SUMMARY OF PRODUCT CHARACTERISTICS
1. NAME OF THE MEDICINAL PRODUCT
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 6,7 mg levomethadone as 7.5 mg levomethadone hydrochloride.
For the full list of excipients, see section 6.1.
3. PHARMACEUTICAL FORM
Tablet
Formal comment Information on the size of the tablet should be added.
White to off-white, oblong, uncoated tablet with break scores on both sides, with a length of approximately 12 mm and a width of approximately 5.5 mm. The tablet can be divided into equal doses.
4. CLINICAL PARTICULARS
4.1 Therapeutic indications
Severe pain in adults.
4.2 Posology and method of administration
Levomethadone must be titrated individually. In general, the lowest effective analgesic dose should be chosen. The following recommended doses should be used as guidance. In case of severe pain conditions (e.g. cancer pain) doses may vary.
It is recommended that the patient should rest during levomethadone’s duration of action.
Posology
Adults For adults a single dose of 7.5 mg levomethadone hydrochloride is recommended. In certain cases the initial dose might be 2.5 mg levomethadone hydrochloride.
In case of decreasing efficacy administration can be repeated after 4-6 hours. In order to avoid a cumulative effect generally the second and all following doses should be lower than the initial dose.
For the total daily dose it is recommended not to exceed 4 to 6 times the single dose.
For the treatment of chronic pain administration following a fixed dose schedule should be preferred.
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Notes Levomethadone is roughly twice as effective as the methadone racemate. There are indications that levomethadone degradation is enhanced when the methadone racemate is administered, thereby possibly altering this ratio. This must be taken into account when dosing.
Special populations
Elderly patients Reduction of the dose is recommended in elderly patients.
Patients with renal and/or hepatic impairment Reduction of the dose is recommended in patients with renal diseases or severe chronic liver diseases.
Paediatric population The safety and efficacy of levomethadone in children and adolescents aged <18 years have not been established.
Method of administration For oral use. The tablets should be taken with a sufficient amount of liquid (e.g. ½ glass of water).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
During the first trimester of pregnancy levomethadone must not be used (see section 4.6).
Treatment with MAO inhibitors or within two weeks after their discontinuation.
Narcotic antagonists or other narcotic agonists/antagonists (e.g. pentazocine and buprenorphine) must not be used during treatment with levomethadone, except for treatment of overdose.
4.4 Special warnings and precautions for use
Strict indication and particularly close medical surveillance are required in case of: presence of impaired consciousness concomitant use of other central nervous system and/or respiratory depressant medicinal products and substances conditions where depression of the respiratory centre must be avoided raised intracranial pressure hypotension in case of hypovolaemia prostatic hypertrophy with residual urine formation pancreatitis biliary tract disorders obstructive and inflammatory bowel disease phaeochromocytoma hypothyroidism moderate to severe impairment of the respiratory centre and respiratory function bradycardia treatment with classes I and III antiarrhythmics opioid dependence acute abdominal conditions: Treatment with levomethadone, in common with other μ-agonists, may hamper diagnosis or mask the clinical progression in patients with acute abdominal conditions. Therefore, patients with signs of acute abdomen during treatment should be monitored closely until an exact diagnosis has been established. infants, children and adolescents <18 years of age.
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Lung and respiration Levomethadone should be used with caution in patients with: asthma chronic obstructive pulmonary disease cor pulmonale substantially impaired respiratory reserve pre-existing impairment of respiratory function hypoxia or hypercapnia
Even at usual therapeutic doses, respiratory activity may be reduced in these patients, while simultaneously airway resistance may increase resulting in apnoea. In patients predisposed to such atopic phenomena, exacerbation of pre-existing asthma, skin eruptions and blood dyscrasias (eosinophilia) may occur.
Intracranial pressure The respiratory-depressant effect of opioids and their capacity to raise the cerebrospinal fluid pressure may be enhanced clinically relevant in case of pre-existing raised intracranial pressure. In view of the efficacy profile of levomethadone as a μ-agonist, it should be used with extreme caution and only when deemed essential for the treatment of such patients.
Potential for dependence Levomethadone has a primary dependence potential and may produce addiction. With prolonged use physical and psychological dependence as well as tolerance develops. When used as directed in patients with chronic pain the risk of developing physical or psychological dependence is markedly reduced or needs to be assessed in a differentiated manner. Upon abrupt discontinuation severe and sometimes life-threatening withdrawal symptoms are to be expected.
There is a cross-tolerance to other opioids.
Risk from concomitant use of sedative medicinal products such as benzodiazepines or related medicinal products: Concomitant use of
Cardiac diseases Levomethadone should be administered with special caution to patients with known or suspected prolonged QT interval or an electrolyte imbalance, especially hypokalaemia/cardiac arrhythmias. During treatment with μ-opioid receptor agonists prolongation of QT interval and subsequent polymorphic ventricular tachycardia (torsade de pointes) has to be expected.
In principle, all patients must be asked about their cardiac medical history and about any unexplained syncope prior to initiation of therapy. The patient should be informed about the possibility of cardiac arrhythmias.
Prior to initiation of therapy and after two weeks of treatment, an ECG must be taken to establish and quantify the effect of the substitution substance on the QT interval. Similarly, it is advisable to take an ECG before any dose increase, as well as a follow-up at least once a year. In the event of unexplained syncope, the possibility of a cardiac cause should be considered. If there is any change in co- medication, the possibility of interaction affecting the QT interval must be considered.
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Adrenal insufficiency Opioids 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.
Hypoglycaemia Hypoglycaemia has been observed in the context of methadone (a racemic mixture of levomethadone and dextromethadone) overdose or dose escalation. Regular monitoring of blood sugar is recommended during dose escalation (see section 4.8 and section 4.9).
Decreased Sex Hormones and increased prolactin Long-term use of opioids may be associated with decreased sex hormone levels and increased prolactin. Symptoms include decreased libido, impotence or amenorrhea.
Doping test Athletes must be aware that this medicinal product may cause a positive reaction to ‘anti-doping’ tests. Use of levomethadone as doping agent may become a health hazard.
4.5 Interaction with other medicinal products and other forms of interaction
The effects of levomethadone can be influenced both by pharmacodynamic and pharmacokinetic interactions. Depending on the clinical picture, the dose of levomethadone and/or concomitant medicinal products will have to be adjusted in the event of interactions described in the following section.
The following combinations are contraindicated (see section 4.3): Use of MAO inhibitors within the last 14 days prior to opioid administration (e.g. pethidine) can lead to life-threatening effects, with both depressant and excitatory symptoms on the central nervous system, respiration and on circulatory function. Such reactions cannot be excluded for levomethadone. Pentazocine and buprenorphine (except for treatment of levomethadone hydrochloride overdose).
When co-administering levomethadone with other medicinal products or substances, the following interactions must be taken into consideration: With central nervous system and respiratory function depressant medicinal products and substances mutual potentiation of the CNS or respiratory-depressant effect may occur, e.g. with potent analgesics (including other opiates), alcohol, phenothiazine derivatives, benzodiazepines, barbiturates and other hynotics/anaesthetics, tricyclic antidepressants.
Sedative medicinal products such as benzodiazepines or related medicinal products : The concomitant use of opioids with sedative medicinal products such as benzodiazepines or related medicinal products increases the risk of sedation, respiratory depression, coma and death because of additive CNS depressant effect. The dose and duration of concomitant use should be limited (see section 4.4).
Serotonergic medicinal products: Serotonergic syndrome may occur with concomitant administration of methadone (a racemic mixture of levomethadone and dextromethadone) with pethidine, monoamine oxidase (MAO) inhibitors and 4
Ssnergic medicinal products 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.
The effect of levomethadone can be potentiated by antihypertensives, e.g. reserpine clonidine urapidil prazosin
The plasma concentration of levomethadone can be increased or its duration of action prolonged by medicinal products and substances that inhibit the enzymatic degradation of levomethadone hydrochloride in the liver (cytochrome P450 system), e.g. cimetidine antifungals (e.g. itraconazole, ketoconazole, voriconazole, fluconazole) macrolide antibiotics antiarrhythmics contraceptives SSRIs (selective serotonin reuptake inhibitors), e.g. sertraline, fluvoxamine, fluoxetine and paroxetine) ciprofloxacin
The plasma concentration of levomethadone can be decreased or its duration of action shortened by medicinal products and substances that induce the enzymatic degradation of levomethadone in the liver, e.g. carbamazepine phenobarbital phenytoin rifampicin St. John’s wort spironolactone fusidic acid flunitrazepam efavirenz nevirapine nelfinavir ritonavir amprenavir
Careful monitoring of clinical symptoms of overdose, underdose and/or withdrawal symptoms and appropriate dose adjustment is recommended if: levomethadone is coadministered with medicinal products or substances metabolised by hepatic enzymes. levomethadone is coadministered with medicinal products or substances affecting protein binding (levomethadone is mainly bound to alpha-acid glycoprotein and albumin, see section 5.2). such medicinal products or substances causing the above mentioned effects are discontinued.
Decreased (didanosine and stavudine) or increased (zidovudine) plasma concentrations of antiretroviral medicinal products have been described if used concomitantly with levomethadone, whereas the plasma concentration of levomethadone were unchanged. For these patients, close monitoring for an adequate clinical response or signs of toxicity is required.
4.6 Fertility, pregnancy and lactation
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Pregnancy Levomethadone has not been sufficiently studied. For the evaluation, reference can be made to data on D,L-methadone used during substitution therapy.
A number of human studies have shown that the use of methadone during pregnancy does not lead to a significant increase in congenital anomalies and has no influence on delivery. Children of methadone- substituted mothers had a comparatively lower birth weight and a smaller head circumference than non-drug-exposed children. Withdrawal symptoms occurred in 56 out of 92 newborns born to methadone-substituted mothers. Furthermore, increased incidence of otitis media has been observed, as well as neurological findings with hearing impairment, delays in mental and motor development and ocular abnormalities. An association with increased SIDS (sudden infant death syndrome) is assumed. Studies in animals have shown reproductive toxicity (see section 5.3).
Levomethadone crosses the placenta. In the first trimester levomethadone must not be used for pain therapy. During later pregnancy chronic use must be avoided as it may lead to habituation and dependence in the unborn child and lead to post-partum withdrawal phenomena in the new-born infant.
Levomethadone – if given prior or during labour – may impair uterine contractility and the risk of neonatal respiratory depression. Therefore, the new-born infant should be monitored until substantial respiratory depression can be excluded (at least 6 hours). Depending on the clinical picture administration of opioid antagonists (e.g. naloxone) may be required.
Breastfeeding Levomethadone is excreted in breast milk at low levels.
For levomethadone the decision to recommend breast-feeding should take into account clinical specialist advice and consideration should be given to whether the woman is on a stable maintenance dose of levomethadone and any continued use of illicit substances. If breastfeeding is considered, the dose of levomethadone 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 levomethadone 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.
Fertility Impairment of sexual function in male patients receiving D,L-methadone is a known undesirable effect of the substance. Sexual function was significantly impaired in 29 men receiving substitution therapy with methadone, in whom the ejaculate volume, seminal vesicle secretion and prostate secretion were reduced by more than 50% compared to 16 men with heroin dependence and 43 control subjects.
4.7 Effects on ability to drive and use machines
Even when used as directed, levomethadone can alter responsiveness to such an extent that the ability to drive or use machines is impaired. This particularly applies in combination with alcohol.
The decision about the ability to drive should be made by the attending physician in each individual case, taking into account the individual response and the respective dose.
4.8 Undesirable effects
Frequencies of adverse reactions are based on the following categories: Very common (≥1/10) Common (≥1/100 to <1/10)
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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)
Immune system disorders Not known: Hypersensitivity reaction up to shock
Metabolism and nutrition disorders Not known: Hypoglycaemia
Psychiatric disorders Common: Mood changes (usually euphoria, occasionally dysphoria), changes in activity (usually reduced activity, occasionally an increase) and, altered cognitive and sensory capacities (for example the ability to make decisions, perception problems such as confusion, disorientation) Levomethadone induces various psychiatric adverse events, which vary individually regarding nature and severity (i.e. depending on the personality and treatment duration).
Nervous system disorders Common: Dizziness, headache and undesirable effects of the vagotrope type (especially following i.v. injection) such as nausea, vomiting, dry mouth, hiccups, bronchospasms, smooth muscle spasms, micturition disorders and constipation. A characteristic accompanying symptom is pupillary constriction. An accompanying effect in long-term use is increased sweating. Rare: Excitatory symptoms Not known: CNS effects such as sedation (somnolence, fatigue, drowsiness), respiratory depression, cerebral convulsions, especially with high doses. Respiratory depression may be life-threatening (respiratory arrest). The risk for respiratory depression is especially increased with too high levomethadone hydrochloride doses or with concomitant use of other respiratory depressive medicinal products (see section 4.5).
Cardiac disorders Uncommon: Clinically relevant drop in heart rate (bradycardia)
Vascular disorders Uncommon: Clinically relevant drop in blood pressure
Respiratory, thoracic and mediastinal disorders Uncommon: Non-cardiogenic lung oedema in ICU patients
Skin and subcutaneous tissue disorders Uncommon to common: Urticaria, pruritus
During use of high-dose levomethadone in the substitution treatment the following undesirable effects have additionally been reported, which cannot be excluded during treatment of pain with lower doses: Anorexia, Insomnia, restlessness, Visual disturbances, Tachycardia, cardiac arrhythmias (syncope), cardiac arrest, Seeping haemorrhage, orthostatic hypotension, impaired circulatory function, Biliary tract spasms, Skin rash, Decreased urine output, 7
Asthenia, oedema, Flushing.
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
Particularly in opiate-naïve persons (especially children), serious intoxication can be induced even by doses lower than those commonly used in substitution therapy. In children up to 5 years, this is possible from about 0.5 mg, in older children from about 1.5 mg and in opiate-naïve adults from about 10 mg levomethadone hydrochloride.
A dose reduction is recommended if patients show signs and symptoms of an excessive levomethadone-effect, characterised by symptoms such as “feeling strange”, poor concentration skills, drowsiness and possibly dizziness upon standing.
Hypoglycaemia has been reported.
Furthermore, cases of overdose are characterised by respiratory depression (Cheyne-Stokes respiration, cyanosis), extreme drowsiness tending to impaired consciousness and even coma, miosis, musculoskeletal flaccidity, cold and clammy skin and sometimes by bradycardia and hypotension. Massive overdoses can cause apnoea, circulatory failure, cardiac arrest and death.
Emergency medical care or, if necessary, intensive-care measures are required immediately (e.g. intubation and ventilation). For treating symptoms of intoxication, specific opiate antagonists (e.g. naloxone) can be used. The dose of individual opiate antagonists varies (refer to the product information). In particular, it should be considered that levomethadone can have long-lasting respiratory-depressant effects (up to 75 hours), whilst opiate antagonists have a much shorter duration of action (1 to 3 hours). Subsequent injections may therefore be required after the antagonistic effects have subsided. Measures to maintain body warmth and volume replacement may be necessary.
In the event of oral intoxication with levomethadone, gastric lavage may be performed only after antagonism has taken place. It is particularly important to protect the airways by intubation both when performing gastric lavage and prior to administering antagonists (vomiting may be induced). In the treatment of intoxication, alcohol, barbiturates, bemegride, phenothiazines and scopolamine must not be used.
Levomethadone is not dialysable.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Levomethadone ATC code: N07BC05
Levomethadone is a fully synthetic opioid analgesic which, as a basic diphenylmethane derivative, can be structurally derived from morphine.
1 Levomethadone is the R(–) enantiomer of methadone. The S(+) enantiomer has only /50 of the analgesic effect of the R(–) enantiomer. The duration of analgesic action varies like for morphine
8 between 4 to 6 hours. Besides analgesia, levomethadone induces a long-lasting respiratory depression, which is most pronounced after 4 hours and can last for up to 75 hours. Bradycardia, hypotension, bronchoconstriction and antidiuresis are among the pharmacological effects of levomethadone, in addition to other classical opioid effects such as sedation, euphoria and miosis. After prolonged intake, levomethadone e also causes dependence comparable to that of morphine and heroin
5.2 Pharmacokinetic properties
Absorption Levomethadone is rapidly absorbed after oral administration. The mean absolute bioavailability after oral ingestion of a solution is about 82%.
Bioavailability In a relative bioavailability study with 34 subjects, bioequivalence between the tablets (5 mg) and 1 ml of the oral solution for substitution (containing 5 mg/ml levomethadone hydrochloride) could be confirmed with regard to rate (Cmax) and extent of absorption (AUC0-72 h) measure. This outcome applies in analogy to the 2.5 mg, 20 mg and 30 mg tablets.
Distribution At a long-term therapy the pharmacokinetic equilibrium (steady state) between absorption, distribution and elimination is achieved within 4 to 5 days. The substance shows a relatively large volume of distribution ranging from 3 to 4 l/kg. This means that a considerable amount of this highly lipophilic substance accumulates in peripheral tissue, fat, muscle and skin. Serum protein binding is approximately 85%. It is primarily bound to alpha-acid glycoprotein and albumin.
Levomethadone is excreted in human milk and crosses the placenta. The umbilical cord blood concentration is lower than maternal plasma concentrations. There is no correlation between maternal plasma/umbilical cord blood concentrations and amniotic fluid levels.
Biotransformation Levomethadone undergoes N-demethylation by CYP isoenzymes, involving among others CYP3A4, 2D6, 2B6 and 2C19. To date, 32 metabolites of methadone have been identified. However, only 2% of the administered dose is made up of two pharmacologically active metabolites. Methadone and its metabolites accumulate mainly in the lung, liver, kidney, spleen and muscle.
Elimination Elimination of levomethadone and its metabolites occurs both renally and biliary. Renal elimination, which is highly pH-dependent, is the main route at higher doses, with approximately 60% excreted unchanged after administration of more than 160 mg. Ten to 45% of the total amount recovered is excreted via the biliary route.
The terminal plasma half-life is subject to considerable individual variability (14 to 55 hours). It is extended when taken over prolonged periods, in higher age and in cases of chronic liver disease.
Levomethadone is not dialysable. However, there is no danger of accumulation in patients with anuria, as excretion in this case occurs exclusively via the faeces.
5.3 Preclinical safety data
After acute intoxication, death occurs by respiratory failure. LD50 values of levomethadone after i.v. administration are 13.6 to 28.7 mg/kg in mice and 8.7 mg/kg in rats.
The major target organs in laboratory animals after subchronic and chronic administration were the respiratory system (respiratory depression) and the liver (increased ALAT activity, hepatocellular hypertrophy, eosinophilic cytoplasmic changes).
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Mutagenic and tumorigenic potential In vitro and in vivo genotoxicity studies on methadone have produced inconsistent findings with indications of a weak clastogenic potential. At present, no risk can be inferred for clinical use. Long- term studies in rats and mice produced no evidence of a carcinogenic potential.
Toxicity to reproduction Levomethadone has not been sufficiently studied. For the evaluation, reference can be made to data on D,L-methadone. In rats, 5-day administration of methadone 20 mg/kg/day led to reduced weight of the prostate, seminal vesicle and testes. The progeny of methadone-treated males (up to 38 mg/ kg/day) showed increased neonatal mortality of up to 74%. Juveniles of methadone-dependent female rats showed delayed postnatal brain growth, lower body weight and increased neonatal mortality. Oral methadone doses in rats from gestational days 14 to 19 led to a significant decrease in blood testosterone levels in the male offspring (antagonism via naloxone possible).
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Microcrystalline cellulose Dextrates (7.8-9.2%) Mannitol (Ph. Eur.) Sodium starch glycolate (type A) (Ph. Eur.) Silica, colloidal anhydrous Magnesium stearate (Ph. Eur.)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Blister 4 years
HDPE bottles 18 months After first opening: 3 months
6.4 Special precautions for storage
Store in the original package in order to protect from light.
6.5 Nature and contents of container
Child resistant aluminium//PVC/PE/PVDC perforated unit-dose blisters with 10, 14, 20, 28, 30, 50, 56, 60, 98, 100 tablets. HDPE bottles with child-resistant polypropylene screw cap with 28, 56, 98, 100, 250 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal.
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Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. MARKETING AUTHORISATION HOLDER
[To be completed nationally]
{Name and address} {tel} {fax} {e-mail}
8. MARKETING AUTHORISATION NUMBER(S)
[To be completed nationally]
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: {DD month YYYY}
[To be completed nationally]
10. DATE OF REVISION OF THE TEXT
{MM/YYYY}
[To be completed nationally]
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