SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methadone 10mg/ml Solution for Injection

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Methadone hydrochloride 10mg in 1ml For full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Solution for injection A clear and colourless solution

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Methadone injection may be used in the management of opioid dependence; as an analgesic for moderate to severe pain as an alternative to morphine.

Opioid dependence:

The use of injectable methadone for this indication must be initiated by physicians with adequate expertise and experience in addiction therapy.

The use of methadone in opiate addiction must be part of a broader treatment programme including regular treatment reviews and must be supervised by specialist services.

4.2 Posology and method of administration

Method of Administration: by intramuscular or subcutaneous injection.

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.

To avoid the injection of large volumes of the product, higher strengths should be considered for patients requiring treatment with larger doses of methadone.

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. After stabilisation, the dose is gradually decreased until total withdrawal is achieved.

The dose should be adjusted according to the individual needs of the patient 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. (See Sections 4.4 and 4.5 below).

Treatment of moderate to severe _ pain:

Usually 5-10 mg every six to eight hours, should be adjusted according to response. In prolonged use it should not be administered more than twice a day.

Elderly and debilitated patients:

Reduce dose. If repeated doses are required, use 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 patient group.

Children:

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

Hepatic impairment:

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

Renal impairment:

The dose may need to be reduced in moderate or severe renal impairment.

4.3 Contraindications

Known hypersensitivity to methadone or any other ingredients contained in the product.

Respiratory depression and obstructive airways disease. Use during an acute asthma attack is not advisable.

Methadone should not be administered to patients with head injuries or raised intracranial pressure as there is a risk of respiratory depression which may lead to a further elevation of CSF pressure. The sedation and pupillary changes produced may interfere with accurate monitoring of the patient.

Monoamine oxidase inhibitor drugs given concurrently or within two weeks of discontinuation.

Acute alcoholism

Phaeochromocytoma.

Risk of paralytic ileus.

Obstetric use is not recommended because of the increased risk of neonatal depression due to the long duration of action.

Use in children under 16 years.

4.4 Special warnings and precautions for use Addiction/tolerance/dependence

Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2). Methadone has a long half life and can therefore accumulate, especially in elderly or debilitated patients. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possible death.

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 morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.

Even at low doses methadone is a special hazard to children if ingested accidentally.

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. Use with caution or reduce dose in patients with asthma or decreased respiratory reserve.

Hepatic disorders

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

Pregnancy and risks to the neonate (see also section 4.6 Pregnancy and Lactation):

Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management. Babies born to mothers receiving methadone may suffer withdrawal symptoms. Methadone should not be withdrawn abruptly and infants will require careful monitoring for signs of respiratory depression and/or opioid withdrawal.

Further warnings

Methadone should be used with great caution in patients with convulsive disorders.

In the case of elderly or ill patients the drug should be used with caution due to its long half-life.

Risk benefit should be assessed and methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hypertrophy, hypotension, shock, biliary tract disorders, inflammatory or obstructive bowel disorders or myasthenia gravis.

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

Even at low doses methadone is a special hazard to children if ingested accidentally.

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,

-    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.

4.5 Interaction with other medicinal products and other forms of interaction

Methadone is metabolised in the liver by cytochrome P450 isoenzymes, including CYP3A4, CYP1A and CYP2D6. Interactions are likely with enzyme inhibitors or inducers; for example, cimetidine may enhance the effects of methadone, while phenytoin may increase its metabolism; similarly, an increase in its urinary excretion has been reported with rifampicin.

MAOIs

The current use of Monoamine oxidase inhibitors (MAOIs) is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone. Severe CNS excitation, delirium, convulsions or respiratory depression is possible with concurrent use of opiates and MAOIs.

Hyperpyrexia and CNS toxicity has been reported when selegiline was coadministered with opioid analgesics.

CNS depressants

Concomitant use with other central nervous system depressants is not advised. Anaesthetics, hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole), anxiolytics and barbiturates may increase the general depressant effects of methadone. Antipsychotics may enhance the sedative effects and hypotensive effects of methadone. The plasma concentration 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.

Alcohol

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

Opioid agonist

Additive effects on CNS depression, respiratory depression and hypotension can occur with concomitant use of pethidine and other opioid agonist analgesics.

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.

Anticonvulsants

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

Histamine Hyantagonists

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

pH of urine

Drugs that acidify or alkalinise the urine may affect methadone clearance as it is increased at acidic pH and decreased at alkaline pH.

Antiviral drugs used in HIV

Plasma concentrations of methadone may be reduced by the nucleoside reverse transcriptase inhibitor, abacavir, the protease inhibitors, nelfinavir and ritonavir, which are metabolised by cytochrome P450 enzyme systems, and the non-nucleoside reverse transcriptase inhibitors, efavirenz and nevirapine, which interact with a number of drugs metabolised in the liver. Narcotic withdrawal syndrome has been reported in patients treated with nevirapine and methadone concomitantly.

Methadone maintained patients beginning nevirapine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. 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 inhibition of CYP 1A2 and CYP 3A4. Reduced serum concentrations of ciprofloxacin may occur. Co-administration of ciprofloxacin with methadone may result in profound sedation, confusion and respiratory depression. This combination should be avoided.

Erythromycin theoretically may increase methadone levels due to decreased methadone metabolism.

Rifabutin may decrease methadone levels due to increased metabolism.

Cyclizine and other sedating antihistamines

May have additive psychoactive effects; antimuscarinic effects at high doses. Fluconazole and ketoconazole

May raise methadone levels, due to decreased methadone metabolism. Grapefruit _ juice

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

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/metoclopramide on gastro-intestinal activity.

Antiarrhythmics

Methadone delays the absorption of mexiletine.

Other drugs

Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal motility.

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

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.

Pregnancy Tests

Methadone may interfere with the urine testing for pregnancy.

4.6 Pregnancy and lactation

Pregnancy:

There is inadequate 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.

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

Lactation:

Methadone is excreted in breast milk. Specialist care from 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.

4.7 Effects on ability to drive and to use machines

Patients should not drive or use machines while taking methadone. Methadone may cause drowsiness and reduce alertness and the ability to drive. The physician must decide the time after which activities may be safely resumed.

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

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

Methadone is associated with undesirable effects common to other opioid analgesics. The most common side effects are nausea, vomiting, drowsiness, constipation, dizziness, confusion and euphoria, but the most serious hazard is respiratory depression (see also section 4.9 Overdose).

Respiratory Disorders

Respiratory depression particularly with larger doses.

Gastrointestinal Disorders

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

CNS Disorders

Dependence, drowsiness, dizziness, vertigo, headache, confusion, restlessness can occur. Changes of mood, including euphoria, and hallucinations are occasionally reported.

Renal and Urinary Disorders

Less commonly micturition difficulties are observed.

Cardiovascular Disorders

Bradycardia, palpitation and orthostatic hypotension can occur. Cases of QT prolongation and torsades de pointes have been rarely reported.

Skin Disorders Sweating, rashes.

Other Undesirable Effects

Other side effects which occur more commonly in ambulant patients, include pruritus, urticaria, facial flushing, hypothermia, dry eyes and nose, decreased libido, dysmenorrhoea and amenorrhoea, and miosis can also occur. Raised intracranial pressure and muscle rigidity have been reported.

Methadone causes pain at injection sites. Local irritation has been observed at the injection site and induration may occur with repeated subcutaneous injection.

4.9 Overdose Symptoms

These are similar to those of morphine.

Serious overdosage is characterised by respiratory depression extreme somnolence progressing to coma or stupor, cyanosis, maximally constricted pupils, skeletal muscle flaccidity, cold clammy skin and occasionally bradycardia and hypotension.

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

Treatment

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

Treatment consists of the establishment of a patent airway and assisted ventilation should be administered as necessary. Narcotic antagonists may be required if there is evidence of significant respiratory or cardiovascular depression. 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 (0.1mg per kg) or Levallorphan (0.02mg per kg) should be given intravenously as soon as possible and repeated, if necessary, every 15 minutes.

Administration of a narcotic antagonist will precipitate an acute withdrawal syndrome in a patient physically dependent upon narcotics. 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.

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

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Analgesics-Diphenylpropylamine derivatives.

ATC Code: N07BC02

Methadone is an opioid agonist which predominantly interacts with the p receptors in the central nervous system although there is some activity on the 5 receptors. The l-isomer is responsible for the analgesic activity of methadone. The d-isomer lacks analgesic or respiratory depressant activity, but does have antitussive effects. It may also act as an euphoriant. It has analgesic properties and an extended duration of activity in suppressing withdrawal symptoms in physically dependant individuals. It is predominantly a central nervous depressant but it has stimulant actions resulting in nausea, vomiting and miosis.

Many pharmacological properties of methadone, including its effect on bowel movement, cough reflex, biliary tone and the secretion of pituitary hormone are similar, qualitatively, to those seen with morphine. As with many basic drugs, methadone enters mast cells and releases histamine by a non-immunological mechanism.

With repeated administration, methadone shows persistent effects, and effects on miosis and respiration can be detected for more than 24 hours even after a single dose. Although methadone is itself addicting, withdrawal symptoms appear more slowly, after about 24 to 48 hours, and are of lesser intensity but of longer duration, than those associated with morphine abstinence.

Other effects of methadone include reduction of heart rate, systolic blood pressure and body temperature, and a slowing of the a rhythm of the EEG, but increasing the 5 wave activity.

5.2 Pharmacokinetic properties

Methadone is one of the more lipid soluble opioids and is well absorbed from the gastrointestinal tract but undergoes fairly extensive first pass metabolism.

Methadone Injection is intended to be administered by either the subcutaneous or intramuscular route. Injection by the intramuscular route is likely to produce a faster rate of absorption than by the subcutaneous route.

With an intramuscular dose of 10mg, a peak plasma concentration of 75pg/l is reached in 1 hour. After regular oral doses of 100-120mg daily, plasma concentrations rise from trough levels of approximately 500pg/l to a peak of about 900pg/l in 4 hours. The half-life of a single intramuscular dose is 6-8 hours, and after a single oral dose 12-18 hours. With regular doses the tissue reservoir is partially filled and the half life is extended to 13-47 hours reflecting only clearance.

The half-life is therefore longer than most other opiates and may be more variable in children (3.8 to 62 hours in one study). Neonates who may have more adipose tissue and higher plasma protein levels, may be particularly susceptible to slower elimination of the drug (see sections 4.2 and 4.4).

The level and speed of absorption of methadone may be dependant upon the site of intramuscular injection and interpatient variability in clearance resulting in variable plasma levels. The peak plasma levels after deltoid administration were significantly greater than those after gluteal injections. In addition, the area under the concentration-time curve from 0 - 4 hours was significantly less, approximately half, following gluteal injection of methadone as compared to deltoid. Pain relief at 15, 30 and 60 minutes following deltoid injections of methadone was significantly greater than that following gluteal injections.

Methadone is 60 to 90% bound to albumin and other plasma proteins, and to tissue proteins. The distribution in the blood and brain being lower than in the kidney, lung and spleen. The drug also diffuses across the placenta, can be found in saliva and sweat and can be detected in breast milk.

Methadone is extensively metabolised in the liver, resulting in the formation of EDDP which undergoes further N-demethylation to form EMDP. These are further metabolised to form water-soluble metabolites which are primarily the gluconuride conjugate of EMDP. These metabolites do not exert any antagonistic or agonistic analgesic properties.

Methadone is excreted in the urine and the bile; as a consequence methadone and its metabolites can be recovered from the urine and faeces. Approx 15-60% is recovered from the urine and as the dose is increased so a higher proportion of non-metabolised methadone is found there. Acidification of the urine can increase renal clearance by a factor of at least three and thus appreciably reduce the half life of elimination.

5.3 Preclinical safety data

There are no preclinical safety data of relevance to the prescriber which are additional to those already included in other sections of the SPC.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Hydrochloric Acid 0.1M

Sodium Hydroxide Solution 0.01M Water for Injections

6.2 Incompatibilities

Physical incompatibility as judged by loss of clarity was reported when an intravenous solution of methadone hydrochloride was mixed with those of aminophylline, ammonium chloride, amylobarbitone sodium, chlorothiazide sodium,

heparin sodium, methicillin sodium, nitrofurantoin sodium, novobiocin sodium, pentobarbitone sodium, phenobarbitone sodium, phenytoin sodium, quinalbarbitone sodium, sodium bicarbonate, sodium iodide, sulphadiazine sodium, sulphafurazole diethanolamine or thiopentone sodium.

6.3 Shelf life

36 months (unopened).

6.4 Special precautions for storage

Protect from light.

Do not store above 25°C.

6.5 Nature and contents of container

Pack of 10 neutral glass ampoules. Each ampoule contains 1, 2, 3.5, 5, 7.5 or 10ml of solution.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

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

7 MARKETING AUTHORISATION HOLDER

Wockhardt UK Limited Ash Road North Wrexham LL13 9UF United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 29831/0135

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/06/1996 / 21/03/2007

DATE OF REVISION OF THE TEXT

30/01/2015