1. NAME OF THE MEDICINAL PRODUCT

[Product name] 2.5 mg tablets [Product name] 5 mg tablets [Product name] 10 mg tablets [Product name] 20 mg tablets [Product name] 30 mg tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

[Product name] 2.5 mg tablets 1 tablet contains 2.5 mg hydrochloride. Excipients with known effect 1 tablet contains 53.9 mg lactose (as monohydrate) and 6.1 mg sucrose.

[Product name] 5 mg tablets 1 tablet contains 5 mg levomethadone hydrochloride. Excipients with known effect 1 tablet contains 107.7 mg lactose (as monohydrate) and 12.2 mg sucrose.

[Product name] 10 mg tablets 1 tablet contains 10 mg levomethadone hydrochloride Excipients with known effect 1 tablet contains 107.7 mg lactose (as monohydrate) and 12.2 mg sucrose.

[Product name] 20 mg tablets 1 tablet contains 20 mg levomethadone hydrochloride. Excipients with known effect 1 tablet contains 215.5 mg lactose (as monohydrate) and 24.3 mg sucrose.

[Product name] 30 mg tablets 1 tablet contains 30 mg levomethadone hydrochloride. Excipients with known effect 1 tablet contains 323.2 mg lactose (as monohydrate) and 36.5 mg sucrose.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Tablets

2.5 mg: White to off-white, round tablet, single-sided convex with embossing “L2” on one side, breaking line on the other side, with a diameter of 7.1 ± 0.2 mm and a thickness of 2.8 ± 0.5 mm. The tablet can be divided into halve doses.

5 mg: White to off-white, round tablet, single-sided convex with embossing “L5” on one side, breaking line on the other side, with a diameter of 9.2 ± 0.2 mm and a thickness of 3.9 ± 0.5 mm. The tablet can be divided into halve doses.

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10 mg: White to off-white, oblong tablet, biconvex with embossing “L10” on one side, breaking line on the other side, with a length of 13.5 ± 0.2 mm, a width of 5.5 ± 0.2 mm and a thickness of 3.6 ± 0.5 mm. The tablet can be divided into halve doses.

20 mg: White to off-white, round tablet, single-sided convex with embossing “L20” on one side, cross break notch on the other side, with a diameter of 12.1 ± 0.2 mm and a thickness of 4.8 ± 0.6 mm. The tablet can be divided into halve and quarter doses.

30 mg: White to off-white, oval tablet, biconvex with embossing “L30” on one side, breaking line on the other side, with a length of 17.5 ± 0.2 mm, a width of 9.0 ± 0.2 mm and a thickness of 6.2 ± 0.8 mm. The tablet can be divided into halve doses.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Levomethadone hydrochloride G.L. is indicated in adults ≥ 18 years for substitution therapy of opioid dependence in conjunction with appropriate medical, social and psychosocial care.

4.2 Posology and method of administration Levomethadone should preferably be initiated by a specialist as part of an integrated treatment program with drug-assisted rehabilitation of opioid addiction in adults, which includes medical, social and psychological care, approved by the relevant authority.

Levomethadone is approximately twice as potent as the racemate and they can generally safely be replaced by each other on a 2:1 ratio. There are indications that the release of levomethadone can be more pronounced when methadone racemate is administered, which may shift this ratio. This has to be considered in the dosage.

Posology The dose is established based on the onset of withdrawal symptoms and must be adjusted for each patient according to the individual situation and to the subjective perception. Generally, the maintenance dose is the minimum dose that controls withdrawal symptoms.

The usual initial dose is 5-15 mg. For patients with high opioid tolerance, the initial dose is 12.5- 20 mg. The dose is increased in steps of 5 mg at a time over a period of three weeks, usually to 35 or 40 mg. After a recommended stabilisation period of four weeks, the dose is adjusted until the patient has no intoxication dependence and does not show clinical signs of psychomotor function effects or abstinence symptoms.

The usual dose is 30-60 mg of levomethadone per day, but some individuals may require higher doses. A dose higher than 50-60 mg of levomethadone hydrochloride may be administered in exceptional cases of proven necessity only, after having excluded reliably the concomitant use of other substances. Levomethadone is normally administered once daily.

If the patient has been treated with a combined agonist/antagonist (e.g. ), the dose should be reduced gradually when the levomethadone treatment is initiated. If the levomethadone treatment is interrupted and a switch to sublingual buprenorphine treatment is planned (especially in combination with ), the levomethadone dose should be reduced to 15 mg/day initially to avoid withdrawal symptoms caused by buprenorphine/naloxone.

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As a consequence of interactions and/or enzymatic induction caused by other medicinal products (see section 4.5) the daily dose of levomethadone needed can be increased. For this reason, even patients with adjusted stable treatment should be monitored for possible withdrawal symptoms and the dose further adjusted, if needed.

Reference is made to National Guidelines for levomethadone treatment

Discontinuation of treatment Treatment should be discontinued if the efficacy is not sufficient or if the patient cannot tolerate it. The effect must be evaluated in accordance with national guidelines.

When the treatment is to be discontinued, this should be done with a gradual dose reduction. The dose may be reduced relatively rapidly in the beginning, but reduction must be slow in the final phase (from 20 mg daily and downwards).

Special Populations Elderly It is recommended to reduce the dose in elderly patients.

Hepatic impairment Chronic viral hepatitis is common in addicts. Caution is advised if [Product name] must be used in patients with hepatic impairment. In patients with liver cirrhosis the metabolism is delayed and the first-passage¬effect is decreased. This may result in higher plasma levels of levomethadone. [Product name] should be administrated in a lower dose than the recommended and the clinical response of the patient should be used as guidance for further dosage.

Renal impairment Caution is advised if levomethadone is used in patients with renal impairment. The dosage should be reduced accordingly

Paediatric population The safety and efficacy of levomethadone in children and adolescents under 18 years have not been established.

Other conditions Patients with hypothyroidism, myxoedema, urethral stricture, asthma or decreased lung volume or prostate hypertrophy must receive a lower initial dose.

Method of administration: This product is for oral use only. The tablets can be taken whole or readily be dissolved in water, orange or apple juice. The solutions are intended for immediate intake (e.g. in drug withdrawal therapy dispensed by a pharmacist).

4.3 Contraindications

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 - Children and adolescents under 18 years - Concurrent administration with MAO inhibitors or within 2 weeks of discontinuation of treatment with them. - During the treatment with levomethadone, narcotic antagonists or other agonists/antagonists (e.g. and buprenorphine) must not be administered, except for the treatment of overdose. - Respiratory depression - Obstructive airways disease. - Patients dependent on non-opioid drugs.

4.4 Special warnings and precautions for use

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When using levomethadone, it is important to consider that levomethadone is about twice as potent as the methadone racemate (see also section 4.2). Patients should be informed about the risk for overdose.

Cases of QT interval prolongation and torsade de pointes have been reported during treatment with levomethadone, particularly at high doses. Levomethadone should be administered with caution to patients at risk for development of prolonged QT interval, e.g. in case of: - known history of QT prolongation - advanced heart disease, - concomitant treatment with drugs that have a potential for QT-prolongation, - concomitant treatment with CYP3A4 inhibitors - electrolyte anomalies (hypokalaemia, hypomagnesaemia)

ECG-monitoring should be considered in patients with risk factors for QT-prolongation, particularly in elderly women.

Special precautions for use of levomethadone are as for use of in general.

Acute asthmatic attack, chronic obstructive pulmonary disease or cor pulmonale, decreased respiratory reserve, hypoxia, or hypercapnia are relative contraindications. Each case must be evaluated individually.

Risk from concomitant use of sedative medicines such as benzodiazepines or related drugs (e.g. opioids, alcohol, barbiturates and other strong sedative and psychoactive drugs): Concomitant use of levomethadone 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 [Product name] 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).

Concurrent treatment with narcotic antagonists or mixed agonist/antagonists should be avoided (with the exception of treatment of overdose) as it may precipitate withdrawal symptoms in physically dependant patients.

At the beginning of the dose increase period the patient must be observed after administration to record any abnormal/adverse reactions. The patient will have increased serum levels for up to two hours, and it is important that any overdose reactions or other dangerous/severe reactions can be recorded.

In cases of impaired hepatic and renal function, levomethadone must be used with caution. The metabolism of levomethadone may be reduced in cases of impaired hepatic function, and dose adjustment may be necessary (see section 4.2). A lower initial dose must be administered to patients with hypothyroidism, myxoedema (it can increase the risk of respiratory depression and prolonged CNS depression), renal (increased risk of convulsions) and hepatic impairment (opioids metabolised in liver), asthma or decreased lung volume (it may decrease respiratory drive and increase airway resistance) urethral stricture or prostatic hypertrophy (it may cause urinary retention) (see section 4.2).

Great caution must be exercised in cases of possible head injury or conditions involving increased intracranial pressure. Levomethadone should not be used in patients with intestinal pseudo- obstruction, acute abdomen and inflammatory bowel disease.

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In patients with kidney calculi and in patients with gallstones it may be necessary to administer atropine or other spasmolytics prophylactically.

Elderly patients and patients suffering from cardiovascular diseases are at increased risk of hypotension and syncope.

Paediatric population Children are more sensitive than adults, therefore poisoning may occur at very low doses. To avoid unintentional intake of levomethadone by children, levomethadone should in cases when it is taken home, be kept in a safe place where children cannot reach it.

[Product name] contains sucrose Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

[Product name] contains lactose Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose- galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Most interaction studies have been performed with methadone and also apply for levomethadone.

Pharmacokinetic interactions P-glycoprotein inhibitors Levomethadone is a substrate for P-glycoprotein; all medicinal products, which inhibit P-glycoprotein (e.g. quinidine, verapamil, ciclosporin) may therefore increase the serum concentration of levomethadone. The pharmacodynamic effect of levomethadone may also increase as a consequence of an increased passage through the blood-brain barrier.

CYP3A4-inducers Levomethadone is a substrate for CYP3A4 (see section 5.2). Induction of CYP3A4 increases the elimination of levomethadone and leads to decreased plasma levels. Inducers of this enzyme (barbiturates, carbamazepine, phenytoin, nevirapine, rifampicin, efavirenz, amprenavir, spironolactone, dexamethasone. Hypericum perforatum (St John's wort)) may induce the hepatic metabolism. For example, after three weeks treatment with 600 mg efavirenz daily, the mean maximal plasma concentration and AUC were decreased with 48% and 57% respectively, in patients treated with levomethadone (15-50 mg daily).

The consequences of the enzyme induction are more marked if the inducer is administrated after the treatment with levomethadone has been initiated. Abstinence symptoms have been reported following of such interactions and it may therefore be necessary to increase the levomethadone dose. If the treatment with a CYP3A4 inducer is interrupted the levomethadone dose should be reduced.

CYP3A4-inhibitors Levomethadone is a substrate for CYP3A4 (see section 5.2). Inhibition of CYP3A4 decreases the elimination of levomethadone. Concomitant administration of CYP3A4-inhibitor (e.g. cannabinoids, clarithromycin, delavirdine, erythromycin, fluconazole, grapefruit juice, itraconazole, ketoconazole, fluvoxamine, cimetidine, nefazodone and telitromycine) may increase plasma concentrations of levomethadone. A 40-100% increase of the quote between the serum levels and the levomethadone dose has been shown with concomitant fluvoxamine treatment. If these medicinal products are prescribed to patients on levomethadone maintenance treatment, one should be aware of the risk of overdose.

Fluoxetine increase the concentrations of levomethadone by inhibition of CYP2D6.

Medicinal products that affect the acidity of the urine

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Levomethadone is a weak base. Acidifiers of the urine (such as ammonium chloride and ascorbic acid) may increase the renal clearance of levomethadone. Patients that are treated with levomethadone are recommended to avoid products containing ammonium chloride.

Concurrent treatment of HIV infection Some protease inhibitors (amprenavir, nelfinavir, abacavir, lopinavir/ritonavir and ritonavir/saquinavir) seem to lower the serum levels of levomethadone. When ritonavir is administrated alone a doubling of AUC for levomethadone has been shown. Plasma levels of zidovudine (a nucleoside analogue) increase with levomethadone use, after both oral and intravenous administration of zidovudine. This is more pronounced when zidovudine is given oral than after intravenous administration. These observations are most probably caused by an inhibition of zidovudine glucuronidation and by the thereby decreased elimination of zidovudine. During levomethadone treatment, the patients must be carefully monitored for signs of toxic effects of zidovudine, which possibly may require a decrease of the zidovudine dose.

Didanosine and stavudine Levomethadone delays the absorption and increases the first pass metabolism of stavudine and didanosine, which results in a decreased bioavailability of stavudine and didanosine.

Abacavir In a pharmacokinetic study, co-administration of 600 mg abacavir twice daily with levomethadone showed a 35% reduction in abacavir Cmax and a one hour delay in tmax but the AUC was unchanged. The changes in abacavir pharmacokinetics are not considered clinically relevant. In this study abacavir increased the mean levomethadone systemic clearance by 22%. The induction of drug metabolising enzymes cannot therefore be excluded. Patients being treated with levomethadone and abacavir should be monitored for evidence of withdrawal symptoms indicating under dosing, as occasionally levomethadone re-titration may be required.

CYP2D6 substrates Levomethadone may double the serum levels of , a CYP2D6 substrate. Inhibition of CYP2D6 may lead to increased plasma concentrations of concomitantly administered medicinal products metabolised via this enzyme. These products include, but are not limited to, tricyclic antidepressants (such as clomipramine, and desipramine), phenothiazine-neuroleptics (e.g. perphenazine and thioridazine), risperidone, , some Type 1c-antiarrhytmics (e.g. propafenone and flecainide) and metoprolol.

Tamoxifen is a pro-drug that requires metabolic activation via CYP2D6. Tamoxifen has an active metabolite, endoxifen that is formed via CYP2D6 and contributes significantly to the effect of tamoxifen. Inhibition of CYP2D6 by levomethadone may lead to decreased plasma concentrations of endoxifen.

Pharmacodynamic interactions Opioid antagonists Naloxone and counteract the effect of levomethadone and induce abstinence. Similarly, buprenorphine may also trigger withdrawal symptoms.

Sedative medicines such as benzodiazepines or related drugs The concomitant use of opioids and medicinal products with a sedative effect on the central nervous system such as benzodiazepines or related drugs increases the risk of respiratory depression, hypotension, strong sedation, coma and death because of additive CNS depressant effect, therefore it may be necessary to reduce the dose of one or both of the medicinal products. The dose and duration of concomitant use should be limited (see section 4.4). With levomethadone treatment, the slowly eliminated substance levomethadone, give rise to a slow tolerance development and every dose increase may after 1-2 weeks give rise to symptoms of respiratory depression. The dose adjustments must therefore be made with caution and the dose increased gradually with careful observation.

Peristalsis inhibition

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Concomitant use of levomethadone and peristalsis inhibiting medicinal products ( and ) may result in severe constipation and increase the CNS depressant effects. Opioids, in combination with anticholinergics, may result in severe constipation or paralytic ileus, especially during long-term use.

QT-prolongation Levomethadone should not be combined with medicinal products, which may prolong the QT-interval, such as antiarrhythmics (sotalol, amiodarone, flecainide), antipsychotics (thioridazine, haloperidol, sertindole, phenothiazines, ziprasidone and risperidone), antidepressants (paroxetine, fluoxetine, citalopram, escitalopram, sertraline) or antibiotics (erythromycin, clarithromycin, levofloxacin, moxifloxacin).

MAO-inhibitors Concomitant administration of MAO-inhibitors may result in reinforced CNS-inhibition, serious hypotonia and or apnoea. Levomethadone should not be combined with MAO-inhibitors or two weeks after such treatment (see section 4.3).

Opioids like levomethadone delay gastric emptying, thereby invalidating test results. Delivery of technetium Tc 99m disofenin to the small bowel may be prevented and plasma amylase and plasma lipase activity may be increased because opioid analgesics may cause constriction of the sphincter of Oddi and increased biliary tract pressure; these actions result in delayed visualization and thus resemble obstruction of the common bile duct. The diagnostic determination of these enzymes may be compromised for up to 24 hours after the medication has been given. Cerebrospinal fluid pressure (CSF) may be increased; effect is secondary to respiratory depression – induced carbon dioxide retention.

4.6 Fertility, pregnancy and lactation

Pregnancy Limited data on the use of levomethadone during pregnancy in humans show no elevated risk of congenital abnormalities. Withdrawal symptoms/respiratory depression may occur in neonates of mothers that were chronically treated with levomethadone during pregnancy. A QT prolonging effect following maternal levomethadone exposure cannot be excluded, and a 12-lead electrocardiogram should be performed if the neonate has bradycardia, tachycardia or an irregular heart rate Data from animal studies have shown reproductive toxicity (see section 5.3). It is generally advisable not to detoxify the patient, especially after the 20th week of pregnancy. If possible, the levomethadone dose should be reduced just before and during birth due to the risk of neonatal respiratory depression.

Breastfeeding Levomethadone is excreted in human milk, and the average milk/plasma ratio is 0.8. Breast-feeding may be given at doses up to 10 mg per day. At higher doses the benefits of the breast-feeding must be weighed against the possible adverse effects on the infant.

Fertility There are no data on potential effects of levomethadone on fertility.

4.7 Effects on ability to drive and use machines

Levomethadone affects the psychomotoric functions until the patient has been stabilized on a suitable level. The patient should therefore not drive or use machines until the stabilization has been achieved and no misuse symptoms have occurred during the last six months. How soon the patient is able to drive or use machines varies to a high extent from individual to individual and must be determined by the physician. For further information, reference is made to National Guidelines for levomethadone treatment.

4.8 Undesirable effects

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The undesirable effects of levomethadone 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 levomethadone outpatient treatment, where the medicinal control is often unsatisfactory.

The most serious side effect of levomethadone is respiratory depression. This can occur during the stabilisation phase. Respiratory arrest, shock, and cardiac arrest have occurred.

Tabulated list of adverse reactions Adverse reactions listed below are classified according to frequency and system organ class. 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).

System organ class Frequency Adverse reaction Blood and lymphatic system Not known Reversible thrombocytopenia has been disorders reported in opioid patients with chronic hepatitis

Metabolism and nutrition Common Fluid retention disorders Uncommon Anorexia

Not known Hypokalaemia, hypomagnesaemia

Psychiatric disorders Common Euphoria, hallucinations

Uncommon Dysphoria, agitation, insomnia, disorientation, reduced libido

Nervous system disorders Common Sedation

Uncommon Headache, syncope

Eye disorders Common Blurred vision, miosis

Cardiac disorders Rare Bradycardia, palpitations, cases of prolonged QT intervals and “torsade de pointes” have been reported in treatment with levomethadone, especially with high doses

Vascular disorders Uncommon Facial flush, hypotension

Respiratory, thoracic and Uncommon Pulmonary oedema, respiratory depression mediastinal disorders

Gastrointestinal disorders Very common Nausea, vomiting

Common Constipation

Uncommon Xerostomia, glossitis

Hepatobiliary disorders Uncommon Bile duct dyskinesia

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Skin and subcutaneous tissue Common Transient rash, sweating disorders Uncommon 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 Uncommon Reduced potency and amenorrhoea disorders General disorders and Common Fatigue administration site conditions Uncommon Oedema of the lower extremities, asthaenia, oedema

Investigations Common Weight increase

During prolonged administration of levomethadone, as in a levomethadone maintenance treatment programme, there is a gradual, yet progressive disappearance of side effects over a period of several weeks. However, constipation and sweating often persist. Review studies have shown that levomethadone maintenance treatment has extremely few side effects, included showing to be non- sedative.

Prolonged use of levomethadone may lead to dependence of the type. The withdrawal symptoms are similar to, but less intense and more prolonged, than those produced by morphine or diamorphine (). 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 national reporting system listed in Appendix V.*

4.9 Overdose

Especially in subjects who are non-tolerant to opioids (children in particular), dangerous intoxications may occur also in case of doses lower than the ones given in the substitution therapy: in children up to 5 years this can happen starting from about 0.5 mg of levomethadone, in older children starting from about 1.5 mg and in adults non-tolerant to opioids starting from about 10 mg.

A dose reduction is recommended if patients show signs and symptoms of excessive levomethadone effects that are characterised by disorders such as: excitability, impaired concentration capability, drowsiness and possibly dizziness when standing.

Moreover, overdoses are characterized by respiratory depression (Cheyne-Stokes respiration, cyanosis), excessive drowsiness with tendency to reduced consciousness and even coma, miosis, relaxation of the skeletal muscles, cold and moist skin and sometimes bradycardia and hypotension. Massive intoxications may cause respiratory arrest, circulatory failure, cardiac arrest and death.

Prompt intervention of emergency medicine or intensive care medicine is mandatory (e.g. intubation and ventilation). For treatment of symptoms of intoxication specific opioid antagonists (e.g. naloxone) can be used. The dose of the individual opioid antagonists varies. In particular it is important to take into account that levomethadone may have long lasting depressive action on the respiration (up to 75 hours), while the opioid antagonists have a much shorter action (1 to 3 hours). Therefore, once the antagonistic effects ease off reinjections may be necessary. Measures to prevent the loss of temperature and to substitute the vascular volume may be necessary.

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In case of oral levomethadone intoxication, a gastric lavage may be performed only after administration of an antagonist. Protection of the respiratory ways through intubation both in case of gastric lavage and before the administration of the antagonists (onset of vomiting is possible) is particularly important. In the treatment of the intoxications alcohol, barbiturates, bemegride, phenothiazine and scopolamine must not be used. An antagonist should not be given if there are no clinical signs of respiratory failure or danger for loss of consciousness. Administration of an antagonist to patients who are physically dependent on will give acute withdrawal symptoms. Use of antagonists to such patients should be avoided if possible and reserved for cases with serious respiratory depression. Then administration should be done with great caution.

Levomethadone is not dialysable.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Drugs used in opioid dependence; ATC code: N07B C05.

Levomethadone hydrochloride is a synthetic opioid, a basic diphenylmethane derivative structurally derived from morphine.

Levomethadone is the R(-)enantiomer of methadone. The S(+)enantiomer has only 1/50 of the analgesic effect of the R(-)enantiomer. The clinical effects of levomethadone in the treatment of /opioid addiction are based on two mechanisms: On the one hand levomethadone, as a synthetic opioid agonist produces morphine-like effects that suppress withdrawal symptoms in opiate/opioid addicted subjects. On the other hand, depending on the dose and the duration of the substitution therapy the chronic use of oral levomethadone can lead to tolerance that blocks the effect of parenterally administered subjectively experienced as euphorigenic.

The effect in the substitution therapy starts after 1-2 hours from the oral administration and in case of a single administration lasts from 6 to 8 hours. After repeated dosing the duration of the effect is prolonged up to 22 to 48 hours, due to the pharmacokinetic balance so that a once daily administration is sufficient.

Levomethadone, being an opioid agonist, induces a long lasting respiratory depression that reaches its peak after 4 hours and may last up to 75 hours. Besides the typical effects of the opioids, such as sedation, euphoria and miosis, levomethadone has other pharmacological effects such as bradycardia, increase of the blood pressure, bronchial constriction and anti-diuresis. The long-term consumption of levomethadone causes addiction, similar to the one from heroin and morphine.

5.2 Pharmacokinetic properties

Absorption Levomethadone is rapidly absorbed after oral administration. The absolute bioavailability after oral administration is on average about 82%.

In case of an oral daily dosage of 30 mg, the steady state of levomethadone plasma levels is reached in 4-5 days.

Distribution Levomethadone has a relatively large volume of distribution of 3-4 l/kg. This means that the strongly lipophilic substance accumulates in considerable amounts in the peripheral tissues, in fat, muscles and skin. About 85% is bound to serum protein predominantly to acid alfa-glycoprotein and albumin.

Biotransformation

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So far 32 metabolites of methadone have been identified. Two pharmacologically active metabolites account for only 2% of the administered dose. Methadone and its metabolites accumulate mainly in lungs, liver, kidney, spleen and muscles.

Elimination The elimination of methadone and its metabolites takes place in the kidney and in the biles. The elimination via kidneys which strongly depends on the pH value is the main route in case of high dosages; in case of administrations exceeding 160 mg, about 60% is excreted as unchanged methadone. 10 to 45% of the total recovered amount is excreted in the bile.

The terminal plasma half-life is subject to considerable individual variability (between 14 and 55 hours) and decreases during long-term treatment due to enzyme autoinduction. The half-life increases in the elderly and in case of chronic liver diseases due to decreased clearance/elimination of methadone.

Levomethadone is not dialysable. However, in case of anuria there is no risk of accumulation as at that point the elimination takes place only via the faeces.

Special patient population Levomethadone is excreted in human milk and crosses the placenta barrier. The concentration in the blood of the umbilical cord is lower than the plasma concentration of the mother. There is no correlation between the concentration in maternal plasma/blood of the umbilical cord and the levels found in the amniotic fluid. Due to increased exposure, caution is advised in the treatment of patients with renal or hepatic impairment (see sections 4.2 and 4.4).

5.3 Preclinical safety data

In preclinical studies, the main target organs following subchronic and chronic administration are the respiratory system (respiratory depression) and the liver (increased SGTP activity, hypertrophy of the liver cells, eosinophilic cytoplasmic changes).

Mutagenic and carcinogenic potential In-vitro and in-vivo investigations carried out on the genotoxicity of methadone have shown contradicting results indicating a slight clastogenic potential. Currently, a risk for the clinical use cannot be deduced. Long term studies carried out in rats and mice have not shown evidence of carcinogenic potential.

Reproductive toxicity Levomethadone has not been sufficiently studied. 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. Rachischisis 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.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, microcrystalline Maize starch, pregelatinised Lactose monohydrate Compressible sucrose (96% sucrose, 4 % maltodextrin)

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Magnesium stearate

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years

6.4 Special precautions for storage

Store in the original package in order to protect from light.

6.5 Nature and contents of container

The tablets are packaged in opaque blisters consisting of PVC-PVdC (base foil) laminated with aluminium sheets (lidding foil) containing 20 or 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBER(S)

[To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: [To be completed nationally]

10. DATE OF REVISION OF THE TEXT

[To be completed nationally]

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