Document: Metadon Evolan oral solution ENG SmPC change

• Metadon Evolan oral solution SmPC
• Metadon Evolan oral solution ENG SmPC

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SUMMARY of PRODUCT CHARACTERISTICS

Metadon Evolan oral solution 1 mg/ml

Methadone hydrochloride 1 mg/ml.

Also contains the excipients:

Liquid Maltitol (E965) 550.00 mg/ml

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Oral solution

Clear colourless liquid

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

-Treatment of withdrawal symptoms for heroin/opiates aimed at detoxification.

-Maintenance treatment in opioid addicts that have no immediate prospects of withdrawal.

4.2 Posology and method of administration

Treatment of withdrawal symptoms

Prescription of methadone should preferably be made in special treatment institutionsin view of the great risks that the treatment involves.

In cases in which this is not possible, contact should be made with the nearest drugsadvice centre.

The initial dose may be estimated from the severity of the withdrawal symptoms. This can usually be set at 20mg orally (preferably in oral solution form). Depending on the reduction in the withdrawal symptoms: the reduction in pulse rate, pupil dilation, hyper peristalsis and erection of body hair, a further 20mg may be administered orally after 3-4 hours. Treatment may be continued with 30-50 mg methadone orally daily (preferably in solution, otherwise in tablet form) and may then be reduced slowly in about 3 weeks.

Maintenance treatment

Initial comment: see “Treatment of withdrawal symptoms”. The initial dose may be set in the same way as in the withdrawal regimen. The daily dose (preferably in oral solution form) is 50-100mg, usually about 60mg. A withdrawal regimen may be considered when physical and psychosocial conditions have improved.

Hepatic function disorder:

Chronic viral hepatitis frequently occurs in intravenous drug users. Particular caution should be exercised if Metadon Evolan must be used in patients with liver function disorder. In patients with liver cirrhosis the metabolic breakdown of methadone is retarded and the first -pass effect is reduced. This may result in higher methadone plasma levels. Metadon Evolan should be administered at a dose lower than that usually recommended and the patient’s response should be used as a guideline for further dosage requirements.

Renal function disorder:

Caution should be exercised in the use of methadone in patients with renal function disorder. The dose interval should be lengthened to a minimum of 8 hours if the glomerular filtration rate (GFR) is 10 – 50 ml/min and to a minimum of 12 hours if the GFR is lower than 10 ml/min.

Metadon Evolan 1mg/ml oral solution must not be administered parenterally.

It should be noted that patients develop auto induction of liver enzymes, causing a more rapid elimination of methadone. Moreover, patients will develop tolerance in due time. Several increments in dosing may be necessary in order to maintain an optimal effect.

The safety and efficacy of methadone in children and adolescents have not been established.

For specific information on prescribing and dispensing methadone, national guidelines should be consulted.

• Brain injury, elevated intracranial pressure and delirium tremens.

• Heart failure.

• Respiratory depression.

• Obstructive airway conditions and cyanosis.

• Hypersensitivity to one of the constituents of the product.

• If hypersensitivity to benzoates is known.

• Concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them.

• Children

Caution is advised and lower doses must be administered to patients with hypothyroidism, myxoedema, prostate hypertrophy, liver disease, and patients suffering from asthma and decreased respiratory reserve.

Patients should be warned to keep methadone from children.

In patients with kidney or gallstones it may be necessary to administer atropine or another spasmolytic prophylactically.

In elderly ambulatory and patients with cardiovascular disease there is an increased risk of hypotension and syncope.

This product contains liquid maltitol: patients with rare hereditary conditions such as fructose intolerance should not use this medicinal product.

Concomitant administration of other opiates, alcohol, barbiturates, benzodiazepines or other psychoactive drugs with a strong sedative effect may increase effects and side effects of methadone and should be avoided.

The serum concentration of methadone may increase for two hours after administration, and it is important that signs of overdose or other dangerous reactions are noted. During the titration period, it may be considered to observe the patient after taking the medication, in order to detect any unwanted reactions.

Caution should be observed in patients suffering from head injury or other conditions causing increased intracranial pressure.

Methadone should not be used in patients with paralytic ileus and associated acute abdomen and caution should be observed in obstructive and inflammatory bowel disease.

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 for development of prolonged QT interval, e.g. in case of: history of cardiac conduction abnormalities, advanced heart disease or ischaemic heart disease, family history of sudden death at a young age, electrolyte abnormalities (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, in particular women, ECG monitoring may be considered.

Pharmacokinetic interactions

P-glycoprotein inhibitors: Methadone is a P-glycoprotein substrate; all medicinal products that inhibit P-glycoprotein (quinidine, verapamil) may therefore raise the serum level of methadone. The pharma­codynamic effect of methadone may also increase due to better passage through the blood-brain-barrier.

CYP3A4 isoenzyme inducers: Methadone is a substrate for cytochrome P-450 isoenzyme 3A4 (CYP3A4) (see 5.2 Pharmacokinetic properties). In case of induction of CYP3A4, clearance of methadone will increase and the plasma level of methadone will fall. Inducers of this isoenzyme (barbiturates, carbamazepine, phenytoin, nevirapine, rifampicin, efavirenz, amprenavir, spironolactone, dexamethasone, hypericum perforatum (St. John’s wort)) may induce hepatic metabolism. For example, after 3 weeks of treatment with 600 mg efavirenz per day the mean peak concentrations of methadone and the AUC were lowered by 48% and 57% respectively in patients on methadone treatment (35-100 mg methadone per day). The consequences of enzyme induction will be more marked if the inducer is administered after treatment with methadone has already been started. Withdrawal symptoms as a consequence of such interactions were reported and consequently it may be necessary to increase the dose of methadone. If treatment with CYP3A4 inducers is stopped, the dose of methadone should be reduced.

CYP3A4-isoenzyme inhibitors: Methadone is a substrate for cytochrome P-450 isoenzyme 3A4 (CYP3A4) (see 5.2 Pharmacokinetic properties). In inhibition of CYP3A4, clearance of methadone will fall. Co-administration of CYP3A4 inhibitors (e.g. cannabinoids, clarithromycin, delavirdine, erythromycin, fluconazole,grapefruit juice, selective serotonin reuptake inhibitors, itraconazole, ketoconazole, fluoxetine, fluvoxamine, nefazodone and telithromycin) may result in increased plasma concentration of methadone. If these drugs are prescribed for methadone maintenance patients an awareness of the risk of overdose is needed.

Fluoxetine may also inhibit the metabolism of methadone likely linked to CYP2D6 inhibition.

Didanosine and stavudine: Methadone retards absorption and stimulates the first pass mechanism of stavudine and didanosine with a consequential decrease in the bioavailability of stavudine and didanosine.

Zidovudine: The plasma levels of zidovudine rise after the use of methadone in both oral and in­travenous administration of zidovudine. This is more marked in oral than in intravenous administration of zidovudine. These effects are probably caused by inhibition of glucuronisation of zidovudine and therefore reduced renal clearance of zidovudine. During treatment with methadone patients must be monitored for possible toxic signs of zidovudine, in which it may be necessary to reduce the dose of zidovudine.

Protease inhibitors: In contrast with what may be expected on the basis of the in vitro properties of protease inhibitors (as protease inhibitors in vitro are potent CYP3A4 inhibitors), it appears from various clinical studies of patients on methadone maintenance treatment that co-medication with ritonavir in combination with other protease inhibitors such as nelfinavir, saquinavir or lopinavir may cause a considerable lowering of the AUC of methadone with consequent withdrawal symptoms. The mechanism that underlies this induction effect on the metabolism of methadone by protease inhibitors is not yet known.

Products that affect the acidity of urine: Methadone is a weak base. Urine acidifiers (such as ammonium chloride and ascorbic acid) may increase the renal clearance of methadone.Patients in treatment with methadone are recommended to avoid products containing ammonium chloride.

Pharmacodynamic interactions

Opioid agonists/antagonists:

Opioid antagonists(naloxone and naltrexone) antagonise the effect of methadone and induce a withdrawal syndrome.

Partial agonists/antagonists(such as nalbuphine and buprenorphine) may partially increase the neurological respiratory suppressant and hypotensive effects of methadone. If these medicinal products are used in combination with methadone they may trigger and exacerbate neurological, respiratory and hypotensive effects. The agonistic or antagonistic effects depend on the dose of methadone and are more frequent if the dose of metha­done is low or moderate. These medicinal products may cause a withdrawal syndrome in the case of chronic treatment.

Medicinal products that suppress the CNS: medicinal products with a depressant effect on the CNS may make respiratory depression increase; it may therefore be necessary to reduce the dose of one or both medicinal products. Due to development of tolerance, the increased risk of respiratory depression is normally only seen with methadone shortly after introduction of CNS-depressants.

Anti-motility drugs: the concurrent use of methadone and anti-motility drugs (diphenoxylate and loperamide) may cause severe constipation and increase depression of the CNS. Opioid analgesics, in combination with antimuscarinics, may bring about severe constipation or paralytic ileus, particularly in chronic use.

Alcohol: May give rise to severe respiratory depression and hypotension.

MAO-inhibitors: Concomitant administration with MAO-inhibitors may result in enhanced dampening of the CNS, severe hypotension and/or respiratory arrest.

Methadone may cause QTc prolongation and patients who use other drugs that prolong cardiac conduction or could cause electrolyte abnormalities may be more at risk (see section 4.4).

4.6 Fertility, pregnancy and lactation

Pregnancy

Methadone administered to pregnant women for the management of opioid addiction has the potential for several adverse effects on the foetus and neonate. Limited data on the use of methadone in pregnancy in humans show no elevated risk of congenital abnormalities.Withdrawal symptoms / respiratory depression may occur in neonates of mothers that were treated with methadone chronically during pregnancy. Data from animal studies have shown reproduction toxicity (see 5.3). It is generally advisable not to detoxify the patient, especially after the 20^thweek of pregnancy, but to administer maintenance treatment with methadone. The use of Methadone oral solution just before and during birth is advised against because of the risk of neonatal respiratory depression.

Lactation

Methadone is excreted in breast milk, and the average milk/plasma ratio is 0.8. Breast feeding may be given at doses of up to 20 mg per day. At higher doses the benefits of breast feeding must be weighed against the possible adverse effects on the infant.

4.7 Effects on the ability to drive and to use machines

The ability to drive and to use machines is adversely affected by methadone. Users of methadone should not drive.

4.8 Undesirable effects

The undesirable effects of methadone treatment are in general the same as when treated with other opioids. The most common side effects are nausea and vomiting that is observed in approximately 20 % of the patients that go through methadone outpatient treatment, where the medicinal control is often unsatisfactory.

The most serious side 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 side effects are more frequently observed in non opioid-tolerant individuals. Frequency groupings are defined according to the following convention: Not known (cannot be estimated from the available data), 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).

System organ class MedDRA	Frequency	Adverse event
Blood and lymphatic system disorders	Not known	reversible thrombocytopenia has been reported in opioid patients with chronic hepatitis
Metabolism and nutrition disorders.	Common Uncommon Not known	Fluid retention anorexia hypokalemia, hypomagnesemia
Psychiatric disorders	Common Uncommon Not known	euphoria, hallucinations dysphoria, agitation, insomnia, disorientation, reduced libido Dependence and mood changes
Nervous system disorders	Common Uncommon	sedation headache, syncope
Eye disorders	Common	Blurred vision, miosis
Ear and labyrinth disorders	Common	Vertigo
Cardiac disorders	Rare Not known	ventricular arrhythmia – VF, VT, bradycardia, palpitations, cases of prolonged QT intervals and “torsade de pointes” have been reported in treatment with methadone, especially with high doses. sudden explained death, cardiac arrest
Vascular disorders	Uncommon Not known	facial flush, hypotension postural hypotension
Respiratory, thoracic and mediastinal disorders	Uncommon	pulmonary oedema, respiratory depression
Gastrointestinal disorders	Very common Common Uncommon Not known	nausea, vomiting obstipation xerostomia, glossitis taste disturbances
Hepatobiliary disorders	Uncommon	bile duct, dyskinesia
Skin and subcutaneous tissue disorders	Common Uncommon	transient rash, sweating pruritus, urticaria, other rash and in very uncommon cases bleeding urticaria
Renal and urinary disorders	Uncommon	Urinary retention and antidiuretic effect
Reproductive system and breast disorders	Uncommon	Reduced potency and amenorrhea
General disorders and administration site conditions	Common Uncommon Not known	fatigue oedema of the lower extremities, asthenia, oedema hypothermia
Investigations	Common	Weight increase

In long term use of methadone, as for maintenance treatment, the undesirable effects diminish successively and progressively during a period of several weeks however, obstipation and perspiration often remain. Long-term use of methadone may lead to morphine-like dependence. The abstinence syndromes are similar to the ones observed with morphine and heroine, however less intense, but more long-lasting.

4.9 Overdose

Symptoms of intoxication

Respiratory depression, depression of the central nervous system (from stupor to coma) hypothermia, bradycardia, hypotension and shock.

Cases of QT-interval prolongation and torsade de pointes have been reported during treatment with methadone, particularly at high doses (>>100mg/d).

Treatment of intoxication

In overdose with methadone the patient should be ventilated if necessary and naloxone administered as an antidote.

The dose of naloxone is 5 – 10 g/kg i.v., repeated every 10 - 20 minutes if necessary.

In view of the long elimination half life of methadone and the short half life of naloxone, several administrations are necessary.

5 PHARMACOLOGICAL PROPERTIES

ATC code: N07BC02

5.1 Pharmacodynamic properties

Methadone is an opioid agonist with an effect predominantly on the µ-receptor.

The analgesic effect of the racemate is almost entirely attributable to the l-isomer, which is at least 10 times as potent as an analgesic as the d-isomer. The d-isomer has no effect of significance on respiratory depression, but does have antitussive effects. Methadone also has some agonistic effects on the and opiate receptors. These effects result in analgesia, respiratory depression, cough suppression, nausea and vomiting (via an effect on the chemo-receptor 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 pA₂values that are similar to its antagonism with regard to mor­phine. It causes a form of addiction of the “morphine type”.

Absorption

Methadone is a basic and lipophilic drug that is almost completely absorbed from the digestive tract. T_maxvaries between 1.5 and 3 hours. Its bioavailability is more than 80%. The steady state is reached in 5-7 days. The distribution volume of methadone is about 5 l/kg.

Distribution

The pharmacokinetic profile of methadone is characterised by extensive distribution. About 89% of the methadone absorbed into the body is bound to proteins. In plasma, methadone is primarily bound to alpha-1-glycoprotein acid. The binding of methadone to extra-vascular tissue proteins is strong and methadone accumulates in the liver, kidneys and other organs. As the release of methadone from peripheral tissue to the central circulation proceeds slowly, the clearance of methadone is retarded. Methadone crosses the placenta and is excreted in breast milk.

Metabolism

Methadone is mainly metabolised by N-demethylation (oxidation) via enzymes in the liver. The two principal metabolites, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) and 2-ethyl-5-methyl-3,3-diphenylpyraline (EMDP), are biologically inactive. Methadone is primarily a substrate for the cytochrome P450 isoenzyme (CYP) 3A4 and to a lesser extent for CYP2D6 and CYP 2B6. Many interactions take place by induction or inhibition of these CYP enzymes (see 4.5 Interactions with other medicinal products and other forms of interaction).

Elimination

The elimination of methadone shows high inter-individual variability. Estimates of the elimination half life of methadone range from 19 to 55 hours in various studies. Relatively short half lives were found in studies with chronic administration of methadone, partly because of auto-induction of elimination. The clearance of methadone is not related to the dose. 15-60% of the total dose of methadone is excreted in urine within 96 hours. The remaining fraction is primarily excreted via bile. The extent of renal clearance depends on the acidity of the urine. More methadone is excreted at a lower pH of the urine.

Special patient groups

With regard to the kinetic parameters of methadone no differences are found between men and women. There is only a minor decrease in clearance of methadone in elderly patients (>65 years).

5.3 Preclinical safety data

Methadone at high doses caused birth abnormalities in marmots, hamsters and mice, in which most reports were of exencephaly and defects in the central nervous system. Rachischis in the cervical region was found occasionally in mice. Non-closure of the neural tube was found in chicken embryos. Methadone was not teratogenic in rats and rabbits. Also a reduced number of young was found in rats and increased mortality, growth retardation, neurological behavioural effects and reduced brain weight were found in the pups. Reduced ossification of the digits, sternum and skull was found in mice and a smaller number of foetuses per litter. No carcinogenicity studies have been carried out.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene glycol,

Benzoic acid,

Sodium hydroxide,

Liquid maltitol,

Purified water

6.2 Incompatibilities

Methadone hydrochloride and hydroxybenzoate preservatives are incompatible. Concurrent use of Methadone oral solution l mg/ml and syrups preserved with hydroxybenzoates is advised against.

6.3 Shelf life

For pack sizes of 100 ml and over: 3 years

For pack sizes smaller than 100 ml: 1 year

6.4 Special precautions for storage

Store below 25°C.

6.5 Nature and contents of container

10 ml, 25 ml, 30 ml, 40 ml, 50 ml, 80 ml, 100 ml, 200 ml, 300 ml, 500 ml, 1 litre and 2 litre type III brown glass bottle with pilfer-proof aluminium screw cap with a lining covered with polyethylene tetraphthalate (PET).

10 ml, 25 ml, 30 ml, 40 ml, 50 ml, 80 ml, 100 ml, 200 ml, 300 ml, 500 ml, 1 litre and 2 litre and 5 Litre HDPE bottle with PP pilfer-proof screw cap.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

Methadone hydrochloride falls under the opium law.

In Sweden: Pack sizes over 100 ml should only be handled by health care personnel.

7 Marketing Authorisation holder

To be completed nationally

8 MARKETING AUTHORISATION NUMBER(S)

To be completed nationally

9 DATE OF AUTHORISATION /RENEWAL OF AUHORISATION

To be completed nationally

10 DATE OF REVISION OF TEXT

2014-08-19