with methadone treatment.  The peak depressive effects persist longer than peak analgesic effects, especially during the initial dosing period. Particular care should be taken during the dose initiation and adjustment period to minimise the risk of dose accumulation (see Section 4.2, Posology and Method of Administration).

In vivo and in vitro studies have demonstrated that methadone inhibits cardiac potassium channels and prolongs cardiac repolarisation (i.e. prolongs the QT interval). QT interval prolongation and serious arrhythmia (Torsade de Pointes) have been observed during treatment with methadone and appear to be more common with higher doses. Particular caution and careful monitoring is recommended in patients at risk of prolonged QT interval (e.g. cardiac hypertrophy, concomitant diuretic use, hypokalaemia, hypomagnesaemia), patients with a previous history of cardiac repolarisation prolongation, those taking medications affecting cardiac repolarisation or methadone metabolism, and in patients with an increased risk of arrhythmia (see Section 4.3, Contraindications and Section 4.5, Interactions).

Patients developing QT prolongation while on methadone treatment should be evaluated for modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism.

In common with all opioids, methadone has the potential to produce dependence of the morphine type.

Discontinuation of therapy with opioid analgesics should be carried out gradually in patients who may have developed physical dependence, to avoid precipitating withdrawal symptoms (see Section 4.8, Undesirable Effects Adverse Reactions).

Methadone should be used with caution in the presence of the following:

·         hypothyroidism

·         adrenocortical insufficiency

·         hypopituitarism

·         prostatic hypertrophy

·         shock.

Extreme caution should be exercised when administering methadone to patients with phaeochromocytoma, since aggravated hypertension has been reported in association with diamorphine.

In vivo and in vitro studies have demonstrated that methadone inhibits cardiac potassium channels and prolongs cardiac repolarisation (i.e. prolongs the QT interval). QT interval prolongation and serious arrhythmia (Torsade de Pointes) have been observed during treatment with methadone and appear to be more common with higher doses. Particular caution and careful monitoring is recommended in patients at risk of prolonged QT interval (e.g. cardiac hypertrophy, concomitant diuretic use, hypokalaemia, hypomagnesaemia), patients with a previous history of cardiac repolarisation prolongation, those taking medications affecting cardiac repolarisation or methadone metabolism, and in patients with an increased risk of arrhythmia (see Contraindications and Interactions).  Patients developing QT prolongation while on methadone treatment should be evaluated for modifiable risk factors, such as concomitant medications with cardiac effects, drugs which might cause electrolyte abnormalities, and drugs which might act as inhibitors of methadone metabolism.

4.9       Overdose

Symptoms and Signs

The symptoms and signs of overdosage with methadone parallel those for other opioids, namely profound respiratory depression, pin-point pupils, hypotension, circulatory failure and pulmonary oedema, and coma and death.

Mydriasis may replace miosis as asphyxia intervenes. Drowsiness, floppiness, pin-point pupils and apnoea have been reported in children.

Treatment

General supportive measures, including ECG monitoring, should be employed as required.

The specific opioid antagonist naloxone is the treatment of choice for the reversal of coma and the restoration of spontaneous respiration; the literature should be consulted for details of appropriate dosage. It should be noted that QT prolongation will not be reversed by naloxone.

In opioid dependent patients the administration of the recommended dose of an opioid antagonist may precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. The use of an opioid antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent patient the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.

Patients should be monitored closely for at least 48 h after apparent recovery in case of relapse, since the duration of action of the antagonist may be substantially shorter than that of methadone.

The use of other respiratory or central stimulants is not recommended.

Acidification of the urine will enhance urinary excretion of methadone.

Methadone is not dialysable by either peritoneal or haemodialysis.

6.5       Nature and Contents of Container

Amber glass bottle with child-resistant cap.

Amber glass bottle with either a child resistant polypropylene cap with LDPE/PVDC/LDPE liner or a child resistant, tamper evident, polypropylene cap with an LDPE liner.

Pack size: 500ml