SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT 2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Transcription

1 SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT Methadone 10mg/ml Injection / Physeptone 10mg/ml Injection 2 QUALITATIVE AND QUANTITATIVE COMPOSITION Contains: Methadone Hydrochloride BP 10mg/ml 3 PHARMACEUTICAL FORM Sterile solution for injection 4 CLINICAL PARTICULARS 4.1 Therapeutic indications The treatment of Opioid drug addiction as a narcotic abstinence syndrome suppressant. As an analgesic where the sedative effects of morphine are contra-indicated. 4.2 Posology and method of administration Sterile solution for subcutaneous or intramuscular injection. If repeated doses are required the intramuscular route should be used. 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. As an analgesic. 5-10mg every 6-8 hours as needed. In prolonged use it should not be administered more than twice daily. The elderly In the case of the elderly or ill patients, repeated doses should be given with extreme caution.

2 Children Not recommended. 4.3 Contraindications Respiratory depression, obstructive airways disease, concurrent administration of MAOI drugs or within 2 weeks of discontinuation of treatment with them. Use during an acute asthma attack is not advisable. Obstetric use not recommended, because in labour the prolonged duration of action increases the risk of neonatal depression. Methadone is not suitable for children. 4.4 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). The formulation does not contain preservatives or antioxidants and therefore could be administered via the intravenous or intraspinal route. However, this should only be attempted by those with appropriate skill and experience in such administration and is at the discretion of the physician. 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 QTprolongation, - concomitant treatment with drugs that have a potential for QTprolongation, - concomitant treatment with drugs which may cause electrolyte abnormalities, - concomitant treatment with cytochrome P450 CYP 3A4 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 100 mg/d and at seven days after titration.

3 4.5 Interaction with other medicinal products and other forms of interaction Alcohol may induce serious respiratory depression and hypotension. Cimetidine and Phenytoin cause potentiation of opiate action, due to displacement of methadone from protein binding sites. Rifampicin and other rifamycins reduce the opiate effect due to increased metabolism. Mono Amine Oxidase Inhibitors possibility of CNS excitation or depression. Urinary acidifiers increase rate of excretion of drug thus decreasing plasma concentrations. CNS depressants, the major and minor tranquillisers, sedatives and tricyclic antidepressants may result in increased CNS depression, respiratory depression and hypotension. Opioid agonist analgesics result in additive CNS depression, respiratory depression and hypotension. Naloxone antagonises the analgesic, CNS and respiratory depressant effects of methadone. Naltrexone administration to a patient addicted to methadone will rapidly precipitate long term withdrawal symptoms. Administration of Buprenorphine or Pentazocine to patient addicted to methadone will rapidly precipitate withdrawal symptoms. Based on the known metabolism of methadone, nevaripine may decrease plasma concentrations of methadone by increasing its hepatic metabolism. Narcotic withdrawal syndrome has been reported in patients treated with nevaripine and methadone concomitantly. Methadone maintained patients beginning nevaripine therapy should be monitored for evidence of withdrawal and methadone dose should be adjusted accordingly. Ciprofloxacin may increase levels of methadone by inhibiting its metabolism. Cytochrome P4503A4 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. 4.6 Fertility, pregnancy and lactation There is no or inadequate evidence of safety in human pregnancy, but the drug has been widely used for many years without apparent ill consequence and animal studies have not shown any hazard. It should not be used during labour. Methadone is excreted in breast milk. This may be permissible during maintenance dosage Effects on Ability to Drive and Use Machines

4 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 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 It was not affecting your ability to drive safely 4.8 Undesirable effects Nausea, vomiting and dizziness. Methadone has the potential to increase intracranial pressure, particularly where it is already raised. It causes pain at the injection site; subcutaneous injection causes local tissue irritation and induration. In prolonged use as an analgesic it should not be administered more than twice daily to avoid the risk of accumulation and overdosage. Cases of QT prolongation and torsade de pointes have been rarely reported. 4.9 Overdose 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. 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.

5 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, vassopressors 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. 5 PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Methadone acts as a potent analgesic in a manner similar to that of morphine. It acts mainly on the CNS system and smooth muscle. This action is caused by the response of structurally and sterically specific opiate receptor sites in the brain, spinal cord and other nervous tissue. Methadone acts in the treatment of opioid addiction as an abstinence syndrome suppressant and/or by blocking the effects of other intravenous opiates (narcotic blockade). 5.2 Pharmacokinetic properties Methadone is widely distributed throughout the tissues with higher concentrations in the liver, lungs and kidneys than the blood. The main metabolic reaction is N-demethylation resulting in a substance which spontaneously cyclises to form the major metabolites, 2-ethylidene 1,5- dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenyl- 1-pyrroline (EMDP), neither of which are active. Hydroxylation to methadol followed by N-demethylation to normethadol also occurs to some extent. Other metabolic reactions occur and there are at least eight known metabolites. In subjects on methadone maintenance, about 20 to 60% of a dose is excreted in the urine in 24 hours, with up to 33% as unchanged drug and up to 43% as EDDP. EMDP accounts for about 5 to 10% of the dose. The ratio of EDDP to unchanged methadone is usually very much higher in the urine of patients on methadone maintenance treatment than in simple overdose cases. Urinary excretion of unchanged drug is ph dependent, being increased in acid urine. Up to 30% of a dose may be eliminated in the faeces, but this appears to decrease with increasing dosage. About 75% of the total excreted material is unconjugated. Protein binding: Up to 90% but considerable inter-subject variation about 15% is bound to immunoglobulin the remainder to albumin. Distribution in blood: Plasma: Whole blood ratio about 1:3.

6 Clearance: Plasma clearance about 2ml/min/kg Volume of distribution: approx. 5L/kg Half-life: single dose, hours repeated doses, hours Therapeutic concentration In plasma, usually in the range of μg/ml. During methadone maintenance treatment considerable fluctuations occur day to day. 5.3 Preclinical safety data No additional data of relevance to the prescriber. 6 PHARMACEUTICAL PARTICULARS 6.1 List of excipients Methadone Injection BP contains Water for Injections. 6.2 Incompatibilities No major incompatibilities known 6.3 Shelf life 30 months 6.4 Special precautions for storage Protect from light 6.5 Nature and contents of container Clear colourless ampoules of neutral glass containing 1, 2, 3.5 or 5ml of solution. 10 ampoules and a patient leaflet are packed in a cardboard carton. In addition, the 1ml ampoules are also available in packs of 100 with 10 patient leaflets. 6.6 Special precautions for disposal None 7 MARKETING AUTHORISATION HOLDER

7 Macarthys Laboratories Ltd T/A Martindale Pharmaceuticals Bampton Road, Harold Hill, Romford, RM3 8UG 8 MARKETING AUTHORISATION NUMBER(S) PL 01883/ DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 12/03/ DATE OF REVISION OF THE TEXT 08/05/2015