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Qualitative and quantitative composition	Each ml contains 10mg of Methadone Hydrochloride
Pharmaceutical form	Sterile solution for injection Clear, colourless Solution

1: Clinical particulars

1.1 Therapeutic indications

The treatment of opioid drug addiction as a narcotic abstinence syndrome suppressant (substitution or maintenance therapy). This should be part of a broader treatment programmed including regular treatment reviews and must be supervised by specialist services. Treatment of moderate to severe pain as an alternative to morphine.

1.2 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 minimize the risk of addiction and drug withdrawal syndrome. 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

Adults

In the treatment of opioid drug addiction.

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. Providing a dosage schedule is difficult as it is largely subjective based on the addict’s reported drug use and a clinical assessment of their dependence. A cautious approach is usually adopted starting at a low dose and following with incremental increases as judged appropriate bearing in mind the general health of the patient.

In the treatment of moderate to severe pain

Usually 5 – 10mg every 6 – 8 hours although doses should be adjusted according to response. In prolonged use it should not be administered more than twice daily.

Elderly and debilitated patients

In the case of the elderly or ill patients, repeated doses should be given with extreme caution due to the long plasma half-life. There may be a greater risk of respiratory depression, with or without any associated renal or hepatic impairment in this age group.

Paediatric population

As methadone has not been studied in children, it should not be used in children under the age of 16 years until further data becomes available

Hepatic impairment

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

Method of administration

Sterile solution for subcutaneous or intramuscular injection. If repeated doses are required the intramuscular route should be used. Methadone 10mg at Shopmethadone.com

The intramuscular route is preferred when repeated administration is required. Volumes greater than 2ml (20mg) may need to be given in divided doses at different sites especially at shopmethadone.com

1.3. Contraindications

• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

• Patients with respiratory depression and obstructive airways disease.

• Use during an acute asthma attack.

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

• Phaeochromocytoma. Opiates may induce the release of endogenous histamine and stimulate catecholamine release.

• Risk of paralytic ileus.

• Comatose patients.

1.4 Special warnings and precautions for use

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

Drug dependence, tolerance and potential for abuse

Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). 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 continuing opioid substitution therapy should be reviewed regularly.

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.

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. 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).

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.

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.

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.

Cardiac effects

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.

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.

Pregnancy and risks to the neonate

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

Methadone should not be withdrawn abruptly and infants require careful monitoring for signs of respiratory depression and/or opioid withdrawal.

Hepatic impairment

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

Renal impairment

Reduce doses to avoid increased and prolonged effect, increased cerebral sensitivity.

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.

Hypoglycaemia

Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation.

Other warnings

Methadone 10mg 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.

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

The drug should be used with caution in elderly or debilitated patients due to its long half-life. It should also be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, biliary tract disorders, inflammatory or obstructive bowel disorders or myasthenia gravis.

Local reactions at the site of injection can occur and therefore these sites should be inspected regularly. Injections may be painful.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:

Concomitant use of Methadone 10mg/ml Solution for injection Physeptone 10mg/ml Solution for injection 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 10mg/ml Solution for injection

Physeptone 10mg/ml Solution for injection 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.

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

Methadone is metabolised by the liver cytochrome P450 isoenzymes including CYP 3A4. CYP 1A and CYP 2D6. Interactions are likely with enzyme inhibitors or inducers.

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).

Monoamine Oxidase Inhibitors:

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

Opioid agonists:

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

Opioid antagonists:

Naloxone and naltrexone antagonize the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms. Similarly, buprenorphine and pentazocine may precipitate withdrawal symptoms.

CNS drugs:

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

There is an increased risk of ventricular arrhythmias when methadone is given with the CNS stimulant, atomoxetine.

Alcohol:

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

Antiviral Drugs used in HIV:

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

Antibacterials:

Reduced plasma levels and increased urinary excretion of methadone can occur with concurrent administration of rifampicin. Adjustment of the dose of methadone may be necessary. Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to the inhibition of CYP1A2 and CYP3A4. Reduced serum concentrations of ciprofloxacin may occur. Erythromycin theoretically may increase methadone levels due to decreased methadone 10mg metabolism. Rifabutin may decrease methadone levels due to increased metabolism.

Anticonvulsants:

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

Barbiturates:

May stimulate hepatic enzymes that increase methadone metabolism, reducing methadone 10mg levels. There may be increased sedation and additive CNS depression.

Cyclizine and other sedating antihistamines:

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

Fluconazole, ketoconazole and voriconazole:

May raise methadone levels, due to decreased methadone metabolism.

Reducing the dose of methadone should be considered.

Grapefruit Juice:

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

Cimetidine:

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

Antimuscarinics:

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

Drugs affecting gastric emptying:

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

pH of urine:

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

Effects of methadone on other drugs:

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

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.

The hypnotic effect of sodium oxybate may be enhanced by opioid analgesics; concomitant use should be avoided.

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.

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 10mg 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.

1.6. Fertility, pregnancy and lactation

Pregnancy:

There is inadequate evidence of safety in human pregnancy.

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

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

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

Breast-feeding:

Methadone 10 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. Specialized care from obstetric and pediatric staff with experience in such management is required.

1.7 Effects on ability to drive and use machines

Patients should not drive or use machines while taking methadone 10mg .

Methadone may cause drowsiness and reduce alertness and the ability to drive after the administration of methadone.

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

1.8 Undesirable effects

Methadone is associated with undesirable effects similar to other opioid analgesics. There are no modern clinical studies available that can be used to determine the frequency of undesirable effects. Therefore, all the undesirable effects listed are classed as “frequency unknown”.

Endocrine Disorders:

Hyperprolactinaemia.

Psychiatric Disorders:

Confusion, mood change including euphoria and dysphoria, hallucinations, restlessness, sleep disturbances. Drug dependence.

Nervous System Disorders:

Drowsiness, dizziness, vertigo.

Eye Disorders:

Dry eyes, visual disturbances such as miosis.

Cardiac Disorders:

Bradycardia, tachycardia, palpitations, QT prolongation, torsades de pointes.

Vascular Disorders:

Orthostatic hypotension.

Respiratory, Thoracic & Mediastinal Disorders:

Gastrointestinal Disorders:

Nausea, vomiting (particularly at the start of treatment), constipation, biliary spasm, dry mouth.

Skin & Subcutaneous tissue Disorders:

Sweating, facial flushing, rashes (urticaria, pruritus), oedema.

Musculoskeletal, Connective Tissue & Bone Disorders:

Muscle rigidity.

Renal & Urinary Disorders:

Micturition difficulties, urinary retention, ureteric spasm

Metabolism and nutrition disorders SOC:

Hypoglycaemia.

Reproductive System & Breast Disorders:

Decreased libido, dysmenorrhoea, amenorrhoea, sexual dysfunction

General & Administration Site Disorders:

Hypothermia, drug withdrawal syndrome.

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.

1.9 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:

Similar to those for morphine.

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

In severe overdosage, apnoea, circulatory collapse, pulmonary oedema, cardiac arrest and death may occur.

Management:

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

A patent airway must be established with assisted or controlled ventilation. Narcotic antagonists may be required if there is evidence of significant respiratory or cardiovascular depression. Methadone 10mg

However, treatment with these antagonists must be repeated as necessary because of the longer duration of depressant activity of methadone (36 to 48 hours) compared to the antagonists (1 to 3 hours).

Nalorphine or Levallorphine should be given intravenously as soon as possible and repeated every 15 minutes if necessary. In a person addicted to narcotics, administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome.

In such cases, use of an antagonist should be avoided unless there is serious respiratory depression when they should be administered with great care.

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

2. Pharmacological properties

2.1 Pharmacodynamic properties

Pharmacotherapeutic group: Diphenylpropylamine derivatives.

ATC code N07BC02.

Methadone is a drug of addiction and repeated administration can result in dependence and tolerance. Cross-tolerance with other opioids can occur.

It is a synthetic opioid analgesic similar to morphine although less sedative. It acts on the CNS system and smooth muscles via the peripheral nervous system. Methadone 10mg

The analgesic effect of methadone occurs about 10 to 20 minutes following parenteral administration. Miosis and respiratory depression can occur for more than 24 hours after a single dose.

Methadone also reduces heart rate, systolic blood pressure and body temperature. Sedation is seen in some patients receiving repeated doses and sudden cessation of treatment can result in withdrawal symptoms.

Like morphine, it also has effects on bowel motility, biliary tone and secretion of pituitary hormones as well as on cough suppression. Methadone 10mg also causes the release of histamine from mast cells resulting in a number of allergic-type reactions.

2.2 Pharmacokinetic properties

Absorption

Methadone is rapidly absorbed following intramuscular or subcutaneous injection, however there are wide inter-individual variations.

Distribution

Methadone is widely distributed in the tissues, diffuses across the placenta and is excreted in breast milk. It is extensively protein bound.

Biotransformation

It is metabolized in the liver (forming inactive metabolites) and excreted via the bile and urine.

Elimination

Urinary excretion is pH-dependent, the lower the pH the greater the clearance.

Methadone has a prolonged half-life (15 to 40 hours) and can accumulate on repeated administration. Methadone 10mg

2.3 Preclinical safety data

No additional data of relevance to the prescriber.

3. Pharmaceutical particulars