METHADOSE 20 MG / 1ML ORAL CONCENTRATE - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Methadose 20mg/1ml Oral Concentrate

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Active Ingredient                                                    P­er 5ml

Methadone Hydrochloride BP                         ­100mg

Excipients with known effect:

Methyl hydroxybenzoate (E218)

Propyl hydroxybenzoate (E216)

Propylene Glycol (E1520)

For full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Pale brown solution for oral administration.

4. CLINICAL PARTICULARS

4.1. Therapeutic Indications

For use in the treatment of opioid drug addiction (as a narcotic abstinence syndrome suppressant)

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: Initially 10–20mg per day, increasing by 10–20mg per day until there are no signs of withdrawal or intoxication. The usual dose is 40–60mg per day. The dose is adjusted according to the degree of dependence with the aim of gradual reduction.

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

Children: Not recommended for children.

Method of Administration

For oral administration only. This product is intended to be used with a diluent.

4.3. Contraindications

Respiratory depression, obstructive airway disease. Use during an acute asthma attack is not recommended.

Acute alcoholism (see section 4.5).

Concurrent administration with MAO inhibitors, including moclodemide, or within two weeks of discontinuation of treatment with them (see section 4.5).

Patients dependent on non-opioid drugs.

Use during labour is not recommended, the prolonged duration of action increases the risk of neonatal depression.

Methadone is not suitable for children (serious risk of toxicity).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Raised intracranial pressure (further rise in intracranial pressure – see section 4.8: papillary response affected) or head injury.

Phaeochromocytoma.

Risk of paralytic ileus (including drug induced gastrointestinal hypotonia).

4.4. Special warnings and precautions for use

Caution should be exercised in patients with hepatic dysfunction or renal dysfunction.

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

Drug dependence, tolerance and potential for abuse

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.

Methadone is a drug of addiction and is controlled under the Misuse of Drugs Act 1971 (Schedule 2). It 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 possible death.

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.

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.

Biliary tract disorders.

Adrenal insufficiency

Opioid analgesics may cause reversible adrenal insufficiency requiring monitoring and glucocorticoid replacement therapy. Symptoms of adrenal insufficiency may include nausea, vomiting, loss of appetite, fatigue, weakness, dizziness, or low blood pressure.

Decreased Sex Hormones and increased prolactin

Long-term use of opioid analgesics may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.

Hypoglycaemia

Hypoglycaemia has been observed in the context of methadone overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see section 4.8 and section 4.9)

Paediatric population

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

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.

Further warnings

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 history of asthma (see section 4.3), convulsive disorders, depressed respiratory reserve, hypothyroidism, prostatic hyperplasia, hypotension, shock, inflammatory or obstructive bowel disorders or myasthenia gravis. 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 torsades de pointes have been reported during treatment with methadone, particularly at high doses (>100 mg/d).

Methadone should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of:

– history of cardiac conduction abnormalities,

– advanced heart disease or ischaemic heart disease,

– Liver disease,

– family history of sudden death,

– Electrolyte abnormalities, i.e. hypokalaemia, hypomagnesaemia

– concomitant treatment with drugs that have a potential for QT-prolongation, – concomitant treatment with drugs which may cause electrolyte abnormalities,

– concomitant treatment with cytochrome P450 CYP3A4 inhibitors (see section 4.5).

In patients with 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 100mg/d and at seven days after titration.

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

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

Concomitant use of Methadone and sedative medicines such as benzodiazepines or related drugs may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicines should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe Methadone concomitantly with sedative medicines, the lowest effective dose should be used, and the duration of treatment should be as short as possible.

The patients should be followed closely for signs and symptoms of respiratory depression and sedation. In this respect, it is strongly recommended to inform patients and their caregivers to be aware of these symptoms (see section 4.5).

Excipient warnings:

This product contains

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

Propylene glycol. This medicine contain 155.6mg propylene glycol per

5ml.

While propylene glycol has not been shown to cause reproductive or developmental toxicity in animals or humans, it may reach the foetus and was found in milk. As a consequence, administration of propylene glycol to pregnant or lactating patients should be considered on a case by case basis.

Medical monitoring is required in patients with impaired renal or hepatic functions because various adverse events attributed to propylene glycol have been reported such as renal dysfunction (acute tubular necrosis), acute renal failure and liver dysfunction.

4.5. Interaction with other medicinal products and other forms of interaction

MAOI’s:

The concurrent use of MAOI’s is contraindicated (see 4.3 Contraindi­cations) as they may prolong and enhance the respiratory depressant effects of methadone.

CNS depressants:

Anaesthetics, hypnotics (including benzodiazepines, chloral hydrate and chlormethiazole), anxiolytics, sedatives, barbiturates, phenothiazines, some other major tranquillizers and tricyclic antidepressants may increase the general depressant effects of methadone when used concomitantly. (See 4.4 Special warnings and precautions for use). Antipsychotics may enhance the sedative effects and hypotensive effects of methadone.

Methadone may increase desimipramine levels by up to a factor of two.

There are reports that antidepressant drugs (e.g. fluvoxamine and fluoxetine) may increase serum levels of methadone.

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.

Alcohol may enhance the sedative and hypotensive effects of methadone and increase respiratory depression.

Histamine H2 Antagonists:

Histamine H2 antagonists such as cimetidine, can reduce the protein binding of methadone resulting in increased opiate action.

Antibacterials

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.

Ciprofloxacin:

Plasma levels of methadone may increase with concurrent administration of ciprofloxacin due to inhibition of CYP 1A2 and CYP 3A4. Reduced serum concentrations of ciprofloxacin may occur. Concomitant use may lead to sedation, confusion and respiratory depression.

Erythromycin: Theoretically this may increase methadone levels due to decreased methadone metabolism.

Antifungals: Fluconazole, voricanozole and ketoconazole: May raise methadone levels, due to decreased methadone metabolism.

Anticonvulsants (Phenytoin, Phenobarbital, Carbamazepine and Primidone): Induces methadone metabolism with the risk of precipitating withdrawal syndrome. Adjustment of the dose of methadone should be considered.

pH of urine:

Drugs that acidify or alkalinise the urine may have an effect on clearance of methadone as it is increased at acidic pH and decreased at alkaline pH.

Opioid agonist analgesics:

Additive CNS depression, respiratory depression and hypotension

Opioid antagonists:

Naloxone and naltrexone antagonises the analgesic, CNS and respiratory depressant effects of methadone and can rapidly precipitate withdrawal symptoms (See Section 4.9 Overdose). Similarly buprenorphine and pentazocine may precipitate withdrawal symptoms.

Antiretroviral Agents such as Nevirapine, Efavirenz, Nelfinavir, Ritonavir, Abacavir:

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 the methadone dose should be adjusted accordingly.

Cyclizine and other sedating antihistamines

May have additive psychoactive effects; antimuscarinic effects at high doses.

Other Drugs:

Methadone may have an effect on other drugs as a consequence of reduced gastro-intestinal 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.

Grapefruit Juice:

There are several anecdotal reports of raised methadone levels due to decreased methadone metabolism.

Drugs affecting gastric emptying:

Domperidone and metoclopramide may increase the speed of onset but not the extent of methadone absorption by reversing the delayed gastric emptying associated with opioids. Conversely, methadone may antagonise the effect of domperidone/me­toclopramide on gastro-intestinal activity.

Antiarrhythmics:

Methadone delays the absorption of mexiletine.

Methadone and QT interval prolongation:

In patients taking drugs affecting cardiac conduction, or drugs which may affect electrolyte balance there is a risk of cardiac events when methadone is taken concurrently. Please refer to Section 4.4.

Centrally acting alpha-adrenergic blockers

There is an increased risk of hypotension, cognitive effects and ECG changes (including PR interval and QT interval prolongation) when methadone is coadministered with centrally acting alpha-adrenergic blockers (lofexidine and clonidine).

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).

4.6. Fertility, pregnancy and lactation

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.

During labour there is a risk of gastric stasis and inhalation pneumonia in the mother and foetal distress. Methadone should not be used during labour, (see 4.3 Contraindi­cations).

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 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.

Reports of visual disorders have been reported in neonates following exposure to methadone during pregnancy. However, other factors have also been present and a definitive causal link to methadone has not been established (see section 4.4).

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 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:

The medicine is likely to affect your ability to drive

Do not drive until you know how the medicine affects you

It is an offence to drive while under the influence of this medicine

However, you would not be committing an offence (called ‘statutory defence’) if:

– The medicine has been prescribed to treat a medical or dental problem and

– You have taken it according to the instructions given by the prescriber and in the information provided with the medicine and

– It was not affecting your ability to drive safely.

4.8. Undesirable effects

The adverse effects of methadone are generally the same as with other opioids, most commonly nausea and vomiting, which are observed in approximately 20% of the patients who undergo methadone out-patient treatment, where the medicinal control is often unsatisfactory.

The most serious adverse effect of methadone is respiratory depression, which may emerge during the stabilisation phase. Apnoea, shock and cardiac arrest have occurred.

Adverse reactions listed below are classified according to frequency and system organ class. These reactions are more frequently observed in non-opioid-tolerant individuals. Frequency groupings are defined according to the following convention: very common (> 1/10), common (> 1/100 to <1/10), uncommon (> 1/1,000 to < 1/100), rare (> 1/10,000 to < 1/1,000), very rare (<1/10,000), not known (cannot be estimated from the available data).

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 the 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, apnoea, circulatory collapse, cardiac arrest and death may occur. Hypoglycaemia has been reported.

Treatment: A patent airway and assisted or controlled ventilation must be assured.

Narcotic antagonists may be required but it should be remembered that Methadone is a long acting depressant (36 to 48 hours) whereas antagonists act for 1 to 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 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 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 propertiesATC 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 li receptor. The analgesic activity of the racemate is almost entirely due to the 1isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have antitussive 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 anti-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 gastrointestinal 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 the 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 l0mg, a peak plasma concentration of 75 pg per litre is reached in one hour. With regular oral doses of 100–120mg daily, plasma concentrations rise from trough levels of approximately 500 pg/L to a peak of about 900 pg/L in 4 hours. Marked variations in plasma levels occur in dependent persons on a stable dose of oral Methadone, without any relation to symptoms. Methadone is secreted in sweat and found in saliva and in high concentration in gastric juice. The concentration in cord blood is about half the maternal levels.

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 to 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 life time of elimination.

5.3. Pre-clinical Safety Data

None stated

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene Glycol

Propyl Hydroxybenzoate

Methyl Hydroxybenzoate

Caramel E150

Purified Water

6.2. Incompatibilities

None known

6.3. Shelf Life

Shelf life – 2 years

Shelf life after first opening container – 3 months

Shelf life after dilution – 3 months

6.4. Special Precautions for Storage

Store between 25oC but not in a refrigerator.

6.5. Nature and contents of container

Bottle:           Amber (type III) glass bottle

Closure: HDPE, EPE wadded, child resistant tamper evident closure Capacity: 150ml or 500ml

Not all pack sizes may be marketed.

6.6. Instruction for Use/Handling

This product is intended for use with a diluent.

7. MARKETING AUTHORISATION HOLDER

Rosemont Pharmaceuticals Ltd

Rosemont House

Yorkdale Industrial Park

Braithwaite Street

Leeds

LS11 9XE

8. MARKETING AUTHORIZATION NUMBER

PL 0427/0100

9. DATE OF FIRST AUTHORISATION/RE­NEWAL OF AUTHORISATION

31 January 1996