SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

EPTADONE 1mg/ml oral solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each bottle contains 1mg/ml methadone hydrochloride in single dose bottles containing 60mg methadone hydrochloride

For excipients, see section 6.1

3    PHARMACEUTICAL FORM

Oral solution.

Clear green liquid with lemon taste.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

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

For use as an analgesic for moderate to severe pain.

4.2.    Posology and method of administration

For oral administration only.

Addiction:
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 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.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients.

Respiratory depression, obstructive airways disease, concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them.

Patients dependent on non-opioid drugs.

Use during an asthma attack is not recommended.

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

Methadone is not suitable for children.

4.4 Special warnings and precautions for use

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

Methadone can cause a morphine-like drug dependence. Following repeated administrations, psychic dependence, physical dependence and tolerance can occur, therefore it must be prescribed and administered with the same caution utilized for morphine.

Extreme caution must be taken in the following cases:

Cranial lesions and high intracranial pressure. The respiratory depressant effects of methadone and its capacity to increase the cerebrospinal fluid pressure can be considerably increased in the presence of an increase of the intracranial pressure; furthermore narcotics produce undesirable effects, that can hide neurological symptoms in patients with cranial lesions.

Asthma and other respiratory conditions. In patients with acute asthma attacks, in those with chronic obstructive pulmonary disease or cor pulmonare and in individuals with a substantially decreased respiratory reserve in pre-existing respiratory depression, hypoxia or hypercapnia, even the usual therapeutic dosages of narcotics may reduce the respiratory drive and increase the airway resistance to the point of apnoea.

Acute abdominal conditions. The use of methadone or other narcotics may confound the diagnosis or the clinical course in patients with acute abdominal conditions.

Hypotensive effect. The administration of methadone can cause serious hypotension in hypovolemic subjects or with concomitant intake of medicinal products like phenothiazine or certain anaesthetics.

Outpatient use. In outpatients methadone may cause orthostatic hypotension.

Use of narcotic antagonists. In an individual with narcotic physical addiction, the administration of the usual dose of a narcotic antagonist can trigger an acute withdrawal syndrome. The severity of the syndrome will depend on the degree of physical dependence and on the dose of antagonist administered. The use of a narcotic antagonist in this subject should possibly be avoided. When this must be used for treatment of a severe respiratory depression in a patient physically addicted, the antagonist must be administered with extreme caution and gradually with dosages below the usual ones.

Special risk patients. Methadone must be administered with caution and the initial dose must be reduced in elderly and debilitated patients and patients with hypothyroidism, Addison’s disease, prostatic hypertrophy, urethral stricture.

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

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.

Severe risk patients. Suicide attempts with opiates, especially combined with tricyclic antidepressants, alcohol and other substances affecting the central nervous system, are part of the clinical features of dependency.

Cardiac arrhythmia. Since high doses of methadone have been associated with the occurrence of torsade de pointes (prolongation of the QT-interval), patients with risk factors for torsade de pointes should be treated with caution. The risk factors are:

-    Electrolyte disorders, in particular hypokalaemia, hypocalcaemia and hypomagnesaemia.

-    Congenital or acquired QT-prolongation.

-    Cardiomyopathy, in particular in the presence of symptoms of cardiac failure.

-    Sinus bradycardia.

-    Symptomatic rhythm disorders.

-    Concurrent medication known to prolong the QT-interval (in particular certain antiarrhythmics, neuroleptics, antibiotics, antidepressants and antihistaminics).

In patients for whom the potential benefits of a methadone-based treatment outweigh the risk of tachycardia onset, an electrocardiogram must be performed before therapy begins and after two weeks of treatment, with the aim of verifying and quantifying the effect of methadone hydrochloride on the QT interval. An electrocardiogram is also recommended before increasing the dose assumed.

Sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Eptadone contains small amount of ethanol, less than 100mg per 100ml.

Eptadone contains tartrazine (E102) as a colouring agent. It may cause allergic reactions.

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

Pharmacokinetic interactions

Inhibitors of P-glvcoprotein: methadone is a P-glycoprotein substrate, therefore all the drugs that inhibit it (quinidine, verapamil) can increase the serum concentration of methadone.

CYP3A4 isoenzyme inducers: the inducers of this isoenzyme (barbiturates, carbamazepine, phenytoin, nevirapine, rifampicin) can induce the hepatic metabolism, which could be more significant if the inducer is added after the methadone therapy has started. Following such interactions withdrawal symptom cases have been reported, therefore it was necessary to increase the dosage of methadone. When the CYP3A4 inducing drugs therapy is suspended, the dosage of methadone must be reduced.

CYP3A4 isoenzyme inhibitors: the interaction between metadone and cannabinoids (marijuana, hash, hemp, pot) has been proposed due to common CYP3A4 pathway. The interaction may result in altered or unpredicatable metabolism. The interaction between clarithromicin and methadone as well as the interaction between erithromycin and methadone have been predicted due to the strong inhibition of CYP3A4 enzyme by erithomicyn and clarithromycin. Clarithromycin and erithromycin may raise serum methadone level and/or increase methadone effects. The interaction between delavirdine and methadone has not been formally studied. It has been predicted due to the CYP3A4 inhibition by delavirdine, that may raise serum methadone level and/or increase methadone effects. Fluconazole has been shown to modify methadone kinetics in patients under methadone treatment. After 14 days of fluconazole 200 mg/day, serum methadone AUC and mean peak and trough concentrations increased by 35%, 27% and 48% respectively, while oral clearance was reduced by 24 %. Although exposed to increased concentrations of methadone, patients exhibited neither signs of methadone overdose nor changes. The exact reason for this interaction is not fully understood, but a likely explanation is that fluconazole inhibits the metabolism of methadone because of its ability to inhibit several CYP enzymes, including CYP3A4 enzyme. The interaction between ketoconazole and methadone has been predicted due to CYP3A4 enzyme inhibition, that may raise serum methadone level and/or increase methadone effects. Because of extensive metabolism by the hepatic cytochrome P4503A4 system, itraconazole potentially interacts with drugs metabolized by this route. Itraconazole may decrease the elimination of drugs metabolized by CYP3A4 resulting in elevated plasma concentrations, which may prolong and/or increase both the therapeutic and the adverse effects of these drugs. Fluoxetine did not appear to alter the plasma methadone levels and no special precautions would therefore seem to be necessary if fluoxetine is added to methadone. Paroxetine is a strong CYP2D6 inhibitor; at a dosage of 20 mg/day, significantly increased (R)-methadone concentrations in a group of eight CYP2D6 extensive metabolisers by a mean value of 32%.

Fluvoxamine has been shown to increase the plasma concentrations of both enantiomers of methadone. The reason appears to be that fluvoxamine can inhibit the liver metabolism of the methadone by cytochrome P450 isoenzyme CYP3A4, as confirmed by in vitro studies. The available information indicates that the effects of starting or stopping fluvoxamine should be monitored in patients on methadone, eventually adjusting the methadone dosage. Sertraline may inhibit methadone metabolism during the first few weeks of coadministration. Nefazodone is a potent inhibitor at CYP3A4 enzyme of the liver. No formal studies have been performed with co-administration of methadone and nefazodone, but an interaction has been predicted due to CYP3A4 enzyme inhibition, that may raise serum methadone level and/or

increase methadone effects. Grapefruit Juice has a known inhibitory effect on CYP3A4 enzyme at intestinal level and P-glycoprotein. Juice administration is associated with a modest increase in methadone bioavailability, but it cannot be excluded that much stronger effect may occur in some patients,and thus grapefruit juice intake is not recommended during methadone treatment. Didanosine and stavudine: methadone reduces the AUC and Cmax of didanosine and of stavudine, reducing the bioavailability of these drugs. Furthermore, methadone can slow down the absorption and increase the first passage metabolism of the aforementioned drugs.

Zidovudine: methadone increases the plasma concentration of zidovudine for both oral and intravenous administration, and also provokes an increase in the AUC of zidovudine for oral administration, more than for intravenous administration. Such effects are due to the inhibition of the glucuronidation of zidovudine and it's reduced kidney clearance. During treatment with methadone, patients have to be monitored for a possible zidovudine toxicity, whereby it could be necessary to reduce the zidovudine dosage. The patients that take both drugs can develop typical symptoms of opioid withdrawal syndrome (headache, myalgia, fatigue and irritability).

Antiretroviral protease inhibitors: the antiretroviral protease inhibitors can inhibit the metabolism of methadone; the more significant reactions are obtained with ritonavir.

Abacavir: nineteen patients entering methadone treatment were given a single dose of abacavir (600 mg), begun methadone and, after 14 days, coadministered abacavir and methadone for the following 14 days. The results showed, in the last 14 days, a statistically significant increase (23%) in the rate of clearance of methadone,but no changes in the time to peak concentration or half-life. In addition, a significant decrease (34%) in the peak concentration and increase (67%) in the time to peak concentration of abacavir were observed in the first 14 days. The introduction of abacavir and amprenavir in 5 dependent patients in methadone treatment resulted in median decrease to 35% of the original concentration of methadone, with adverse effects compatible with withdrawal reactions in two patients.

Efavirenz: efavirenz induces the methadone metabolism through cytochrome P4503A4. Following a three-week therapy with efavirenz, the mean peak concentrations of methadone and the AUC were reduced by 48% and 57% respectively. Efavirenz added to a patient under methadone therapy could induce a withdrawal syndrome that usually starts after two weeks of efavirenz therapy, but can go on for up to 28 days. For this reason it may be necessary to adjust the methadone dosage.

Nevirapine: nevirapine induces methadone metabolism through cytochrome P450 family.The coadministration of nevirapine and methadone in twenty-five human immunodeficiency virus-infected subjects significantly decreased the mean dose-adjusted AUC of methadone by 41%. Methadone dose adjustments are justified when methadone is coadministered with nevirapine.

Urine acidifiers: methadone is a weak base. Urine acidifiers (ammonium chloride) can increase methadone kidney clearance. In this situation the methadone dosage should be increased.

Pharmacodynamic interactions

Opioid agonists/antagonists: naloxone and naltrexone antagonise the methadone action and provoke a withdrawal syndrome.

Butorphanol, nalbuphine and pentazocine can partially block the analgesia and increase the respiratory and central nervous system (CNS) depression due to methadone. These drugs used in combination with methadone can provoke and increase neurological, respiratory and hypotensive effects. The additive or antagonist effects depend on the methadone dosage and are more frequent when the methadone dosage is low or moderate. These drugs can cause withdrawal syndrome in patients on chronic therapy.

CNS depressant: drugs with a depressive action on the CNS can provoke an increase of respiratory depression, therefore it may be necessary to decrease the dosage of one or both drugs.

Antidiarrhoeals: the concomitant use of methadone and antidiarrheals (diphenoxylate and loperamide) can cause severe constipation and an increased depression of the CNS. Opioid analgesics, combined with antimuscarinic drugs can cause severe constipation or paralytic ileus, especially with chronic use.

Octreotide: can reduce the analgesic effect of methadone and morphine, therefore if a reduction or loss of pain control occurs octreotide suspension has to be taken into consideration.

Alcohol: may induce serious respiratory depression and hypotension.

4.6.    Pregnancy and lactation

Pregnancy

There is no, or inadequate evidence of safety in human pregnancy.

Female addicts who are pregnant will require specialised care from obstetric and paediatric staff with experience in such management. A careful risk benefit assessment should be made before administration to pregnant women. Possible adverse effects on the foetus and neonate include respiratory depression, low birth weight, neonatal withdrawal syndrome and increased rate of stillbirths.

During labour there is a risk of gastric stasis and inhalation pneumonia in the mother.

Lactation

Methadone is excreted in breast milk and may cause respiratory depression in the newborn. Breast feeding is usually not recommended. However, a careful risk benefit assessment case by case is suggested, taking into account that methadone could prevent the possibility of an overdose syndrome in the newborn.

4.7.    Effects on ability to drive and use machines

Patients should not drive or use machines while taking methadone. Methadone may cause drowsiness and reduce alertness and the ability to drive. The time after which such activities may be safely resumed is extremely patient-dependent and must be decided by the Physician.

4.8. Undesirable effects

Respiratory Systems: From very common (> 1/10) to common (> 1/100, < 1/10): respiratory depression.

From uncommon (> 1/100, < 1/1000) to rare (> 1/10000, < 1/1000): respiratory arrest.

Central nervous system: From very common (> 1/10) to common (> 1/100, < 1/10): euphoria, dysphoria, weakness, headache, sedation, insomnia, agitation, disorientation, feeling of empty head, visual disturbances, dizziness,miosis. Gastrointestinal tract and liver: From very common (> 1/10) to common (> 1/100, < 1/10): nausea, vomiting, constipation, xerostomia, anorexia and spasms of the biliary tract.

Cardiovascular apparatus: From very common (> 1/10) to common (> 1/100, < 1/10): rushing, bradycardia, palpitations, fainting, orthostatic hypotension and syncope.

From uncommon (> 1/100, < 1/1000) to rare (> 1/10000, < 1/1000): shock and cardiac arrest. Torsade de pointes can also occur with high doses. Urinary-genital apparatus: From very common (> 1/10) to common (> 1/100,

<    1/10): urinary retention and difficulty to urinate, anti-diuretic effect and libido reduction and/or sexual impotence.

Skin and Annexes: From very common (> 1/10) to common (> 1/100, < 1/10): excessive sweating, itchiness, nettlerash, other skin reactions, oedema. From uncommon (> 1/100, < 1/1000) to rare (> 1/10000, < 1/1000): hemorrhagic nettlerash.

Blood: From uncommon (> 1/100, < 1/1000) to rare (> 1/10000, < 1/1000): haemorragia

Endocrine Systems: From uncommon (> 1/100, < 1/1000) to rare (> 1/10000,

<    1/1000): Long-term administration may produce raised prolactin levels. Possible undesirable effects due to excipients: the medicinal product contains the following excipient that may cause undesirable effects: glycerol (harmful at high doses): may cause headache, stomach upset and diarrhoea.

4.9. Overdose

Symptoms and signs: similar to those for morphine. 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: treatment is supportive. Patients should be kept conscious wherever possible. 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

Pharmacotherapeutic group: drugs used in opioid dependence 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 l-isomer, which is at least 10 times more potent as an analgesic than the d-isomer. The d-isomer lacks significant respiratory depressant activity but does have anti-tussive effects. Methadone also has some agonist actions at the K and 5 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 a basic and lipophilic drug, which is rapidly absorbed from the gastrointestinal tract with peak plasma levels between 1.5 and 3 h and an oral bioavailability of no less than 80%. Its pharmacokinetics are characterized by a rapid and extensive distribution phase followed by a slow elimination phase The drug is subjected to considerable tissue distribution, yielding a relatively high volume of distribution and it is largely bound to plasma proteins (approximately 89%). The sequestration of methadone at extravascular binding sites, followed by slow release into plasma, contributes to the prolonged duration of methadone half-life in plasma and urine. Pharmacokinetic studies in normal individuals, postoperative patients and methadone maintenance patients indicate that methadone has a variable (both within and among studies) terminal elimination half-life, with mean values ranging from 19 to 55 hours. Thus, there is potential for accumulation when methadone is administered at short intervals. The relative unpredictability of methadone pharmacokinetics renders difficult to devise a uniform dosing schedule and underlines the importance of individualized dosage. The oxidative biotransformation of methadone is the main route of drug

elimination, which occurs primarily in the liver. In the first 96 h after administration, 15-60% can be recovered from the urine. The two major urinary metabolite lack pharmacological activity. Urinary pH is an important determinant of elimination half-life.

5.3. Preclinical safety data

Not applicable.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Sucrose

Glycerol

Sodium Benzoate (E211)

Citric Acid monohydrate

Lemon Flavour (including Citropten, Citral, and ethanol)

Tartrazine (E102)

Brilliant blue (E133)

Purified Water.

6.2.    Incompatibilities

Not applicable.

6.3.    Shelf life

3 years.

6.4.    Special precautions for storage

Keep bottle in the outer carton.

6.5.    Nature and contents of container

Amber, transparent, non-plasticised PVC 60-ml bottle with aluminium pilfer proof screw cap fitted with polyethylene liner, equipped with a cover-cap to make it child resistant.

6.6.    Instruction for use and handling

No special requirements.

7 MARKETING AUTHORISATION HOLDER

L Molteni & C Dei F.Llialtti Societa Di Esercizio SPA Strada Statale 67, Granatieri I-50018 Scandicci (Firenze)

Italy

8.    MARKETING AUTHORISATION NUMBER

PL 16046/0006

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

24/11/2010

10 DATE OF REVISION OF THE TEXT

29/10/2010