Teratological, Peri‐ and Postnatal Studies on Ferastral®, an Iron‐poly (sorbitol‐gluconic acid) complex

Abstract

This paper presents a review of the teratological and peri-and postnatal studies performed in rats and rabbits on FerastralB, an iron-poly (sorbitol-gluconic acid) complex.The test compound was given intramuscularly in doses varying from 1 to 100 mg Fe3+/kg. I n the teratological studies the compound was given daily during the whole or part of the period of organogenesis, and in the peri-and postnatal study in rats from day 16 of pregnancy through lactation to 21 days post partum. I n a separate study the effects of FerastralB on blood coagulation and fibrinolysis were studied in pregnant rats treated with 50 mg Fea+/kg. Jectoferm (iron-sorbitol) and ImferonB (iron-dextran)were used as reference compounds in some of the studies. Pregnant rats reacted in a totally different way compared to pregnant rabbits when treated with high doses of Ferastral. Pregnant rats, but not rabbits, developed focal necrosis in the liver, placenta and spleen. These changes were dose-dependent and not observed with lower doses ( 1, 4 and 16 mg Fe3+/kg). Similar pathological alterations were also seen after treatment with Jectofer, but not with Imferon. The pathological changes, being similar to those seen after elicitation of a generalized Shwartzman reaction (GSR),were not interpreted as an expression of such a reaction. The most common features of the GSR, bilateral cortical necrosis, capillary thrombi, and changes in the blood coagulation and fibrinolytic activity, were not observed in the pregnant rats. The maternal toxicity was accompanied by secondary effects on the foetuses manifested in reduced maturation of the foetal skeleton. Treatment with Ferastral in doses not inducing maternal toxicity did not adversely affect litter size, foetal loss, litter weight or embryonic or foetal development in either rats or rabbits.

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose

“…Inthisfirst rabbits tudy,the maternaland foetalNOAELsw erecon- cluded tobe9and 4.5 mg iron/kg/day.However,the second rabbits tudyfailed toconfirmane ffectof FCM on skeletalo ssification in the foetus,even atmaternally toxicdosages(9 mg iron/kg/day) [33].Noe videnceo f embryo-foetaltoxicity wasfound atanydosage in this study(1 -9 mg iron/kg/day),a nd the maternaland foe-talNOAELsw eref ound tobe4 .5 and 9mgi ron/kg/day, respectively. Asin others tudiesof the effects of i. v.i ron preparationson developing animale mbryos,itw asoften impossible tod istinguishspecificeffects of FCM on the embryoo rfoetus from the generale ffects of iron overloado nthe maternalp hysiology.The generalp atterno f changess een in thesestudiesiss imilart othats een in reproductivestudiesw ithi ron-poly(sorbitol-gluconic acid) complex [35]a nd iron sucrose [36,37].Overall, the NOAEL foreffects on embryo-foetald evelopment in rats and rabbits canberegarded as9mgi ron/kg/ day,i. e. 63 mg iron/kg/week,whichi sabout four times the maximumweeklyclinicald osef orhumans.…”

A Clinical Investigation of an Iron‐poly (sorbitol‐gluconic acid) complex, Ferastral®, for the Treatment of Iron Deficiency Anaemia

“…(1971) studied complexes of iron and polymers containing sorbitol and gluconic acid. Further studies with an iron-poly (sorbitolgluconic acid) complex were performed by Domeij et al (1977), Eriksson & Svard (1977) and Flodh et al (1977). Based on these results clinical evaluation was initiated by Andersson & Grafford ( 1977).…”