Source: European Medicines Agency (EU)
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. In the second and third trimesters, levomethadone must not be used long-term (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.
Strict indication and particularly close medical surveillance are required in case of:
Levomethadone should be used with caution in patients with:
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.
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.
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 levomethadone and sedative medicinal products such as benzodiazepines or related medicinal products may result in sedation, respiratory depression, coma and death. Because of these risks, concomitant prescribing with these sedative medicinal products should be reserved for patients for whom alternative treatment options are not possible. If a decision is made to prescribe levomethadone concomitantly with sedative medicinal products, 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).
The concomitant use of opioids, including levomethadone, and alcohol may cause sedation, respiratory depression, coma, and death. The intake of alcohol during treatment with levomethadone should be avoided (see section 4.5).
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 levomethadone 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 comedication, the possibility of interaction affecting the QT interval must be considered.
It is recommended to reduce the dose in elderly and in patients with renal disease, severe chronic liver disease or in reduced general condition (see section 4.2).
Levomethadone should be used with caution in patients with adrenal insufficiency, as opioids may reduce cortisol production.
Regarding the impairment of sexual function in male patients see section 4.6.
[Blue box information on anti-doping-warning to be added nationally based on national requirements. E.g. “Anti-Doping Warning: Athletes must be aware that this medicinal product may cause a positive reaction to sports doping control tests. Use of levomethadone as a doping agent may become a health hazard.”]
Levomethadone contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially ‘sodium-free’.
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):
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
The concomitant use of opioids with sedative medicines 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).
The effect of levomethadone can be potentiated by antihypertensives, e.g.
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 in the liver (cytochrome P450 system), e.g.
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.
Careful monitoring of clinical symptoms of overdose, underdose and/or withdrawal symptoms and appropriate dose adjustment is recommended if:
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.
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.
Levomethadone is excreted in human milk. During levomethadone treatment breast-feeding is disadvised, as the effects on the infant have not been sufficiently investigated. In case of a single levomethadone administration, however, discontinuation of breast-feeding is not generally necessary.
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.
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.
Frequencies of adverse reactions are based on the following categories:
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)
Not known: Hypersensitivity reaction up to shock
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).
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 doses or with concomitant use of other respiratory depressive medicinal products (see section 4.5).
Uncommon: Clinically relevant drop in heart rate (bradycardia)
Uncommon: Clinically relevant drop in blood pressure
Uncommon: Non-cardiogenic pulmonary oedema in intensive care patients
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:
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.
Not applicable.
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