Methadone Injection Bp 10mg/Ml 1ml 2ml 5ml And 10ml

SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Methadone Injection B.P. 10mg/ml, 1ml, 2ml, 5ml & 10ml

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml solution contains methadone hydrochloride BP 10 mg

3 PHARMACEUTICAL FORM

Clear, colourless, sterile aqueous solution intended for subcutaneous or intramuscular administration to human beings.

4.1. Therapeutic Indications

1. For use as an analgesic for moderate to severe pain.

2. For use in the treatment of opioid drug addiction (as a narcotic abstinence syndrome depressant).

This medicine is indicated in adults and adolescents over the age of 16 years.

4.2. Posology and method of administration Posology

For subcutaneous or intramuscular injection.

Adults:

Use as an analgesic; the usual single dose is 5 to 10 mg.

Methadone has a long half-life and caution should be observed with repeated dosage in very ill or in elderly patients. The usual initial dose is 5 to 10 mg, repeated 6 to 8 hourly as required, later adjusted to the degree of pain relief obtained. If repeated doses are required, the I.M. route should be used.

Use to treat opioid addiction; initially 10 - 20 mg per day, increasing by 10 -20 mg per day until no signs of withdrawal or intoxication. Usual dosage 10 -60 mg per day. Thereafter, the aim should be to gradually reduce the dosage. The I.M. route should be used for repeated doses.

Paediatric population:

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

Elderly patients

Caution is required with repeated dosages in elderly or in ill patients.

4.3 Contraindications

Hypersensitivity to methadone or to any of the excipients listed in section 6.1. Respiratory depression and obstructive airways disease. Use during an acute asthma attack is not advisable.

Acute alcoholism and where risk of paralytic ileus. Concurrent administration with monoamine oxidase inhibitors or within two weeks of discontinuing therapy with MAOIs.

Patients dependant on non-opioid drugs.

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.

Pheochromocytoma.

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

Use in children under 16 years is not recommended .

4.4 Special warnings and precautions for use

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

Reduce dose in elderly or debilitated patients. Reduce the dosage or avoid use of methadone in cases of renal and hepatic impairment.

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.

Tolerance and dependence may occur as with morphine.

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.

Withdrawal:

Abrupt cessation of treatment can lead to withdrawal symptoms which, although similar to morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.

Respiratory depression:

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two and may exacerbate asthma due to histamine release.

Hepatic disorders:

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

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 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.

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

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

Cases of QT interval prolongation and torsade de pointes have been reported during treatment with methadone, particularly at high doses (>100mg/d).

Methadone should be administered with caution to patients at risk for development for 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, hypomagnesemia

- 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 recognized 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 stabilization. ECG monitoring is recommended, in patients without recognized risk factors for QT prolongation, before dose titration above 100 mg/d and at seven days after titration.

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

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.

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, and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).

MAOIs

The concurrent use of Monoamine oxidase inhibitors (MAOIs) is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone.

CNS depressants

Concomitant use with other central nervous system depressants is not advised. Alcohol, anaesthetics, hypnotics and 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)

There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.

Histamine H2 antagonists

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

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.

Anticonvulsants (Phenytoin, Phenobarbital, Carbamazepine and Primidone):

Induce methadone metabolism with the risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.

Opioid agonist analgesics:

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. 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.

Antiretroviral Agents such as Nevirapine, Efavirenz, Nelfinavir, Ritonavir:

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 the methadone dose should be adjusted accordingly.

Ciprofloxacin:

Concomitant use may lead to sedation, confusion and respiratory depression.

Other Drugs:

Methadone may have an effect on other drugs as a consequence of reduced gastrointestinal motility.

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.

Pregnancy Tests

Methadone may interfere with the urine testing for pregnancy.

St. John’s Wort:

May lower plasma concentrations of methadone.

4.6 Pregnancy and lactation

There is no adequate 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.

Methadone should not be used during labour (see "Section 4.3 contraindications ")

It diffuses across the placenta and causes prolonged neonatal depression. During labour there is risk of gastric stasis and inhalation pneumonia in the mother and foetal distress.

Lactation:

Methadone is excreted in breast milk. Breast feeding is not recommended during methadone treatment.

4.7. Effects on ability to drive and use machines

Methadone can produce drowsiness and clouding of consciousness and patients should be warned not to operate machinery while taking the drug. When methadone is discontinued, the time after which these activities may be safely resumed is variable 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

A tabulated list of undesirable effects is outlined below:

System organ class	Frequencies	Adverse reaction
Nervous system disorders	Not known	• Dependence • Somnolence • Dizziness • Vertigo • Headache • Confusional state • Restlessness • Mood altered • Euphoric mood • Hallucinations • Intracranial pressure increased*
Eye disorders	Not known	• Dry eyes • Miosis
Ear and labyrinth disorders	Not known	• Dry nose
Cardiac disorders	Not Known	• Bradycardia • Palpitation • Arrhythmia • Orthostatic Hypotension • Sudden Cardiac death
	Rare	• Torsade de pointes • QT prolongation
Respiratory, thoracic and mediastinal disorders	Not known	Respiratory depression
Gastrointestinal disorders	Not known	• Nausea* • Vomiting* • Constipation • Dry mouth
Skin and subcutaneous tissue disorders	Not known	• Hyperhidrosis • Rash
Renal and urinary disorders	Not known	Difficulty in passing urine
Reproductive system and breast disorders	Not known	decreased libido, dysmenorrhoea amenorrhoea, galactorrhoea,
Congenital, familial and genetic disorders	Rare	congenital opthalmological abnormalities including nystagmus.^a
General disorders and administration site conditions	Not known	facial flushing, hypothermia, pain at the injection site, local tissue irritation

induration.

*Methadone has the potential to increase intracranial pressure, particularly in circumstances where it is already raised.

**Respiratory depression particularly with larger doses

***Nausea and vomiting particularly at the start of treatment

^aMethadone administration in pregnancy can rarely lead to congenital ophthalmological abnormalities including nystagmus.

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 Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms:

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

In severe overdosage, apnoea, circulatory collapse, cardiac arrest and death may occur, as well as rare events of sensorineural deafness, leukoencephalopathy.

Treatment:

Treatment of overdosage consists of the establishment of a patent airway together with other supportive measures, and administration of a specific opioid antagonist such as naloxone hydrochloride. A dose of 0.4 to 2.0mg of naloxone is administered intravenously and repeated at intervals of 2 to 3 minutes, if necessary, up to 10mg. Because the duration of action of naloxone is shorter than that of methadone, repeated doses of naloxone may be required.

In children, the usual initial dose of naloxone is 10 micrograms per kg bodyweight intravenously followed, if necessary, by a dose of 100 micrograms per kg. Neonates may be given naloxone 10micrograms per kg by I.V., I.M. or S.C. injection, repeated at intervals of 2 to 3 minutes if necessary.

Narcotic antagonists may be required but it should be remembered that methadone is a long acting depressant (36 to 48 hours) whereas antagonists act for 1 to 3 hours, so that treatment with the latter must be repeated as needed.

An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression.

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.

In a person physically dependent on narcotics, administration of the usual dose of 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.

Intensive supportive therapy, including oxygen, intravenous fluids and vasopressors, may be required to correct respiratory failure and shock.

Patients should be monitored for signs of relapse for at least 48 hours.

5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmacodynamic group: Analgesics- Diphenylpropylamine derivatives ATC Code: N07BC02

Methadone is a synthetic opioid analgesic with the same general properties as morphine.

Methadone is an opioid agonist with actions predominantly at the p receptor. The analgesic activity of the racemate is almost entirely due to the l-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the K and a opiate receptors. These actions result in analgesia, depression of respiration, suppression of cough, nausea and vomiting (via an effect on the chemoreceptor trigger zone) and constipation. An effect on the nucleus of the automotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with a pA₂ value similar to its antagonism of Morphine. Like many basic drugs, Methadone enters mast cells and releases histamine by a non-immunological mechanism. It causes a dependence syndrome of the Morphine type.

5.2. Pharmacokinetic Properties

Absorption:

Methadone is one of the more lipid soluble opioids and is well absorbed from the gastrointestinal tract but in some cases may undergo 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. The half-life of a single intramuscular dose is 6-8 hours. With regular doses the tissue reservoir is partially filled and the half life is extended to 1347 hours reflecting only clearance.

In addition to marked interindividual variations, there are differences in the pharmacokinetics of methadone after single or multiple doses. Elimination half-lives vary considerably (a range of 4.2-130 hours has been quoted) and may be much longer than the 18 hours reported after a single dose. Careful adjustment of doasage is necessary with repeated doses.

Distribution:

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.

Biotransformation:

Methadone is extensively metabolised by CYP 3A4 in the liver, although other cytochrome P450 isoenzymes also play a role resulting in the formation of major metabolite 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and minor metabolite 2-ethyl-3,3-diphenyl-5-methylpyrrolidine (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. These metabolites are excreted in the faeces and urine along with unchanged methadone.

Elimination:

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.

Hepatic Impairment: Overall hepatic dysfunction does not seem unduly to disrupt methadone metabolism and it has been suggested that maintenance dosage of methadone need not be changed in stable chronic liver disease, although abrupt changes in hepatic status might result in substantial alterations in methadone disposition recquiring dosage adjustments.

Renal impairment: The urinary excretion of methadone was reduced in renal failure, but plasma concentrations were within the usual range and faecal excretion accounted for the majority of the dose. Very little methadone was removed by peritoneal dialysis or haemodylysis.

Paediatric groups: The half-life of methadone is 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).

5.3. Preclinical Safety Data

No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride BP 7.2 mg, sodium hydroxide BP(as a 10% w/v solution) or hydrochloric acid BP 10% w/v and water for injections BP.

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, methicilin 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

3 years (36 months)

6.4. Special Precautions for Storage

Store below 25 °C Protect from light.

6.5. Nature and Contents of Container

1ml, 2ml, 5ml and 10ml Clear glass ampoules, glass typel, Ph.Eur.

The ampoules are packed in cardboard cartons to contain 5 or 10 ampoules.

6.6. Instruction for Use/Handling

If only part of an ampoule is used, discard the remaining solution.

7 MARKETING AUTHORISATION HOLDER

Mercury Pharma International Ltd 4045, Kingswood Road,

City West Business Park,

Co Dublin, Ireland

8. MARKETING AUTHORISATION NUMBER(S)

PL 02848/0182

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

09/03/2009

10 DATE OF REVISION OF THE TEXT

27/05/2015