Revision Year: 2018 Publisher: Bial –Portela & Ca SA, A Av da Siderurgia Nacional, 4745 – 457, S. Mamede do Coronado, Portugal
Pharmacotherapeutic group: Iron in combination with Folic Acid
ATC Code: B03AD03
FOLIFER contains as active substances, two important micronutrients – iron and folic acid. Iron, which appears as ferrous sulfate, is released slowly from the nucleus of the tablet, while folic acid present in the coating is released more rapidly.
Ionic iron is indispensable for the haemoglobin and myoglobin synthesis – compounds that are necessary for transport and utilisation of oxygen. Iron is also a component of a number of enzymes necessary for energy transfer, e.g., cytochrome oxidase, xanthine oxidase and succinic dehydrogenase.
Folic acid is an indispensable vitamin for a number of metabolic reactions essential to life such as the synthesis of purines, synthesis of pirimidinic nucleotides, amino acids interconversion (serine to glycine, histidine to glutamic acid, homocysteine to methionine).
Iron and folic acid are, essentially, two factors necessary in successive phases of haematopoyesis.
Absorption of iron can occur along the entire length of the GI tract, it is greatest in the duodenum and proximal jejunum and becomes progressively less distally. It is influenced by many factors including the administered dose, iron stores, the degree of erythropoiesis, iron present in diet and the form in which it is administered (iron sulfate is the salt that presents best bioavailability). Approximately 5-15% of dietary iron is absorbed in healthy individuals and about 60% in irondeficient individuals. However iron absorption is decreased when it is administered with many foods or with some drugs.
Iron absorption decreases when iron stores are high. A healthy individual may control GI absorption of iron, even when it is administered at high doses, but that does not happen in individuals with hemochromatosis genotype.
Following oral administration, iron passes through GI mucosal cells directly into the blood and is immediately bound to Transferrin. Transferrin, a glycoprotein 1-globulin, transports iron to the bone marrow where it is incorporated into haemoglobin, during hematopoiesis. Iron sulfate half life is approximately 6 hours. Iron metabolism occurs in a virtually closed system. Only a small amount of iron is excreted and most of the iron liberated by destruction of haemoglobin is reused by the body.
Daily excretion of iron in healthy men amounts to only 0.5-2 mg.
Folic acid is absorbed rapidly from the GI tract following oral administration, mainly from the proximal portion of the small intestine. Naturally occurring folate polyglutamates are enzymatically hydrolized in the GI tract to monoglutamate forms of folic acid prior to absorption. The mucosa of duodenum and upper part of jejunum is rich in dihydrofolate reductase, able to perform methylation of reduced folates which are absorbed. Following oral administration, peak folate activity in blood occurs within 30-60 minutes. Normal serum folate concentrations range from 0.005–0.015 micrograms/mL. In general, serum folate concentrations below 0.005 micrograms/mL indicate folate deficiency and concentrations below 0.002 micrograms/mL usually results in megaloblastic anemia.
Tetrahydrofolic acid and its derivatives are distributed into all body tissues; the liver contains about one-half of the total body folate stores. Folates are actively concentrated in CSF and normal CSF concentrations are reported to be about 0.016 – 0.021 micrograms/mL. Folic acid is a water-soluble B complex vitamin, whose elimination is mainly renal, and accumulation is not observed. Following oral administration of single 0.1 to 0.2 mg doses of folic acid in healthy adults, only a trace amount of the drug appears in urine.
When the maximum renal tubular reabsorption is exceeded, after oral administration beyond daily needs, the folate is excreted unchanged in urine.
About 0.05 mg per day of normal body folate stores is lost by a combination of urinary and fecal excretion.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
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