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METHADONE 1MG-ML ORAL SOLUTION SUGAR-FREE

Active substance(s): METHADONE HYDROCHLORIDE / METHADONE HYDROCHLORIDE / METHADONE HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Methadone 1mg/ml oral solution sugar-free

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains methadone hydrochloride 1mg.
Excipients with known effect
Contains excipients Liquid Maltitol (E 965) 0.4 ml/ml and Sunset Yellow
(E110) 0.008 mg/ml.
For the full list of excipients, see section 6.1

3

PHARMACEUTICAL FORM
Oral solution
A clear, green oral solution

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
The treatment of opioid drug addiction as a narcotic abstinence syndrome
suppressant.

4.2

Posology and method of administration
Posology
The dose is adjusted according to the degree of dependence with the aim of
gradual reduction.
Adults
Initially 10 - 20mg per day, increasing by 10 - 20mg daily until there is no sign
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 be given with
extreme caution.
Paediatric population
Not recommended (see section 4.3)
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 opiod antagonists may be required.
Method of administration

For oral use only.

4.3

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
Acute alcoholism (See section 4.5)
Head injury and raised intracranial pressure (further rise in intracranial
pressure – see section 4.8: papillary response affected)
Concurrent administration of MAOI drugs, including moclobemide, or for 2
weeks after stopping (See section 4.5)
Use during labour (prolonged duration of action increases the risk of neonatal
depression)
Children (serious risk of toxicity)







4.4



Patients with ulcerative colitis, since methadone may precipitate toxic dilation
or spasm of the colon.



Patients dependent on non-opioid drugs



Patients with severe hepatic impairment as it may precipitate encephalopathy



Patients with biliary and renal tract spasm.

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). 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 of the morphine type may occur. Methadone should be
given with caution to patients with 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.
Methadone can produce drowsiness and reduce consciousness although tolerance to
these effects can occur after repeated use.
Cases of QT interval prolongation and torsade 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 CYP 3A4 inhibitors (see
section 4.5).
In patients with recognised risk factors for QT prolongation, or in case of concomitant
treatment with drugs that have a potential for QT-prolongation,
ECG monitoring is recommended prior to methadone treatment, with a further
ECG test at dose stabilisation.
ECG monitoring is recommended, in patients without recognised risk factors for QT
prolongation, before dose titration above 100 mg/d and at seven days after titration.
Caution should be exercised in patients who are concurrently taking CNS depressants.
This product contains sunset yellow which may cause allergic reaction.
Patients with rare hereditary problems of fructose intolerance should not take this
medicine.
Methadone, as with other opiates, has the potential to increase intracranial pressure
especially where it is already raised.
Babies born to mothers receiving methadone may suffer withdrawal symptoms
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.
Hepatic impairment
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.

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).
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
Contains Liquid Maltitol (E 965). Patients with rare hereditary problems of fructose
intolerance should not take this medicine

4.5

Interaction with other medicinal products and other forms of interaction
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 concomintantly. (See 4.4 Special
warnings and precautions for use).
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.
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.
MAOI's:
The concurrent use of MAOl'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.
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 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

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. 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.
It should not be used during labour, see "contra-indications"
Lactation:
Methadone is excreted in breast milk, though it is unclear whether this contributes to
adverse effects on the nursing infant

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. The time after which such activities can be
safely resumed is extremely patient dependent 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:

4.8



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

Undesirable effects
Endocrine Disorders
Raised prolactin levels with long-term administration.
Psychiatric disorders
Dependence, confusion particularity 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.
Gastrointestlnal 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 urinarv disorders
Less commonly micturition difficulties are observed.

Reproductive system and breast disorders
Galactorrhoea, dysmenorrhoea, amenorrhoea
General disorders
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.

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,
apnea, circulatory collapse, cardiac arrest and death may occur.
Treatment

A patent airway and assisted or controlled ventilation must be assured.
Narcotic antagonists may be required but it should be remembered that
methadone is a long acting depressant (36 - 48 hours), whereas antagonists act
for 1 -3 hours, so that treatment with the latter must be repeated as needed.
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
(0.1mg/kg) or Levallorphan (0.02mg/kg) should be given intravenously as
soon as possible and repeated, if necessary, every 15 minutes. Oxygen,
intravenous fluids, 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
Pharmacotherapeutic group: (Nervous system, other nervous system drugs, drugs
used in addictive disorders, methadone).
Methadone is a strong opioid agonist with actions predominantly at the µ receptor.
The analgesic activity of the race mate 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 δ 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
Absorption
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.
Distribution
With an intramuscular dose of 10 mg, a peak plasma concentration of 75 µg
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 µg/L to a
peak of about 900 µg/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.
Biotransformation
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.
Elimination
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 those already included in other sections of the SmPC.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Liquid maltitol (E965),
Sodium Benzoate (E211),
Green S (E142),
Sunset Yellow (E110),
Quinoline Yellow (E104),
Hydrochloric acid (for pH-adjustment)
Purified Water.

6.2

Incompatibilities

Not applicable

6.3

Shelf life
2 years
Use within 28 days of opening

6.4

Special precautions for storage
Do not Store above 25°C.

6.5

Nature and contents of container
30ml, 50ml, 100ml and 500ml of the oral solution in Type III amber glass bottles
fitted with child resistant closures. Contact material: Polypropylene.
500ml and 1L HDPE bottle with tamper evident and child resistant cap. The material
of construction of the closure is HDPE with an EP wad.
2.5L and 5L bottle with tamper evident cap or tamper evidence will be provided with
a tamper evident seal. The material of construction of the closures is HDPE with an
EP wad.
Not all pack sizes may be marketed.

6.6

Special precautions for disposal
Any unused product or waste material should be returned to the pharmacy or
doctor for disposal.

7

MARKETING AUTHORISATION HOLDER
Martindale Pharmaceuticals Ltd
Bampton Road,
Harold Hill,
Romford,
RM3 8UG, U.K.

8

MARKETING AUTHORISATION NUMBER(S)
PL 00156/0321

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 2nd June 2010

10

DATE OF REVISION OF THE TEXT
23/03/2017

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Source: Medicines and Healthcare Products Regulatory Agency

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