METHADONE HYDROCHLORIDE DTF (SUGAR FREE) 1 MG / 1ML ORAL SOLUTION - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Methadone Hydrochloride DTF (Sugar Free) 1mg/1ml Oral Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Methadone Hydrochloride 1mg/1ml

For the full list of excipients see section 6.1.

3 PHARMACEUTICAL FORM

Oral Solution

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For use in the treatment of opioid drug addictions (as a narcotic abstinence syndrome suppressant) and the treatment of moderate to severe pain.

4.2 Posology and method of administration

Posology

Addiction:

Adults: Initially 10–20mg per day, increasing by 10–20mg per day until there are no signs of withdrawal or intoxication.

Elderly: In the case of the elderly or ill patients repeated doses should only be given with extreme caution.

Children: Not recommended for children.

Pain:

Adults: Usual single dose 5 to 10mg orally. Owing to its long plasma half life, caution with repeated dosage should be observed in the very ill or elderly. The usual initial dose should be 5 to 10mg, 6 to 8 hourly, later adjusted to the degree of pain relief obtained.

Elderly: Use caution with repeated dosage in elderly and ill patients.

Children: Not suitable.

Prior to starting treatment with opioids for pain, 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 dose is adjusted according to the degree of dependence with aim of gradual reduction.

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. Patients at risk of paralytic ileus. Patients dependent on non-opioid drugs and alcohol. Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression. Methadone is not suitable for children. Known hypersensitivity to methadone or any ingredients in the medicine. Use during an acute asthma attack is not recommended. Patients with head injury and raised intracranial pressure.

4.4 Special warnings and precautions for use

In cases of hepatic or renal impairment caution should be exercised.

In the case of elderly or ill patients, repeated doses should only be given with extreme caution.

Drug dependence, tolerance and potential for abuse

Prolonged use of this product may lead to drug dependence (addiction), even at therapeutic doses. 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 treatment should be reviewed regularly in all patients.

When used to treat pain 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). Additional support and monitoring may be necessary when prescribing for patients at risk of opioid misuse. A comprehensive patient history should be taken to document concomitant medications, including over-the-counter medicines and medicines obtained on-line, and past and present medical and psychiatric conditions. Patients may find that treatment is less effective with chronic use and they may express a need to increase the dose to obtain the same level of pain control as initially experienced. Patients may also supplement their treatment with additional pain relievers. These could be signs that the patient is developing tolerance. The risks of developing tolerance should be explained to the patient.

Tolerance and dependence may occur as with morphine.

Methadone can produce drowsiness and reduce consciousness although tolerance to these effects can occur after repeated use.

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.

When used for substitution or maintenance therapy 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.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs

Concomitant use of Methadone Solution 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 Solution 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).

Hyperalgesia

Patients on long-term opioid therapy for analgesia may present with increased pain diagnosed as hyperalgesia. This might be qualitatively and anatomically distinct from pain related to disease progression or to breakthrough pain resulting from development of opioid tolerance. Pain associated with hyperalgesia tends to be more diffuse than the pre-existing pain and less defined in quality. Symptoms of hyperalgesia may resolve with a reduction of opioid dose.

Respiratory depression

Due to the slow accumulation of methadone in the tissues, respiratory depression may not be fully apparent for a week or two. Asthma may be exacerbated due to histamine release. Concomitant treatment with other agents with CNS depressant activity is not advised due to the potential for CNS and respiratory depression (see also section 4.5 Interactions).

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 glucocorticoi­dreplacement 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).

Neonates/children

As there is a risk of greater respiratory depression in neonates and because there are currently insufficient published data on the use in children, methadone is not recommended in those under 16 (see sections 4.2, 5.2).

Further warnings

Babies born to mothers receiving methadone may suffer withdrawal symptoms.

Methadone should be used with great caution in patients with acute alcoholism, convulsive disorders and head injuries.

Methadone, as with other opiates, has the potential to increase intracranial pressure especially where it is already raised.

Methadone should be used with caution in patients with hypothyroidism, adrenocortical insufficiency, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders, myasthenia gravis, a family history of sudden death or electrolyte abnormalities.

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.

Caution should be exercised in patients who are concurrently taking CNS depressants.

Excipient warnings:

This product contains

E110 and E104 which may cause allergic reactions.

Methyl and Propylhydroxy­benzoates. These may cause allergic reactions (possibly delayed).

Maltitol – If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

4.5 Interaction with other medicinal products and other forms of interaction

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 additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).

Serotonergic drugs:

Serotonergic syndrome may occur with concomitant administration of methadone with pethidine, monoamineoxidase (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.

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.

Antiarrhythmics

Mexiletine absorption may be inhibited by methadone

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:

Concurrent use or within 2 weeks of discontinuation of MAOI's is contraindicated (see 4.3 Contraindi­cations) as they may prolong and enhance the respiratory depressant effects of methadone.

Gastrointestinal Drugs

The effects of metoclopramide and domperidone may be antagonised by 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 4.8 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

Pregnancy

There is no evidence of safety in human pregnancy. A careful risk/benefit assessment should be made before administration to pregnant women because of possible adverse effects on the foetus and neonate including respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths. However, methadone has not been associated with congenital malformations.

It may be necessary to increase the dose of methadone if withdrawal symptoms develop. Increased clearance and reduced plasma levels have been reported during pregnancy.

Regular use during pregnancy may cause drug dependence in the foetus, leading to withdrawal symptoms in the neonate.

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.

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 breastfed 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 as it may cause drowsiness and reduce alertness. The time after which such activities may be safely resumed is extremely patient dependant and must be decided by the physician.

4.8 Undesirable effects

Cardiac Disorders

Bradycardia and palpitations can occur. Cases of QT prolongation and torsades de pointes have been rarely 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.

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.

Renal and urinary disorders

Less commonly micturition difficulties are observed.

Skin and subcutaneous tissue disorders

Rashes. Long-term administration may produce excessive sweating

Endocrine Disorders

Raised prolactin levels with long-term administration.

Vascular disorders

Orthostatic hypotension, facial flushing.

General disorders and administrative site conditions

Hypothermia

Uncommon: drug withdrawal syndrome

Reproductive system and breast disorders

Galactorrhoea, dysmenorrhoea, amenorrhoea

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. Restlessness and decreased libido.

Metabolism and nutrition disorders SOC

Hypoglycaemia (frequency not known).

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 Website: 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: 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.

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 (0.1mg per Kg) or Levallorphan (0.02mg per Kg) should be given intravenously as soon as possible and repeated, if necessary, every 15 minutes.

Oxygen, intravenous fluids, vasopressors and other supportive measures should be employed as indicated. In a person physically dependent on narcotics, administration of the usual dose of a narcotic antagonist will precipitate an acute withdrawal syndrome; use of the antagonist in such a person should be avoided, if possible, but if it must be used to treat serious respiratory depression it should be administered with great care.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

ATC Code: N07BC02

Methadone is a strong opioid agonist with actions predominantly at the p receptor. The analgesic activity of the racemate is almost entirely due to the 1-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects.

Methadone also has some agonist actions at the K and 8 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 10mg, a peak plasma concentration of 75gg per litre is reached in one hour. With regular oral doses of 100120mg daily, plasma concentrations rise from trough levels of approximately 500^ig/L to a peak of about 900^g/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

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lycasin, quinoline yellow (E104), sunset yellow (E110), green s (E142), potassium sorbate, hydrochloric acid (E507) and purified water.

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

Amber (type III) glass bottle: 2 years

Use within 28 days of opening.

6.4 Special precautions for storage

Do not store above 25°C

Store in original container

Protect from light

Do not refrigerate

Store in an upright position

6.5 Nature and contents of container

Amber glass (type III) bottle containing 500ml

Closure: HDPE tamper evident child-proof closure

6.6 Special precautions for disposal

Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (schedule 2). Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Ayrton Saunders Ltd

9 Arkwright Road

Astmoor Industrial Estate

Runcorn

Cheshire

WA7 1NU

8 MARKETING AUTHORISATION NUMBER(S)

PL 16431/0183