4.1. Therapeutic indications

The treatment of opioid drug addiction as a narcotic abstinence syndrome suppressant.

4.2. Posology and method of administration

Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with methadone in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4). The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).

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 60 - 120mg/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

Opioid Use Disorder (abuse and dependence)

Methadone is an opioid analgesic and is highly addictive in its own right. 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.

As with other opioids, tolerance, physical, and/or psychological dependence may develop upon repeated administration of methadone.

Abuse or intentional misuse of Methadone/ Physeptone Mixture DTF 1mg/ml may result in overdose and/or death.

The risk of developing Opioid Use Disorder is increased in patients with a personal or a family history (parents or siblings) of substance use disorders (including alcohol use disorder), in current tobacco users or in patients with a personal history of other mental health disorders (e.g., major depression, anxiety and personality disorders).

Patients will require monitoring for signs of drug-seeking behaviour (e.g., too early requests for refills). This includes the review of concomitant opioids and psycho-active drugs (like benzodiazepines). For patients with signs and symptoms of OUD, consultation with an addiction specialist should be considered.

Tolerance and dependence of the morphine type may occur, though it is said that methadone has a greater respiratory depressive effect and a lesser sedative effect than an equianalgesic dose of morphine. Toxic doses are highly variable, regular usage giving tolerance. Pulmonary oedema is a frequent corollary of overdosage whilst the dose-related histamine-releasing property of methadone may account for at least some of the urticaria and pruritis associated with methadone administration. Methadone may lead to an increase in intracranial pressure.

Adverse effects occurring more rarely in patients being treated for opioid addiction are as follows:

(a) A number of heroin patients have been reported to die within a few days of starting a methadone maintenance programme. Evidence of chronic persistent hepatitis was detected in ten heroin patients, who died within 2-6 days of starting methadone treatment. The mean prescribed dose at the time of death was about 60mg. It has been suggested that these sudden deaths may have arisen as a result of accumulation of methadone over several days resulting in death from complications such as cardiac arrhythmias or cardiovascular collapse as methadone, like dextropropoxyphene, has membrane stabilising activity and can block nerve conduction.

In view of the possibility of reduced clearance and raised plasma levels it is recommended that liver function tests and urine tests be carried out prior to maintenance and that lower starting doses of methadone be used.

(b) Evidence of hypoadrenalism has been found in chronic methadone patients. Findings consistent with both deficient ACTH production and subsequent secondary hypoadrenalism and methadone induced primary adrenal cortical hypofunction have been reported.

(c) Choreic movements involving the upper limbs, torso and speech mechanisms have been reported in a 25-year-old man receiving methadone hydrochloride maintenance therapy (45-60 mg/day) for 2 years. Discontinuation of methadone resulted in complete alleviation of the abnormal movements with no recurrence during the subsequent eight months.

(d) The function of the secondary sex organs was found to be markedly impaired in 29 male participants in a methadone maintenance programme. The ejaculate volume and seminal vesicular and prostatic secretions in subjects maintained on methadone (mean daily dose 66.9 mg) were reduced by over 50% compared to 16 heroin patients and 43 opioid-free controls. Serum testosterone levels were also approximately 43% lower in those on methadone. Whilst the sperm counts of the methadone users were more than twice the control level, reflecting a lack of sperm dilution by secondary sex organ secretion, the sperm motility of these subjects was markedly lower than normal.

Methadone should be given with caution to patients with asthma, convulsive disorders, depressed respiratory reserve, hypotension, hypothyroidism or prostatic hypertrophy. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.

Drug dependence, tolerance and potential for abuse

For all patients, prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g. major depression).

Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse.

A comprehensive patient history should be taken to document concomitant medications, including overthe- counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions.

Patients may find that treatment is less effective with chronic use and express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else.

Patients should be closely monitored for signs of misuse, abuse, or addiction.

The clinical need for analgesic treatment should be reviewed regularly.

Drug withdrawal syndrome

Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with methadone.

Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal. Tapering from a high dose may take weeks to months.

The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations. Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.

If women take this drug during pregnancy, there is a risk that their new-born infants will experience neonatal withdrawal syndrome.

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 the development of prolonged QT interval, e.g. in case of:

-history of cardiac conduction abnormalities,

- advanced heart disease or ischaemic heart disease, known history of QT prolongation

- 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.

Hypoglycaemia

Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see section 4.8 and section 4.9)

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Decreased Sex Hormones and increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.

Hyperalgesia

Hyperalgesia may be diagnosed if the patient on long-term opioid therapy presents with increased pain. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Sleep-related breathing disorders

Opioids can cause sleep-related breathing disorders including central sleep apnoea (CSA) and sleep-related hypoxemia. Opioid use increases the risk of CSA in a dose-dependent fashion. In patients who present with CSA, consider decreasing the total opioid dosage.

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).Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs: Concomitant use of methadone and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe methadone concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Paediatric population

Children are more sensitive than adults and intoxication may follow a low dose intake of methadone. To avoid such intoxication following dose administration by mistake, methadone should be kept in a safe place out of reach by children when located at home

This product contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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

The concomitant use of opioids and gabapentinoids (gabapentin and pregabalin) increases the risk of opioid overdose, respiratory depression, and death.

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 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.

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 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 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.

Sedative medicines such as benzodiazepines or related drugs:

The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Co-administration of Methadone with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of Methadone with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and Methadone are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.

Serotonergic drugs:

Serotonergic syndrome may occur with concomitant administration of methadone with pethidine, monoamine oxidase (MAO) inhibitors and serotonin agents such as Selective Serotonin Re-uptake Inhibitor (SSRI), Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) and tricyclic antidepressants (TCAs). The symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.

Cannabidiol

Concomitant administration of cannabidiol may result in increased plasma concentrations of methadone.

Fluconazole:

Fluconazole may raise methadone levels due to decreased methadone metabolism.

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 breastmilk at low levels. The decision to recommend breast-feeding should take into account clinical specialist advice and consideration should be given to whether the woman is on a stable maintenance dose of methadone and any continued use of illicit substances. If breastfeeding is considered, the dose of methadone should be as low as possible. Prescribers should advise breastfeeding women to monitor the infant for sedation and breathing difficulties and to seek immediate medical care if this occurs. Although the amount of methadone excreted in breast milk is not sufficient to fully suppress withdrawal symptoms in breast-fed infants, it may attenuate the severity of neonatal abstinence syndrome. If it is necessary to discontinue breastfeeding it should be done gradually, as abrupt weaning could increase withdrawal symptoms in the infant.

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

Unknown

Drug dependence (see section 4.4)

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,

Not Known

Central sleep apnoea syndrome

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, drug withdrawal syndrome

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Patients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.

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. Hypoglycaemia has been reported.

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.

Toxic leukoencephalopathy has been observed with methadone overdose.