Summary of medicine characteristics - METHADONE 1 MG / ML ORAL SOLUTION SUGAR FREE
1 NAME OF THE MEDICINAL PRODUCT
Methadone 1 mg/ml Oral Solution Sugar Free
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 1ml of solution contains 1mg of methadone hydrochloride
Also contains:
Tartrazine (E102) 0.07mg per ml
Sunset yellow (E110) 0.008mg per ml
Sodium benzoate (E211) 1mg per ml
Sodium saccharin 1mg 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
Posology
Prior to starting treatment with opioids, a discussion should be held with patients to put in place a strategy for ending treatment with methadone in order to minimise the risk of addiction and drug withdrawal syndrome (see section 4.4). The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).
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.
Method of administration
For oral administration only.
4.3 Contraindications
Respiratory depression, obstructive airways disease,
Concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them.
Use during labour is not recommended; the prolonged duration of action increases the risk of neonatal depression.
Methadone is not suitable for children.
Hypersensitivity to methadone or any of the excipients.
Patients dependent on non-opioid drugs
Patients with acute alcoholism, head injury and raised intra-cranial pressure.
Patients with ulcerative colitis, since methadone may precipitate toxic dilation or spasm of the colon.
Patients with severe hepatic impairment as it may precipitate hepatic encephalopathy.
Patients with biliary and renal tract spasm.
4.4 Special warnings and precautions for use
Caution should be exercised in patients with hepatic dysfunction or renal dysfunction.
In the case of elderly or ill patients, repeated doses should only be given with extreme caution.
Drug dependence, tolerance and potential for abuse
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.
Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. The risks are increased in individuals with current or past history of substance misuse disorder (including alcohol misuse) or mental health disorder (e.g., major depression). Overuse or misuse may result in overdose and/or death. It is important that patients only use medicines that are prescribed for them at the dose they have been prescribed and do not give this medicine to anyone else. Patients should be closely monitored for signs of misuse, abuse, or addiction. The clinical need for opioid substitution therapy should be reviewed regularly.
Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.
Drug withdrawal syndrome
Prior to starting treatment with any opioids, a discussion should be held with patients to put in place a withdrawal strategy for ending treatment with methadone. The decision to maintain a patient on a long-term opioid prescription should be an active decision agreed between the clinician and patient with review at regular intervals (usually at least three-monthly, depending on clinical progress).
Drug withdrawal syndrome may occur upon abrupt cessation of therapy or dose reduction. When a patient no longer requires therapy, it is advisable to taper the dose gradually to minimise symptoms of withdrawal.
The opioid drug withdrawal syndrome is characterised by some or all of the following: restlessness, lacrimation, rhinorrhoea, yawning, perspiration, chills, myalgia, mydriasis and palpitations.
Other symptoms may also develop including irritability, agitation, anxiety, hyperkinesia, tremor, weakness, insomnia, anorexia, abdominal cramps, nausea, vomiting, diarrhoea, increased blood pressure, increased respiratory rate or heart rate.
If women take this drug during pregnancy, there is a risk that their newborn infants will experience neonatal withdrawal syndrome.
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.
Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs:
Concomitant use of methadone and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe methadone concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.
The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).
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.
Adrenal insufficiency
Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.
Decreased Sex Hormones and increased prolactin
Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.
Hypoglycaemia
Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see section 4.8 and section 4.9).
Paediatric population
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
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, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis.
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 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.
Caution should be exercised in patients who are concurrently taking CNS depressants.
Excipient warnings:
This medicine contains
Tartrazine (E102) and sunset yellow (E110), which may cause allergic reactions.
This medicine contains less than 1 mmol sodium (23 mg) per 60mg dose, that is to say essentially ‘sodium-free’.
Sodium benzoate. This medicine contains 1mg sodium benzoate (E211) in each ml. Sodium benzoate may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
4.5 Interaction with other medicinal products and other forms of interaction
Serotonergic drugs:
Serotonergic syndrome may occur with concomitant administration of methadone with pethidine, monoamine oxidase (MAO) inhibitors and serotonin agents such as Selective Serotonin Re-uptake Inhibitor (SSRI), Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) and tricyclic antidepressants (TCAs). The symptoms of serotonin syndrome may include mental-status changes, autonomic instability, neuromuscular abnormalities, and/or gastrointestinal symptoms.
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.
There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.
CNS depressants:
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).
The concomitant use of opioids with sedative medicines such as benzodiazepines or related drugs increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
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):
Induces the metabolism of methadone and there may be a risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.
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.
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.
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 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 gastro-intestinal motility.
Co-administration of methadone hydrochloride with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of methadone hydrochloride with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and methadone hydrochloride are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.
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.
4.6 Fertility, pregnancy and lactation
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.
Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.
Following birth and low birth weight; increased stillbirth rates have also been reported.
If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available.
Administration during labour may depress respiration in the neonate and an antidote for the child should be readily available.
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.
Breast feeding
Methadone is excreted in breastmilk at low levels. The decision to recommend breastfeeding should take into account clinical specialist advice and consideration should be given to whether the woman is on a stable maintenance dose of methadone and any continued use of illicit substances. If breastfeeding is considered, the dose of methadone should be as low as possible. Prescribers should advise breastfeeding women to monitor the infant for sedation and breathing difficulties and to seek immediate medical care if this occurs. Although the amount of methadone excreted in breast milk is not sufficient to fully suppress withdrawal symptoms in breast-fed infants, it may attenuate the severity of neonatal abstinence syndrome. If it is necessary to discontinue breastfeeding it should be done gradually, as abrupt weaning could increase withdrawal symptoms in the infant.
4.7 Effects on ability to drive and use machines
This may be severely affected during and after treatment with Methadone. The time after which such activities may 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:
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
It was not affecting your ability to drive safely”
4.8 Undesirable effects
Endocrine Disorders
Raised prolactin levels with long-term administration.
Metabolism and nutrition disorders
Hypoglycaemia (frequency not known).
Psychiatric disorders
Frequency unknown: Drug dependence (see section 4.4), confusion particularly at the start of the treatment can occur, changes of mood, including euphoria, and hallucinations are occasionally reported.
Nervous System Disorders
Drowsiness and headache. Methadone has the potential to increase intracranial pressure, particularly in circumstances where it is already raised.
Eye Disorders
Miosis, dry eyes
Ear and labyrinth disorders
Vertigo.
Cardiac Disorders
Bradycardia and palpitations can occur. Cases of QT prolongation and torsades de pointes have been rarely reported.
Vascular disorders
Orthostatic hypotension, facial flushing.
Respiratory, thoracic and mediastinal disorders
Exacerbation of existing asthma, dry nose, respiratory depression particularly with larger doses.
Gastrointestinal disorders
Nausea and vomiting particularly at the start of treatment can occur. Constipation, dry mouth.
Skin and subcutaneous tissue disorders
Rashes. Long-term administration may produce excessive sweating
Renal and urinary disorders
Less commonly micturition difficulties are observed.
Reproductive system and breast disorders
Galactorrhoea, dysmenorrhoea, amenorrhoea
General disorders and administration site conditions
Uncommon: drug withdrawal syndrome.
Hypothermia
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 at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdosePatients should be informed of the signs and symptoms of overdose and to ensure that family and friends are also aware of these signs and to seek immediate medical help if they occur.
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. Hypoglycaemia has been reported.
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. 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.
5.1 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 li receptor. The analgesic activity of the racemate is almost entirely due to the 1isomer, 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
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tartrazine (E102)
Sunset yellow (E110)
Green S (E142)
Sodium saccharin
Hydrochloric acid (E507)
Sodium benzoate (E211)
Glycerol (E422)
Purified Water
6.2 Incompatibilities
Not applicable.
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 the original package to protect from light. Keep the bottle in the outer carton.
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
6.6 Special precautions for disposalMethadone 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
Accord-UK Ltd
(Trading style: Accord)
Whiddon Valley
Barnstaple
Devon
EX32 8NS