Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Ferndale Pharmaceuticals Ltd, Unit 740, Thorp Arch Estate, Wetherby, West Yorkshire, LS23 7FX
Pharmacotherapeutic group: sclerosing agents for local injection
ATC code: C05BB02
Lauromacrogol 400 (also known as polidocanol) is the active ingredient of Aethoxysklerol, has world-wide well-established use for sclerotherapy treatment of varicose veins.
Both primary and secondary nonclinical pharmacodynamic studies show that the pharmacological profile of lauromacrogol 400 is characterized by its local effects on cell membranes and the associated, locally confined, damage to tissue. This pharmacodynamic activity results in the desired sclerosing effect of blood vessels if lauromacrogol 400 is administered correctly, but may cause unintended tissue damage and subsequent adverse reactions if the recommended application procedure is not followed.
Lauromacrogol 400 has a concentration and volume dependent effect on the endothelium of blood vessels and possibly additional layers of the vein wall. In the long term, the affected veins are transformed into a fibrous cord. The result of sclerotherapy is equivalent to the surgical removal of a varicose vein.
Application of compression following sclerotherapy of varicose veins compresses the damaged vein walls so that excessive thrombus formation and recanalisation of the initially formed parietal thrombus is prevented. This gives rise to the desired transformation into fibrous tissue and hence sclerosis.
The main pharmacodynamic effect of lauromacrogol 400 – the induction of tissue damage by interacting with the lipid double layer of cells – diminishes with increasing distance from the site of injection. The pharmacological action of lauromacrogol 400 is therefore considered to be locally restricted.
When converted to a microfoam, lauromacrogol 400 is very effective at treating small, medium and large varicose veins. The microfoam has more time to act compared to the liquid form, using a smaller quantity. However, additional precautions and contraindications are applicable and some adverse events are more frequent following microfoam sclerotherapy compared to liquid sclerotherapy.
Six healthy subjects received an injection of 37 mg 14C-lauromacrogol 400 as a strongly diluted solution into the great saphenous vein. The concentration-time course of lauromacrogol 400 in plasma was biphasic with a terminal elimination half-life of lauromacrogol 400 and its labelled metabolites of 4.09 h. The AUC∞ was 3.16 µg x h/ml and the total clearance 11.68 l/h. 89% of the administered dose was eliminated from the blood within the first 12 hours.
In another study, the plasma concentrations of parent lauromacrogol 400 molecules were determined in 6 patients with varicose veins (diameter >3 mm) after treatment with Aethoxysklerol 30 mg/ml. The plasma half-life was 0.94-1.27 h and the AUC∞ 6.19-10.90 µg x h/ml. The mean total clearance was 12.41 l/h and the distribution volume 17.9 l.
In animal experiments, Aethoxysklerol has a relatively low acute toxicity. Safety pharmacology studies showed negative chronotropic, inotropic and dromotropic effects, with a blood pressure drop. Additional proarrhythmic effects were seen when other local anaesthetics were given concomitantly. After repeated administration of Aethoxysklerol, some animals of all species investigated showed histological alterations in the intestine, adrenal glands and liver, and rabbits additionally in the kidney.
Lauromacrogol 400 caused haematuria in all species investigated. At doses of 4 mg/kg body weight/day and higher, male rats showed an increase in liver weight after daily administration on 7 consecutive days, and an increase in ALAT/GPT and ASAT/GOT activity at doses of 14 mg/kg/day and higher.
Lauromacrogol 400 was tested extensively in vitro and in vivo. All tests were negative, except one in vitro test in which lauromacrogol 400 induced polyploids in mammalian cells. However, if the medicinal product is used according to the instructions, no relevant clinical genotoxic potential is expected.
The daily intravenous administration of lauromacrogol 400 over several weeks or during organogenesis had no influence on male or female fertility or early embryo development in rats, and did not induce teratogenic effects in rats or rabbits; however, embryotoxic and fetotoxic effects (increased embryo/fetal mortality, reduced fetal weights) were seen in the maternal toxic dose range. When administration was restricted to intervals of 4 consecutive days during organogenesis, neither maternal toxic nor embryotoxic/fetotoxic effects occurred (rabbits). Peri- and postnatal development, behaviour and reproduction were not impaired in rats whose mothers received intravenous lauromacrogol 400 every other day during late gestation and in the lactation period. Lauromacrogol 400 crosses the placental barrier in rats.
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