Source: European Medicines Agency (EU) Revision Year: 2024 Publisher: Recordati Rare Diseases, Tour Hekla, 52 avenue du Général de Gaulle, 92800 Puteaux, France
Pharmacotherapeutic group: Vitamins, Other plain vitamin preparations
ATC code: A11HA08
Vitamin E is the principal lipo-soluble antioxidant in the organism. It acts as a free radical chain breaking molecule, stopping the peroxidation of polyunsaturated fatty acids and it is involved in maintaining the stability and integrity of cell membranes.
This medicinal product has been authorised under “exceptional circumstances”. This means that due to the rarity of the disease it has not been possible to obtain complete information on this medicinal product. The European Medicines Agency will review any new information which may become available every year and this SmPC will be updated as necessary.
The active substance d-alpha-tocopherol-polyethylene glycol 1000 succinate (tocofersolan) is a pro-drug; the active metabolite is the d-alpha-tocopherol. At low concentrations, tocofersolan forms micelles which enhance absorption of non-polar lipids such as fat-soluble vitamins. Its critical micellar concentration is low (0.04 to 0.06 mmol/l).
The hydrolysis of tocofersolan occurs in the gut lumen. Taken up by cells, the alpha-tocopherol moiety appears in chylomicrons in the lymph in a manner identical to vitamin E absorbed from the diet. Cellular uptake does not require receptors, binding proteins or metabolic processes and does not occur by pinocytosis. Absorption of deuterated tocofersolan showed a normal pattern in lipoproteins: alpha-tocopherol peaked first in chylomicrons, then in very low-density lipoproteins (VLDL) and finally in low-density lipoproteins (LDL) and high-density lipoproteins (HDL), and the disappearance portions of the curves paralleled those in control subjects.
A study in 12 healthy volunteers compared tocofersolan with a water-miscible reference vitamin E after a single oral loading dose of 1200 IU. The relative bioavailability of tocofersolan tended to be higher (Frel of 1.01 ± 1.74) with AUC0-t of 0.383 ± 0.203 µM.h/mg, Cmax of 0.013 ± 0.006, tmax of 6.0 h (6.0–24.0), and t1/2 of 29.7 h (16.0–59.5).
In a similar study tocofersolan showed a higher bioavailability than a water-miscible reference vitamin E in paediatric patients with chronic cholestasis (n=6), absorption was significantly higher on both plasma concentration maximum increase (p=0.008) and AUC (p=0.0026).
Located principally on cell membranes, within mitochondria and microsomes, vitamin E is ubiquitously distributed (red blood cells, brain, muscle, liver, platelets) and fat tissues are its major reservoir.
Vitamin E is mainly eliminated in the bile (75%) and stools, either as free tocopherol or as oxidized forms. Urine represents a minor elimination route of vitamin E (as glucuro-conjugate).
Non-clinical data in the literature reveal no special hazard for humans based on conventional studies of repeated dose toxicity, genotoxicity and toxicity to reproduction.
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