- Approval Id
- 84f485f7314ee644
- Drug Approval Emc Name
- Methadone Mixture 1mg/ml
- Drug Name
- Methadone Mixture 1mg/ml
- Company Address
- Linthwaite, Huddersfield, West Yorks, HD7 5QH
- Company Website
- http://www.thorntonandross.co.uk
- Company Medical Info Direct Line
- +44 (0) 1484 848164
- Company Medical Info Email
- thorntonross@medinformation.co.uk
- Company Customer Care Direct Line
- +44(0)1484 848200
- Atc Code
- N07BC02
- Legal Category
- Prescription only medicine
- Authorisation Holder
- Thornton & Ross Ltd,
Linthwaite Laboratories,
Huddersfleld,
HD7 5QH.
- Authorisation Number
- PL 00240/0039
- Authorisation Date
- 18 December 1995
- Instruction Authorisation Holder
- Thornton & Ross Ltd,
Linthwaite Laboratories,
Huddersfleld,
HD7 5QH.
- Instruction Authorisation Number
- PL 00240/0039
- Instruction Authorisation Date
- 18 December 1995
- Instruction Composition
- Methadone Hydrochloride 1 mg/ml.
Excipient(s) with known effect
Benzoic Acid Solution (contains benzoic acid and propylene glycol)
Syrup (Sucrose)
Sunset yellow (E110)
Tartrazine (E102)
For the full list of excipients, see section 6.1
- Instruction Dosage Form
- Oral Solution.
- Instruction Clinical Particulars
- 4.1 Therapeutic indications
For the treatment of dependence on opioid drugs.4.2 Posology and method of administration
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).
Posology
\*Adults:\*
10 - 20mg (10 - 20ml) should be taken as an initial daily dose by oral administration. The dose should be increased cautiously by 10 - 20mg daily until no signs of withdrawal or intoxication occur. The usual dose for maintenance is 40 - 60mg daily. The dose can then be gradually decreased, when appropriate, until total withdrawal is achieved.
\*Elderly:\*
Methadone mixture should be used cautiously in elderly patients.
\*Paediatric population:\*
Not suitable for use in children (see section 4.3).
Method of administration
For oral administration only4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Respiratory depression, obstructive airways disease and during an acute asthma attack\*,\*
• Patients dependent on non-opioid drugs,
• Concurrent administration with monoamine oxidase inhibitors (including moclobemide) or within 2 weeks of discontinuation of them.
• Head injury and raised intracranial pressure (further rise in intracranial pressure – papillary response affected; see section 4.8).
• Where there is a risk of paralytic ileus.
• Acute alcoholism (see section 4.5).
• Use during labour (prolonged duration of action increases the risk of neonatal depression).
• Methadone is not suitable for children (serious risk of toxicity).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).
Tolerance and dependence of the morphine type may occur. Methadone should be given with caution to patients with a history of asthma (see section 4.3), convulsive disorders, depressed respiratory reserve, hypotension, shock, prostatic hyperplasia, adrenocortical insufficiency, inflammatory or obstructive bowel disorders, myasthenia gravis or hypothyroidism. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.
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 of 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 treatments with drugs that have a potential for QT-prolongation,
- 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 of 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.
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).
There are reports of neonates exposed to methadone during pregnancy developing visual disorders, including reduced visual acuity, strabismus and nystagmus. The causal relationship to methadone in isolation has not been established as factors such as other drugs taken during pregnancy e.g. benzodiazepines, intake of alcohol, and drugs used to treat neonatal abstinence syndrome e.g. phenobarbital, could play a role in the adverse reactions seen. However, there is sufficient evidence to suggest that an association is possible and therefore consideration of this risk should be taken during prescribing decisions.
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 drugs 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 (where applicable) to be aware of these symptoms (see section 4.5).
Drug dependence, tolerance and potential for abuse
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 continuing opioid substitution therapy should be reviewed regularly.
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 new-born infants will experience neonatal withdrawal syndrome.
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.
Sleep related breathing disorders
Methadone Mixture 1mg/ml can cause sleep-related breathing disorders such as sleep apnoea (breathing pauses during sleep) and sleep related hypoxemia (low oxygen level in the blood). The symptoms can include breathing pauses during sleep, night awakening due to shortness of breath, difficulties to maintain sleep or excessive drowsiness during the day. If you or another person observe these symptoms, contact your doctor. A dose reduction may be considered by your doctor.
Ingredient information
This medicine contains the following ingredients which have a known pharmacological effect:
• Benzoic Acid (~0.10% w/v). Benzoic acid may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
• Propylene Glycol (<1mg/kg/day)
• Sucrose (4.5g/10ml dose). Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
• Tartrazine (E102) and Sunset Yellow (E110) which may cause allergic reactions4.5 Interaction with other medicinal products and other forms of interaction
Interactions potentiating the effects of methadone;
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, ciprofloxacin and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).
Cimetidine and phenytoin – may lead to potentiation of opioid activity due to displacement of methadone from protein binding sites. However, as phenytoin is also a hepatic enzyme inducer, it may lower plasma methadone levels (see below).
Fluvoxamine may increase plasma concentrations of methadone.
The depressant effects of methadone are likely to be enhanced by depressants of the CNS, such as other opioid analgesics, alcohol (see below), anaesthetics, antipsychotics, anxiolytics, hypnotics and sedatives, major and minor tranquilisers and phenothiazines. As well as CNS depression, there may be respiratory depression and/or hypotension. Tricyclic antidepressants may exert a similar effect.
Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression. As a result, caution is advised and acute alcoholism is contraindicated during treatment (see section 4.3).
Sedative medicines such as benzodiazepines or related drugs: 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 CNS depressant effects. The dose and duration of concomitant use should be limited (see section 4.4).
Interactions reducing the effects of methadone;
The opioid antagonists, naloxone and naltrexone, will precipitate an acute withdrawal syndrome in methadone-dependent individuals. Naloxone will also antagonise the analgesic, CNS and respiratory depressant effects of methadone.
Buprenorphine and pentazocine may also rapidly precipitate withdrawal symptoms in patients addicted to methadone.
The hepatic enzyme-inducing drugs, nevirapine, rifampicin (and other rifamycins), phenytoin, phenobarbital and carbamazepine may lower plasma methadone levels and produce symptoms of withdrawal in methadone dependent patients. Similar effects have been reported with efavirenz nelfinavir, ritonavir and possibly abacavir.
Urinary acidifiers: Acidification of the urine will increase the rate of elimination of methadone by the kidney thereby reducing plasma concentrations.
Co-administration of methadone with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of methadone with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and methadone are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.
Effects of methadone on other drugs;
Methadone may increase plasma desipramine levels and increase desipramine side-effects when given concurrently.
Zidovudine – methadone may increase the plasma concentrations of zidovudine.
Mexiletine – methadone may delay mexiletine absorption.
Metoclopramide and domperidone – the gastrointestinal effects may be antagonised by methadone.
Methadone treatment has been found to decrease the rate of absorption and decrease the bioavailability of the nucleoside reverse transcriptase inhibitors didanosine and to a lesser extent stavudine.
Other serotonergic drugs: Methadone is a weak serotonin uptake inhibitor. There is an increased risk of serotonin syndrome when methadone is co-administered with other serotonergic drugs (e.g. SSRIs, SNRIs, TCAs, MAOIs, serotonergic anti-emetics, serotonergic anti-migraine drugs, St. John's Wort). This is not an exhaustive list.
Other important interactions;
In patients taking drugs affecting cardiac conduction, which may affect electrolyte balance or may affect QT prolongation (e.g. centrally acting alpha-adrenergic blockers such as lofexidine and clonidine), there is an increased risk of hypotension, cognitive effects and cardiac events (including ECG changes) when methadone is taken concurrently – see section 4.4.
As serious and sometimes fatal reactions have occurred following administration of pethidine to patients receiving MAOIs, other drugs related to pethidine are contraindicated in patients taking MAOI's (including moclobemide) or within 14 days of stopping such treatment, (see section 4.3) as there is a risk of CNS excitation or depression.
Cross tolerance and cross dependence can be expected between other opioids acting at the same receptors.
Fluconazole may raise methadone levels due to decreased methadone metabolism.
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.
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).4.6 Fertility, pregnancy and lactation
\*Pregnancy:\*
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.
Methadone should only be used in pregnancy if the physician considers that the potential benefits outweigh the risks. It should be used cautiously under the close supervision of a physician if the physician considers it essential to continue or initiate (in the case of an i.v. opioid user) methadone maintenance. It may be necessary to increase the dose of methadone if withdrawal symptoms develop as increased clearance and reduced plasma levels have been reported during pregnancy.
Infants of methadone-maintained mothers may experience symptoms of withdrawal \*in utero\* and following birth.
Reports of visual disorders have been reported in neonates and children following exposure to methadone during pregnancy. Although other factors have also been present, there is sufficient evidence to suggest that an association is possible (see section 4.4).
Methadone should not be used during labour as the prolonged duration of action increases the risk of neonatal depression.
\*Breast-feeding:\*
Methadone is excreted in breast milk at low levels. The decision to recommend breast-feeding 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
Methadone may produce drowsiness and patients should be advised not to drive or operate machinery if affected. Once affected, the time after which such activities may be resumed is extremely variable between patients and should 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
Tabulated list of adverse reactions
Adverse reactions frequency are defined using 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 | Lymphocytosis |
| \*\*Endocrine disorders\*\* | Not known | Adrenal insufficiency, increased prolactin concentrations, decreased testosterone concentrations, hypogonadism, hypoglycaemia |
| \*\*Metabolism and nutrition disorders\*\* | Not known | Hypoglycaemia |
| \*\*Psychiatric disorders\*\* | Not known | Drug dependence (see section 4.4), hallucinations, confusion, mood changes including dysphoria, decreased libido |
| \*\*Nervous system disorders\*\* | Not known | Methadone may increase intra-cranial pressure, particularly when it is already raised. Dizziness, headache, drowsiness |
| \*\*Eye disorders\*\* | Not known | Miosis, nystagmus1, strabismus1, visual acuity reduced1 |
| \*\*Ear and labyrinth disorders\*\* | Not known | Vertigo |
| \*\*Cardiac disorders\*\* | Not known | Cases of QT prolongation and torsade de pointes have been rarely reported. Bradycardia, palpitations, tachycardia |
| \*\*Vascular disorders\*\* | Not known | Hypotension, facial flushing |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | Not known | Respiratory depression, Exacerbation of existing asthma, sleep apnoea |
| \*\*Gastrointestinal disorders\*\* | Not known | Nausea, vomiting, constipation, dry mouth |
| \*\*Hepatobiliary disorders\*\* | Not known | Biliary spasm |
| \*\*Skin and subcutaneous tissue disorders\*\* | Not known | Rashes, pruritus, urticaria, excessive sweating |
| \*\*Renal and urinary disorders\*\* | Not known | Difficulty in micturation, ureteric spasm, antidiuretic effect |
| \*\*Reproductive system and breast disorders\*\* | Not known | Erectile dysfunction, reductions in the ejaculate volume and seminal vesicular and prostatic secretions |
| \*\*General disorders and administration site conditions\*\* | Unknown | Drug withdrawal syndrome. In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage. |
| Not known | Hypothermia. |
| \*\*Investigations\*\* | Not known | Globulins increased, blood albumin increased |
1Visual effects have been reported in infants and children exposed to methadone during pregnancy.
\*\*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 or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.4.9 Overdose
Patients 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\*
Overdosage of methadone is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pulmonary oedema, extreme somnolence, progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Hypoglycaemia has been reported. The presence and signs of drug abuse supports the diagnosis.
In children, methadone overdose produces drowsiness, floppiness, constricted pupils and apnoea.
In severe overdosage, particularly by the intravenous route, apnoea, circulatory collapse, cardiac arrest and death may occur.
\*Emergency procedures\*
If ingestion is recent, gastric aspiration and lavage can be employed after acute poisoning.
Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Narcotic antagonists can be used to counteract the potentially lethal respiratory depression in a nontolerant individual, especially a child. Methadone is, however, a long-acting depressant (36-48 hours) whereas the antagonists act for much shorter periods (1-3 hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the respiratory depression is only due to overdosage with methadone, the use of other respiratory stimulants is not indicated.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists (naloxone, nalorphine or levallorphan) can be used to reverse signs of intoxication and should be given repeatedly until the patient's status remains satisfactory.
Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.
In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. The use of a narcotic antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
Patients should be monitored for signs of relapse for at least 48 hours.
- Instruction Pharmacology
- 5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in opioid dependence
ATC code: N07BC02
Methadone is an opioid agonist with actions predominantly at the µ 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 κ and σ 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
Its long duration of action enables it to be used daily on a supervised basis in opioid dependent individuals.5.2 Pharmacokinetic properties
Absorption
Methadone is well absorbed from the gastrointestinal tract with peak plasma levels occurring 1-5 hours after a single dose. Wide variations in plasma levels occur during maintenance therapy. Plasma levels may decrease on long term maintenance suggesting tolerance to develop possibly as a result of auto-induction of hepatic microsomal enzymes.
Distribution
Methadone is widely distributed in the tissues. It diffuses across the placenta and is excreted in breast milk. Plasma protein binding is 60-90%. After repeated administration, there is a gradual accumulation in the tissues and on discontinuation low concentrations in the plasma are maintained by slow release from extravascular binding sites accounting for the relatively mild but protracted withdrawal syndrome.
Biotransformation / Elimination
N-demethylation to the inactive major metabolite 2-ethylidine-1, 5-dimethyl-3, 3-diphenylpyrrolidine and other pyrrolidines and pyrroline occurs in the liver. These metabolites are excreted in the faeces and urine together with unchanged methadone. Urinary excretion is increased with an acidic urine. The elimination half-life is long and varies considerably with a range of 15-60 hours having been reported. Decreased excretion of methadone and its metabolites occur in liver dysfunction and urinary elimination is reduced in renal failure.
In methadone-maintained pregnant women, trough plasma levels have been found to be significantly lower and total or unbound methadone clearance greater during pregnancy than after delivery.5.3 Preclinical safety data
No relevant data.
- Instruction Pharmaceutical Particulars
- 6.1 List of excipients
Benzoic acid solution (contains benzoic acid and propylene glycol)
Syrup (Sucrose)
Green S dye E142
Tartrazine E102
Sunset yellow E110
Purified water6.2 Incompatibilities
None reported.6.3 Shelf life
3 years unopened
Use within 56 days of first opening6.4 Special precautions for storage
Store below 25ºC.
Keep this medicine out of the sight and reach of children. Store this medicine in a safe and secure storage space, where other people cannot access it. It can cause serious harm and even be fatal to people when it has not been prescribed for them.6.5 Nature and contents of container
500ml: Amber soda lime silica glass bottle with white polypropylene cap with polyethylene laminate wad or 28mm tamper evident plastic cap with polyethylene laminate wad.
500ml: Round high density polythene bottle with 28mm polypropylene cap with polyethylene laminate wad or 28mm tamper evident cap with polyethylene laminate wad.
1Lt, 2Lt and 5Lt high density polyethylene bottle with 38mm polypropylene, tamper evident cap with polyethylene laminate wad.6.6 Special precautions for disposal and other handling
None.
- Instruction Content
- ## Composition
Methadone Hydrochloride 1 mg/ml.
Excipient(s) with known effect
Benzoic Acid Solution (contains benzoic acid and propylene glycol)
Syrup (Sucrose)
Sunset yellow (E110)
Tartrazine (E102)
For the full list of excipients, see section 6.1
## Pharmaceutical Form
Oral Solution.
## Clinical Particulars
4.1 Therapeutic indications
For the treatment of dependence on opioid drugs.4.2 Posology and method of administration
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).
Posology
\*Adults:\*
10 - 20mg (10 - 20ml) should be taken as an initial daily dose by oral administration. The dose should be increased cautiously by 10 - 20mg daily until no signs of withdrawal or intoxication occur. The usual dose for maintenance is 40 - 60mg daily. The dose can then be gradually decreased, when appropriate, until total withdrawal is achieved.
\*Elderly:\*
Methadone mixture should be used cautiously in elderly patients.
\*Paediatric population:\*
Not suitable for use in children (see section 4.3).
Method of administration
For oral administration only4.3 Contraindications
• Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
• Respiratory depression, obstructive airways disease and during an acute asthma attack\*,\*
• Patients dependent on non-opioid drugs,
• Concurrent administration with monoamine oxidase inhibitors (including moclobemide) or within 2 weeks of discontinuation of them.
• Head injury and raised intracranial pressure (further rise in intracranial pressure – papillary response affected; see section 4.8).
• Where there is a risk of paralytic ileus.
• Acute alcoholism (see section 4.5).
• Use during labour (prolonged duration of action increases the risk of neonatal depression).
• Methadone is not suitable for children (serious risk of toxicity).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).
Tolerance and dependence of the morphine type may occur. Methadone should be given with caution to patients with a history of asthma (see section 4.3), convulsive disorders, depressed respiratory reserve, hypotension, shock, prostatic hyperplasia, adrenocortical insufficiency, inflammatory or obstructive bowel disorders, myasthenia gravis or hypothyroidism. In cases of hepatic or renal impairment the use of methadone should be avoided or given in reduced doses.
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 of 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 treatments with drugs that have a potential for QT-prolongation,
- 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 of 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.
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).
There are reports of neonates exposed to methadone during pregnancy developing visual disorders, including reduced visual acuity, strabismus and nystagmus. The causal relationship to methadone in isolation has not been established as factors such as other drugs taken during pregnancy e.g. benzodiazepines, intake of alcohol, and drugs used to treat neonatal abstinence syndrome e.g. phenobarbital, could play a role in the adverse reactions seen. However, there is sufficient evidence to suggest that an association is possible and therefore consideration of this risk should be taken during prescribing decisions.
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 drugs 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 (where applicable) to be aware of these symptoms (see section 4.5).
Drug dependence, tolerance and potential for abuse
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 continuing opioid substitution therapy should be reviewed regularly.
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 new-born infants will experience neonatal withdrawal syndrome.
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.
Sleep related breathing disorders
Methadone Mixture 1mg/ml can cause sleep-related breathing disorders such as sleep apnoea (breathing pauses during sleep) and sleep related hypoxemia (low oxygen level in the blood). The symptoms can include breathing pauses during sleep, night awakening due to shortness of breath, difficulties to maintain sleep or excessive drowsiness during the day. If you or another person observe these symptoms, contact your doctor. A dose reduction may be considered by your doctor.
Ingredient information
This medicine contains the following ingredients which have a known pharmacological effect:
• Benzoic Acid (~0.10% w/v). Benzoic acid may increase jaundice (yellowing of the skin and eyes) in newborn babies (up to 4 weeks old).
• Propylene Glycol (<1mg/kg/day)
• Sucrose (4.5g/10ml dose). Patients with rare hereditary problems of fructose intolerance, glucose galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
• Tartrazine (E102) and Sunset Yellow (E110) which may cause allergic reactions4.5 Interaction with other medicinal products and other forms of interaction
Interactions potentiating the effects of methadone;
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, ciprofloxacin and azole antifungal agents (since the metabolism of methadone is mediated by the CYP3A4 isoenzyme).
Cimetidine and phenytoin – may lead to potentiation of opioid activity due to displacement of methadone from protein binding sites. However, as phenytoin is also a hepatic enzyme inducer, it may lower plasma methadone levels (see below).
Fluvoxamine may increase plasma concentrations of methadone.
The depressant effects of methadone are likely to be enhanced by depressants of the CNS, such as other opioid analgesics, alcohol (see below), anaesthetics, antipsychotics, anxiolytics, hypnotics and sedatives, major and minor tranquilisers and phenothiazines. As well as CNS depression, there may be respiratory depression and/or hypotension. Tricyclic antidepressants may exert a similar effect.
Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression. As a result, caution is advised and acute alcoholism is contraindicated during treatment (see section 4.3).
Sedative medicines such as benzodiazepines or related drugs: 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 CNS depressant effects. The dose and duration of concomitant use should be limited (see section 4.4).
Interactions reducing the effects of methadone;
The opioid antagonists, naloxone and naltrexone, will precipitate an acute withdrawal syndrome in methadone-dependent individuals. Naloxone will also antagonise the analgesic, CNS and respiratory depressant effects of methadone.
Buprenorphine and pentazocine may also rapidly precipitate withdrawal symptoms in patients addicted to methadone.
The hepatic enzyme-inducing drugs, nevirapine, rifampicin (and other rifamycins), phenytoin, phenobarbital and carbamazepine may lower plasma methadone levels and produce symptoms of withdrawal in methadone dependent patients. Similar effects have been reported with efavirenz nelfinavir, ritonavir and possibly abacavir.
Urinary acidifiers: Acidification of the urine will increase the rate of elimination of methadone by the kidney thereby reducing plasma concentrations.
Co-administration of methadone with metamizole, which is an inducer of metabolising enzymes including CYP2B6 and CYP3A4 may cause a reduction in plasma concentrations of methadone with potential decrease in clinical efficacy. Therefore, caution is advised when metamizole and methadone are administered concurrently; clinical response and/or drug levels should be monitored as appropriate.
Effects of methadone on other drugs;
Methadone may increase plasma desipramine levels and increase desipramine side-effects when given concurrently.
Zidovudine – methadone may increase the plasma concentrations of zidovudine.
Mexiletine – methadone may delay mexiletine absorption.
Metoclopramide and domperidone – the gastrointestinal effects may be antagonised by methadone.
Methadone treatment has been found to decrease the rate of absorption and decrease the bioavailability of the nucleoside reverse transcriptase inhibitors didanosine and to a lesser extent stavudine.
Other serotonergic drugs: Methadone is a weak serotonin uptake inhibitor. There is an increased risk of serotonin syndrome when methadone is co-administered with other serotonergic drugs (e.g. SSRIs, SNRIs, TCAs, MAOIs, serotonergic anti-emetics, serotonergic anti-migraine drugs, St. John's Wort). This is not an exhaustive list.
Other important interactions;
In patients taking drugs affecting cardiac conduction, which may affect electrolyte balance or may affect QT prolongation (e.g. centrally acting alpha-adrenergic blockers such as lofexidine and clonidine), there is an increased risk of hypotension, cognitive effects and cardiac events (including ECG changes) when methadone is taken concurrently – see section 4.4.
As serious and sometimes fatal reactions have occurred following administration of pethidine to patients receiving MAOIs, other drugs related to pethidine are contraindicated in patients taking MAOI's (including moclobemide) or within 14 days of stopping such treatment, (see section 4.3) as there is a risk of CNS excitation or depression.
Cross tolerance and cross dependence can be expected between other opioids acting at the same receptors.
Fluconazole may raise methadone levels due to decreased methadone metabolism.
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.
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).4.6 Fertility, pregnancy and lactation
\*Pregnancy:\*
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.
Methadone should only be used in pregnancy if the physician considers that the potential benefits outweigh the risks. It should be used cautiously under the close supervision of a physician if the physician considers it essential to continue or initiate (in the case of an i.v. opioid user) methadone maintenance. It may be necessary to increase the dose of methadone if withdrawal symptoms develop as increased clearance and reduced plasma levels have been reported during pregnancy.
Infants of methadone-maintained mothers may experience symptoms of withdrawal \*in utero\* and following birth.
Reports of visual disorders have been reported in neonates and children following exposure to methadone during pregnancy. Although other factors have also been present, there is sufficient evidence to suggest that an association is possible (see section 4.4).
Methadone should not be used during labour as the prolonged duration of action increases the risk of neonatal depression.
\*Breast-feeding:\*
Methadone is excreted in breast milk at low levels. The decision to recommend breast-feeding 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
Methadone may produce drowsiness and patients should be advised not to drive or operate machinery if affected. Once affected, the time after which such activities may be resumed is extremely variable between patients and should 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
Tabulated list of adverse reactions
Adverse reactions frequency are defined using 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 | Lymphocytosis |
| \*\*Endocrine disorders\*\* | Not known | Adrenal insufficiency, increased prolactin concentrations, decreased testosterone concentrations, hypogonadism, hypoglycaemia |
| \*\*Metabolism and nutrition disorders\*\* | Not known | Hypoglycaemia |
| \*\*Psychiatric disorders\*\* | Not known | Drug dependence (see section 4.4), hallucinations, confusion, mood changes including dysphoria, decreased libido |
| \*\*Nervous system disorders\*\* | Not known | Methadone may increase intra-cranial pressure, particularly when it is already raised. Dizziness, headache, drowsiness |
| \*\*Eye disorders\*\* | Not known | Miosis, nystagmus1, strabismus1, visual acuity reduced1 |
| \*\*Ear and labyrinth disorders\*\* | Not known | Vertigo |
| \*\*Cardiac disorders\*\* | Not known | Cases of QT prolongation and torsade de pointes have been rarely reported. Bradycardia, palpitations, tachycardia |
| \*\*Vascular disorders\*\* | Not known | Hypotension, facial flushing |
| \*\*Respiratory, thoracic and mediastinal disorders\*\* | Not known | Respiratory depression, Exacerbation of existing asthma, sleep apnoea |
| \*\*Gastrointestinal disorders\*\* | Not known | Nausea, vomiting, constipation, dry mouth |
| \*\*Hepatobiliary disorders\*\* | Not known | Biliary spasm |
| \*\*Skin and subcutaneous tissue disorders\*\* | Not known | Rashes, pruritus, urticaria, excessive sweating |
| \*\*Renal and urinary disorders\*\* | Not known | Difficulty in micturation, ureteric spasm, antidiuretic effect |
| \*\*Reproductive system and breast disorders\*\* | Not known | Erectile dysfunction, reductions in the ejaculate volume and seminal vesicular and prostatic secretions |
| \*\*General disorders and administration site conditions\*\* | Unknown | Drug withdrawal syndrome. In prolonged use it should not be administered more than twice daily to avoid the risk of accumulation and overdosage. |
| Not known | Hypothermia. |
| \*\*Investigations\*\* | Not known | Globulins increased, blood albumin increased |
1Visual effects have been reported in infants and children exposed to methadone during pregnancy.
\*\*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 or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.4.9 Overdose
Patients 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\*
Overdosage of methadone is characterised by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), pulmonary oedema, extreme somnolence, progressing to stupor or coma, maximally constricted pupils, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. Hypoglycaemia has been reported. The presence and signs of drug abuse supports the diagnosis.
In children, methadone overdose produces drowsiness, floppiness, constricted pupils and apnoea.
In severe overdosage, particularly by the intravenous route, apnoea, circulatory collapse, cardiac arrest and death may occur.
\*Emergency procedures\*
If ingestion is recent, gastric aspiration and lavage can be employed after acute poisoning.
Primary attention should be given to the re-establishment of adequate respiratory exchange through provision of a patent airway and institution of assisted or controlled ventilation. Narcotic antagonists can be used to counteract the potentially lethal respiratory depression in a nontolerant individual, especially a child. Methadone is, however, a long-acting depressant (36-48 hours) whereas the antagonists act for much shorter periods (1-3 hours). The patient must, therefore, be monitored continuously for recurrence of respiratory depression and treated repeatedly with the narcotic antagonist as needed. If the respiratory depression is only due to overdosage with methadone, the use of other respiratory stimulants is not indicated.
An antagonist should not be administered in the absence of clinically significant respiratory or cardiovascular depression. Intravenously administered narcotic antagonists (naloxone, nalorphine or levallorphan) can be used to reverse signs of intoxication and should be given repeatedly until the patient's status remains satisfactory.
Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated.
In an individual physically dependent on narcotics, the administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome. The severity of this syndrome will depend on the degree of physical dependence and the dose of the antagonist administered. The use of a narcotic antagonist in such a person should be avoided if possible. If it must be used to treat serious respiratory depression in the physically dependent patient, the antagonist should be administered with extreme care and by titration with smaller than usual doses of the antagonist.
Patients should be monitored for signs of relapse for at least 48 hours.
## Pharmacological Properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Drugs used in opioid dependence
ATC code: N07BC02
Methadone is an opioid agonist with actions predominantly at the µ 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 κ and σ 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
Its long duration of action enables it to be used daily on a supervised basis in opioid dependent individuals.5.2 Pharmacokinetic properties
Absorption
Methadone is well absorbed from the gastrointestinal tract with peak plasma levels occurring 1-5 hours after a single dose. Wide variations in plasma levels occur during maintenance therapy. Plasma levels may decrease on long term maintenance suggesting tolerance to develop possibly as a result of auto-induction of hepatic microsomal enzymes.
Distribution
Methadone is widely distributed in the tissues. It diffuses across the placenta and is excreted in breast milk. Plasma protein binding is 60-90%. After repeated administration, there is a gradual accumulation in the tissues and on discontinuation low concentrations in the plasma are maintained by slow release from extravascular binding sites accounting for the relatively mild but protracted withdrawal syndrome.
Biotransformation / Elimination
N-demethylation to the inactive major metabolite 2-ethylidine-1, 5-dimethyl-3, 3-diphenylpyrrolidine and other pyrrolidines and pyrroline occurs in the liver. These metabolites are excreted in the faeces and urine together with unchanged methadone. Urinary excretion is increased with an acidic urine. The elimination half-life is long and varies considerably with a range of 15-60 hours having been reported. Decreased excretion of methadone and its metabolites occur in liver dysfunction and urinary elimination is reduced in renal failure.
In methadone-maintained pregnant women, trough plasma levels have been found to be significantly lower and total or unbound methadone clearance greater during pregnancy than after delivery.5.3 Preclinical safety data
No relevant data.
## Pharmaceutical Particulars
6.1 List of excipients
Benzoic acid solution (contains benzoic acid and propylene glycol)
Syrup (Sucrose)
Green S dye E142
Tartrazine E102
Sunset yellow E110
Purified water6.2 Incompatibilities
None reported.6.3 Shelf life
3 years unopened
Use within 56 days of first opening6.4 Special precautions for storage
Store below 25ºC.
Keep this medicine out of the sight and reach of children. Store this medicine in a safe and secure storage space, where other people cannot access it. It can cause serious harm and even be fatal to people when it has not been prescribed for them.6.5 Nature and contents of container
500ml: Amber soda lime silica glass bottle with white polypropylene cap with polyethylene laminate wad or 28mm tamper evident plastic cap with polyethylene laminate wad.
500ml: Round high density polythene bottle with 28mm polypropylene cap with polyethylene laminate wad or 28mm tamper evident cap with polyethylene laminate wad.
1Lt, 2Lt and 5Lt high density polyethylene bottle with 38mm polypropylene, tamper evident cap with polyethylene laminate wad.6.6 Special precautions for disposal and other handling
None.
- Company Detail Path
- /organization/thornton-and-ross-ltd
