Methadone 1mg/Ml Oral Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Methadone 1 mg/ml Oral Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml of solution contains 1ml of methadone hydrochloride Also contains:
Sucrose 333mg per ml,
Tartrazine (E102) 0.07mg per ml Sunset yellow (E110) 0.008mg per ml For further information see section 4.4.
For full list of excipients see section 6.1
3 PHARMACEUTICAL FORM
Oral solution.
Clear Green solution.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For use in the treatment of opioid drug addictions (as a narcotic abstinence syndrome suppressant).
4.2 Posology and method of administration
For oral administration only.
Addiction:
Adults: Initially 10-20 mg per day, increasing by 10-20 mg per day until there are no signs of withdrawal or intoxication. The usual dose is 40-60 mg per day.
Elderly: In the case of the elderly or ill patients repeated doses should only be given with extreme caution.
Children: Not recommended for children.
Dosage in pregnancy: Drug withdrawal needs to be achieved 4-6 weeks before delivery if neonatal abstinence syndrome is to be certain to be avoided, but abrupt withdrawal can cause intrauterine death. Detoxification to abstinence is least stressful to mother and foetus if undertaken during the mid trimester.
Abstinence syndrome may not occur in the neonate for some days after birth. In the event that withdrawal is not possible prior to delivery, methadone administered to the mother may result in prolonged respiratory depression in the neonate and the administration of opioid antagonists may be required.
4.3 Contraindications
• Respiratory depression, obstructive airways disease and during an acute asthma attack
• Concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them. (See section 4.5)
• Use during labour (prolonged duration of action increases the risk of neonatal depression)
• Children (serious risk of toxicity)
• Hypersensitivity to methadone or any of the excipients.
• Acute alcoholism (See section 4.5)
• Head injury and raised intracranial pressure (further rise in intracranial pressure - see section 4.8: papillary response affected)
• Where there is a risk of paralytic ileus (including drug induced gastrointestinal hypotonia).
4.4 Special warnings and precautions for use
In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.
In the case of elderly or ill patients, repeated doses should only be given with extreme caution.
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. A single dose which will relieve symptoms may, if repeated on a daily basis, lead to accumulation and possibly 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 those with morphine, are less intense but more prolonged. Withdrawal of treatment should therefore be gradual.
QT interval prolongation
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 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 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 100mg/d and at seven days after titration.
Respiratory depression
Methadone should be given with caution to patients with history of asthma (see section 4.3). Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two. Hepatic disorders
Caution as methadone may precipitate porto-systemic encephalopathy in patients with severe liver damage.
As with other opioids, methadone may cause troublesome constipation, which is particularly dangerous in patients with severe hepatic impairment, and measures to avoid constipation should be initiated early.
Neonates/children
As there is a risk of greater respiratory depression in neonates and because there are currently insufficient published data on the use in children, methadone is not recommended in those under 16 (See sections 4.2, 5.2).
Further warnings
Babies born to mothers receiving methadone may suffer withdrawal symptoms.
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.
Methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.
Caution should be exercised in patients who are concurrently taking CNS depressants.
Excipient warnings:
This product contains
• Tartrazine (E102) and Sunset yellow (E110) , which may cause allergic reactions.
• Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine. The product contains 1.67g of sucrose per 5ml and should be taken into account in patients with diabetes mellitus. It may be harmful to teeth.
4.5 Interaction with other medicinal products and other forms of interaction
CNS depressants:
Alcohol, anaesthetics, hypnotics and sedatives, barbiturates, phenothiazines, some other minor and 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).
Alcohol may also enhance the sedative and hypotensive effects of methadone and increase respiratory depression.
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.
Anticonvulsants (Phenytoin, Phenobarbital, Carbamazepine and Primidone):
Induces the metabolism of methadone and there may be a risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.
MAOI's:
The concurrent use of MAOI's is contraindicated (see 4.3 Contraindications) as they may prolong and enhance the respiratory depressant effects of methadone.
pH of urine:
Drugs that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH.
Opioid Agonist Analgesics:
Additive CNS depression, respiratory depression and hypotension.
Buprenorphine and pentazocine rapidly precipitate withdrawal symptoms in patients addicted to methadone.
Opioid antagonists:
Naloxone and naltrexone antagonises 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.
Antivirals
• Nevirapine - may decrease plasma concentrations of methadone by increasing its hepatic metabolism with subsequent withdrawal symptoms. Patients on methadone who start nevirapine should be monitored for withdrawal reactions and the methadone dose adjusted accordingly.
• Efavirenz - similar reaction to nevirapine
• Nelfinavir, ritonavir and possibly abacavir - possible reduction in plasma concentrations of methadone
• Zidovudine - methadone may increase the plasma concentrations of zidovudine.
Antibacterials
Ciprofloxacin: Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to CYP 1A2 and CYP 3A4. Reduced serum concentrations of ciprofloxacin may occur. Concomitant use may lead to sedation, confusion and respiratory depression.
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.
Erythromycin: Theoretically this may increase methadone levels due to decreased methadone metabolism.
Fluconazole and ketoconazole: May raise methadone levels, due to decreased methadone metabolism.
Other Drugs:
Methadone may have an effect on other drugs as a consequence of reduced gastrointestinal motility.
Pregnancy Tests:
Methadone may interfere with the urine testing for pregnancy.
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).
St. John's Wort:
May lower plasma concentrations of methadone.
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.
Grapefruit juice:
There are several anecdotal reports of raised methadone levels due to decreased methadone metabolism.
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.
Methadone and QT interval prolongation
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. Please refer to Section 4.4.
4.6 Fertility, Pregnancy and lactation
Pregnancy
Methadone administered to pregnant women for the management of opioid addiction has the potential for several adverse effects on the foetus and neonate. A careful benefit/risk assessment must be made. Apart from the risk of prolonged respiratory depression in the neonate, the immediate problems are withdrawal syndrome in utero and following birth and low birth weight; increased stillbirth rates have also been reported.
The effects of methadone itself on pregnancy and infants born to methadone-treated mothers are difficult to assess in view of the complicating factors such as poor prenatal care, poor maternal nutrition, smoking, poor environmental and social conditions. Most studies have associated methadone with a low birth weight but methadone has not convincingly 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 in labour (see 4.3 Contraindications).
Lactation
Methadone is excreted in breast milk. Specialist care for 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.
Fertility
There is no fertility data available.
4.7 Effects on ability to drive and use machines
The ability to drive or operate machinery may be severely affected during and after treatment with methadone as it may cause drowsiness and reduce alertness. 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 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
The adverse effects of methadone are generally the same as with other opioids, most commonly nausea and vomiting, which are observed in approximately 20% of the patients who undergo methadone out-patient treatment, where the medicinal control is often unsatisfactory.
The most serious adverse effect of methadone is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest have occurred.
Adverse reactions listed below are classified according to frequency and system organ class. These reactions are more frequently observed in non-opioid-tolerant individuals. Frequency groupings are defined according to the following convention: very common (> 1/10), common (> 1/100 to <1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).
|
System organ class (MedDRA) |
Frequency |
Adverse event |
|
Blood and lymphatic system disorders |
Not known |
Reversible thrombocytopenia has been reported in opioid-dependent patients with chronic hepatitis. |
|
Metabolism and nutrition disorders |
Common |
Fluid retention |
|
Not known |
Anorexia, hypokalaemia, hypomagnesaemia | |
|
Psychiatric disorders |
Common |
Euphoria, hallucinations |
|
Uncommon |
Dysphoria, dependence, agitation, insomnia, mood changes, disorientation, reduced libido and potency | |
|
Nervous system disorders |
Common |
Sedation |
|
Uncommon |
Headache, syncope | |
|
Not known |
Dizziness | |
|
Eye disorders |
Common |
Blurred vision, miosis, dry eyes |
|
Ear and labyrinth disorders |
Common |
Vertigo |
|
Cardiac disorders |
Rare |
Bradycardia, palpitations, cases of prolonged QT interval and torsade de pointes have been reported, especially with high doses of methadone. |
|
Vascular disorders |
Uncommon |
Facial flush, hypotension |
|
Respiratory, thoracic and mediastinal disorders |
Uncommon |
Pulmonary oedema, exacerbation of asthma, dry nose, respiratory depression particularly with large doses, |
|
Gastrointestinal disorders |
Very common |
Nausea, vomiting |
|
Common |
Constipation | |
|
Uncommon |
Xerostomia, glossitis | |
|
Hepatobiliary disorders |
Uncommon |
Biliary dyskinesia |
|
Biliary spasm may occur | ||
|
Skin and subcutaneous tissue disorders |
Common |
Transient rash, sweating |
|
Uncommon |
Pruritis, urticaria, other rash and in very uncommon cases bleeding urticaria | |
|
Endocrine disorders |
Not known |
Raised prolactin levels with long-term administration |
|
Renal and urinary disorders |
Uncommon |
Urinary retention, anti-diuretic effect |
|
Reproductive system and breast disorders |
Uncommon |
Galactorrhoea, dysmenorrhoea and amenorrhoea |
|
General disorders and administration site conditions |
Common |
Fatigue, drowsiness |
|
Uncommon |
Oedema of the lower extremities, asthenia, oedema, hypothermia | |
|
Investigations |
Common |
Weight increase |
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 at www.mhra.gov .uk/yellowcard.
4.9 Overdose
Symptoms: Serious overdosage 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 overdosage, particularly by the intravenous route, apnoea, 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. Observation and supportive measures must be continued for 36-48 hours.
An antagonist should not be administered, however, in the absence of clinically significant respiratory or cardiovascular depression. Nalorphine (0.1 mg per kg) or Levallorphan (0.02 mg per kg) should be given intravenously as soon as possible and repeated, if necessary, every 15 minutes.
Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. In a person physically dependent 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
ATC code: N07BC02 (Nervous system, other nervous system drugs, drugs used in addictive disorders, methadone).
Methadone is a strong opioid agonist with actions predominantly at the p receptor. The analgesic activity of the racemate is almost entirely due to the 1-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 5 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 oculomotor nerve, and perhaps on opioid receptors in the pupillary muscles causes pupillary constriction. All these effects are reversible by naloxone with 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
Methadone is one of the more lipid soluble opioids, and is well absorbed from the gastro-intestinal tract, but undergoes fairly extensive first pass metabolism. It is bound to albumin and other plasma proteins and to tissue proteins (probably lipoproteins), the concentrations in lung, liver and kidneys being much higher than in blood. The pharmacokinetics of Methadone are unusual, in that there is extensive binding to tissue proteins and fairly slow transfer between some parts of this tissue reservoir and the plasma. With an intramuscular dose of 10 mg, a peak plasma concentration of 75 pg per litre is reached in one hour. With regular oral doses of 100-120 mg daily, plasma concentrations rise from trough levels of approximately 500 pg/L to a peak of about 900 pg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral Methadone, without any relation to symptoms. Methadone is secreted into sweat and found in saliva and in high concentration in gastric juice. The concentration in cord blood is about half the maternal level.
The half life after a single oral dose is 12-18 (mean 15) hours, partly reflecting distribution into tissue stores, as well as metabolic and renal clearance. With regular doses, the tissue reservoir is already partly filled, and so the half life is extended to 13-47 (mean 25) hours reflecting only clearance. In the first 96 hours after administration, 15-60% can be recovered from the urine, and as the dose is increased so a higher proportion of unchanged Methadone is found there. Acidification of the urine can increase the renal clearance by a factor of at least three and thus appreciably reduce the half time of elimination.
5.3 Preclinical safety data
There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tartrazine (E102)
Sunset yellow (E110)
Green S (E142)
Sucrose
Hydrochloric acid (E507)
Sodium benzoate (E211)
Glycerol (E422)
Purified Water
6.2 Incompatibilities
None known.
6.3 Shelf life
2 years.
Use within 4 weeks of opening.
6.4 Special precautions for storage
Do not store above 25°C
Store in original container.
6.5 Nature and contents of container
Amber Type III Glass or Amber PET bottle
Child Resistant Tamper Evident Cap- High density polypropylene cap with a polyethylene lining.
5 ml/2.5ml double ended polypropylene Spoon Pack sizes available: 500ml
6.6 Special precautions for disposal
Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2).
Any unused product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Percuro Medica Ltd
Unit 5 Powergate Business Park
Volt Avenue
Park Royal London
NW10 6PW
8 MARKETING AUTHORISATION NUMBER(S)
PL 35517/0001
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
26/11/2010
10 DATE OF REVISION OF THE TEXT
15/05/2015