Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Aspen Pharma Trading Limited, 3016 Lake Drive, Citywest Business Campus, Dublin 24, Ireland
Pharmacotherapeutic group: Thyroid therapy; Thyroid hormones
ATC: H03AA01
The action of synthetic levothyroxine contained in Levothyroxine sodium is identical to that of the naturally occurring thyroid hormone, which is mainly produced by the thyroid gland. The body cannot differentiate between endogenously produced and exogenous levothyroxine.
Following partial conversion to liothyronine (T3) particularly in the liver and kidney and after passage into bodily cells, the characteristic thyroid hormone effects on development, growth and metabolism are observed, mediated by activation of T3 receptors. Thyroid hormone replacement leads to normalisation of metabolic processes. Thus, for example, a rise in cholesterol due to hypothyroidism is significantly reduced by the administration of levothyroxine.
Depending to a large extent on the type of galenic formulation, up to ≤80% of orally administered levothyroxine is absorbed when taken in the fasting state, mainly from the upper small intestine. Absorption is significantly reduced if the product is administered with food. Peak plasma levels are reached about 2 to 3 hours after ingestion.
At the start of oral therapy, onset of action occurs after 3 to 5 days.
The volume of distribution is calculated to be about 10 to 12 l. Levothyroxine is approximately 99.97% bound to specific transport proteins. As this protein hormone binding is not covalent, there is a constant and very rapid exchange between free and bound hormone.
Metabolic clearance for levothyroxine is around 1.2 l plasma/day. It is mainly degraded in the liver, kidney, brain and muscle.
The half-life of levothyroxine is about 7 days, although it is shorter in hyperthyroidism (3 to 4 days) and longer in hypothyroidism (about 9 to 10 days). In man, approximately 20 to 40% of levothyroxine is eliminated in the faeces and approximately 30 to 55% of a dose of levothyroxine is excreted in the urine.
Levothyroxine crosses the placenta only in small amounts. During normal dose therapy, only small amounts of levothyroxine are secreted into breast milk.
Due to its high protein binding, levothyroxine is not amenable to haemodialysis or haemoperfusion.
Renal disease does not appear to have any significant effect on the disposition of levothyroxine.
Due to impaired liver function the conversion into T3 may be decreased and the disposition of levothyroxine may be altered, depending on the severity of decreased hepatic function.
Adverse effects observed in single and repeated dose toxicity studies only occurred at high doses.
Acute toxicity of levothyroxine is very low.
Chronic toxicity studies were performed in different animal species (rats, dogs). At high doses, signs of hepatopathy, increased occurrence of spontaneous nephrosis and organ weight changes were seen in rats. No significant adverse reactions were observed in dogs.
There are no data available with regard to the mutagenic potential of levothyroxine. To date, there has been no suspicion or evidence of offspring damage due to genome changes caused by thyroid hormones. Levothyroxine was not mutagenic in the mouse micronucleus test.
Long term animal studies have not been performed to investigate the tumorigenic potential of levothyroxine.
Thyroid hormones cross the placenta in very small amounts.
Upon administration of levothyroxine during early pregnancy, in rats, adverse effects, including foetal and neonatal deaths, only occurred at very high doses. Some effects on limb formation in mice and effects on central nervous system development in chinchillas were reported but teratology studies in guinea pigs and rabbits did not reveal increases in congenital abnormalities.
Animal studies regarding effects on fertility are not known. There are no available data regarding impairment of male or female fertility. There is no suspicion or evidence that this might occur.
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