Source: European Medicines Agency (EU)
Pharmacotherapeutic group: Analgesics; opioids; diphenylpropylamine derivatives
ATC code: N02AC06
Levomethadone is a fully synthetic opioid analgesic which, as a basic diphenylmethane derivative, can be 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 duration of analgesic action varies like for morphine 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 also causes dependence comparable to that of morphine and heroin.
Levomethadone is rapidly absorbed after oral administration. The mean absolute bioavailability after oral ingestion of a solution is about 82%.
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 (AUC0-72h) measure. This outcome applies in analogy to the 2.5 mg, 20 mg and 30 mg tablets.
Following daily oral use of 30 mg steady state is achieved within 4 to 5 days. The initial volume of distribution for methadone is 50 to 100 l and 500 l in steady state. 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.
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 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% appearing as unchanged levomethadone 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.
After acute intoxication, death occurs by respiratory arrest. 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.
For acute toxicity in humans, see section 4.9.
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).
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. Longterm studies in rats and mice produced no evidence of a carcinogenic potential.
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 resulted in a loss of 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).
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