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. Clinical Particulars
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).
4.2 Posology And Method Of Administration
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 10mg, repeated 6 to 8 hourly as required, later adjusted to the degree of pain relief obtained. If repeated doses are requried, the I.M. route should be used.
Use to treat opioid addiction; initially 10 - 20mg per day, increasing by 10 - 20mg per day until no signs of withdrawal or intoxication. Usual dosage 10 - 60mg per day. Thereafter, the aim should be to gradually reduce the dosage.
The I.M. route should be used for repeated doses.
Children:
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:
Caution is required with repeated dosages in elderly or in ill patients.
4.3 Contraindications
Respiratory depression and obstructive airways disease. Acute alcoholism and where risk of paralytic ileus. Raised intracranial pressure, head injury.
Concurrent administration with monoamine oxidase inhibitors or within two weeks of discontinuing therapy with MAOIs.
Obstetric use is not recommended.
4.4 Special Warnings And Precautions For Use
Administer methadone with caution in cases of hypotension, hypothyroidism, asthma (during an attack). Prostatic hypertrophy. Convulsive disorders.
Reduce dose in elderly or debilitated patients. Reduce the dosage or avoid use of methadone in cases of renal and hepatic impairment. Tolerance and dependence of the morphine type may occur. In prolonged use, methadone should not be administered more often than twice daily to avoid the risk of accumulation and overdosage.
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. hypokalemia, 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 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Monoamine oxidase inhibitors may prolong and enhance the respiratory depressant effects of methadone.
Fluvoxamine has been reported to increase the circulating levels of methadone.
The general depressant effects of methadone may be enhanced by other agents with central nervous system depressant activity such as alcohol, tricyclic antidepressants, phenothiazines and antipsychotics, anxiolytics, hypnotics and barbiturates.
Phenytoin has been reported to enhance the metabolism of methadone.
Carbamazepine may decrease the effect of methadone.
Rifampicin has been reported to reduce circulating levels of methadone and to increase its urinary excretion.
Reduced plasma concentration of ciprofloxacin have been reported following pre-medication with opioid analgesics.
Ritonavir may reduce the plasma concentration of methadone.
Based on the known metabolism of methadone, nevirapine may decrease plasma concentrations of methadone by increasing its hepatic metabolism.
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 levels of zidovudine.
Cimetidine may inhabit the metabolism of opioid analgesics.
The gastro-intestinal effects of cisapride, metoclopramide and domperidone may be antagonised by opioid analgesics.
Opioid analgesics may delay the absorption of mexiletine.
Naloxone reverses the analgesic, CNS- and respiratory-depressant effects of methadone.
Cytochrome P450 3A4 inhibitors: methadone clearance is decreased when coadministered 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 effect electrolyte balance there is a risk of cardiac event when methadone is taken concurrently.
4.6 Pregnancy And Lactation
There is no adequate evidence of safety in human pregnancy, but methadone has been widely used for many years without apparent ill-consequence and animal studies have not shown any hazard.
Methadone should not be used during labour (see "contraindications"). It diffuses across the placenta and is excreted in breast milk.
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 drive or 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.
4.8 Undesirable Effects
Nausea, vomiting, constipation and dizziness may occur, particularly in the ambulant patient. Nausea and vomiting appear to be more frequent after oral administration than after injection. Other side-effects include difficulty with micturation, uretic or biliary spasm, headache, dry mouth, sweating, vertigo, bradycardia, postual hypotension, mood changes, rashes, urticaria, pruritis, hypothermia, hallucinations and decreased libido. As with other opioid drugs, respiratory depression may occur.
Cases of QT prolongation and torsade de pointes have been rarely reported.
Methadone may cause pain at the injection site. Subcutaneous injection may produce local tissue irritation and induration.
4.9 Overdose
Cardinal signs of overdosage include coma, depressed respiration, pinpoint pupils, hypotension and pulmonary oedema. 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.
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
Methadone is a synthetic opioid analgesic with the same general properties as morphine.
5.2 Pharmacokinetic Properties
It is readily absorbed following subcutaneous or intramuscular injection. A single dose of methadone has approximately the same duration of action as morphine. With repeated usage of methadone, cumulative effects become apparent and either a lower dosage or longer intervals between doses become possible.
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 type1, Ph.Eur.
The ampoules are packed in cardboard cartons to contain 5 or 10 ampoules.
6.6 Special Precautions For Disposal And Other Handling
If only part of an ampoule is used, discard the remaining solution.
7. Marketing Authorisation Holder
Antigen International Ltd.,
Roscrea,
Co. Tipperary,
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
09/03/2009
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