FERROUS SUCCINATE
Practically insoluble in water and alcohol: almost completely
soluble in dilute mineral acids.
Adverse Effects
The astringent action of iron preparations some-
times produces gastro-intestinal irritation and ab-
dominal pain with nausea and vomiting when
admmiltered orally. These irritant side-effects are
usually related to the amount of elemental iron taken
rather than the type of preparation. Other gastro-in-
testinal effects may include either diarrhoea or con-
sfipation. Side-effects may be reduced by
administration with or after food (rather than on an
empty stomach) or by beginning therapy with a
small dose and increasing gradually. Modified-
release products are claimed to produce fewer side-
effects but this may only reflect the lower availabil-
ity of iron from these preparations. Oral liquid prep-
arations containing iron salts may blacken the teeth
and should be drunk through a straw. The faeces of
patients taking iron salts may be coloured black.
The adverse effects associated with iron given
parenterally are described under iron dextran .
Since absorbed iron is conserved by the body, iron
overload, with increased storage of iron in various
tissues (haemosiderosis). may occur as a result of
excessive oral or. in particular, parenteral therapy.
Patients mistakenly given iron therapy when not suf-
fering from iron-deficiency anaemia are also at risk
as are those with pre-existing iron storage or absorp-
tion diseases.
Acute iron overdosage can be divided into four
stages. In the first phase, which occurs up to 6 hours
after oral ingestion. gastro-intestinal toxicity. nota-
bly vomiting and diarrhoea, predominates. Other ef-
fects may include cardiovascular disorders such as
hypotension and tachycardia, metabolic changes in-
cluding acidosis and hyperglycaemia. and CNS de-
pression ranging from lethargy to coma. Patents
with only mild to moderate poisoning do not gener-
ally progress past this first phase. The second phase
may occur at 6 to 24 hours after ingestion and is
characterised by a temporary remission or clinical
stabilisation. In the third phase gastro-intestinal tox-
icity recurs together with shock, metabolic acidosis,
convulsions, coma. hepatic necrosis and jaundice,
hypoglycaamia, coagulation disorders, oliguria or
renal failure, and pulmonary oedema. The fourth
phase may occur several weeks after the ingestion and
is characterised by gastro-intestinal obstruction and
possibly late hepatic damage.
Relatively small amounts of iron may produce
symptoms of toxicity. It has been stated that more
than the equivalent of 30 mg of iron per kg body-
weight could lead to some symptoms of toxicity and
that in a young child the equivalent of about 75 mg
of iron per kg should be regarded as extremely dan-
gerous. Estimates of acute lethal dosages have
ranged from the equivalent of 180 mg of iron per kg
upwards. Serum-iron concentrations have also been
employed as an indication of the severity of over-
dosage: a peak concentration of 5 ng or more per
mL is reportedly associated with moderate to severe
poisoning in many patients.
Effects on the cardiovascular system. For a suggestion
that iron overload may contribute to ischaemic heart disease,
see under Precautions, below.
Effects on growth. Iron supplementation in iron-replete
children has been reported to adversely affect their growth-
see below, under Precautions.
Iron overload. Because the body lacks a mechanism for the
excretion of excess iron, abnormally high absorption or re-
peated blood transfusion will result in iron overload, leading
eventually to haemochromatosis. The consequences of
haemochromatosis include pigment deposition in skin and
other organs, mild liver dysfunction, endocrine dysfunction
(failure of the adolescent growth spurt, hypogonadism. some-
times diabetes and hypothyroidism) and heart disease (peri-
carditis, heart failure, and arrhythmias). If unchecked, the
iron build-up can lead to death, mainly through heart failure
or arrhythmia. Where the increased iron intake cannot be
avoided (as in patients receiving regular transfusions for p-
thalassaemia) treatment with the iron chelating
agent desferrioxamine is used to retard accumulation.
Treatment of Adverse Effects
In treating acute iron poisoning, speed is essential to
reduce absorption of iron from the alimentary tract.
Emesis or lavage should be considered and serum-
iron concentrations may be an aid to estimating the
severity of poisoning. Chelation therapy with des-
ferrioxamine may be necessary and the procedure
described under desferrioxamine mesylate should be followed.
Other measures include the symptomatic manage-
ment and therapy of metabolic and cardiovascular
disorders.
Overdosage. References highlighting the specific problem
of iron overdose in children. Child-resistant packaging and
warning labels may be helpful in reducing the problem.
Pregnancy. Limited data on the treatment of iron overdose
in pregnancy from the UK National Teratology Information
Service, suggested that treatment with desferrioxamine
should not be withheld if clinically indicated." Most preg-
nancies had a normal outcome.
Precautions
Iron compounds should not be given to patients re-
ceiving repeated blood transfusions or to patients
with anaemias not produced by iron deficiency un-
less iron deficiency is also present. Oral iron therapy
should not be administered concomitantly with
parenteral iron. Care should be taken in patients
with iron-storage or iron-absorption diseases such
as haemochromatosis, haemoglobinopathies , or
existing gastro-intestinal diseases such as inflam-
matory bowel disease, intestinal strictures and diver-
ticulae.
Liquid preparations containing iron salts should be
well diluted with water and swallowed through a
straw to prevent discoloration of the teeth.
There has been concern, for a number of reasons, about the
potential consequences of iron supplementation in individu-
als and groups who are not actually iron-deficient. Apart from
the suggestion that certain populations may be at somewhat
increased risk of microbial infection following supplementa-
tion (see Infections, below), there is some evidence that sup-
plementation in non-iron-deficient children may retard their
growth. It has also been proposed that iron may be associated
with ischaemic heart disease, by modifying low density lipo-
protein in ways which increase its atherogenic potential and
by sensitising the myocardium to ischaemic injury. Al-
though the role of iron in the pathogenesis of coronary heart
disease is at present undecided, the use of iron should, it
has been suggested, be restricted to patients with proven iron
deficiency or to pregnancy.
Infections. Iron is not only an essential element for humans
but is also essential for many micro-organisms. Thus. it has
been suggested that persons with either adequate iron stores
or iron overload may provide optimum conditions for micro-
bial growth and therefore be susceptible to an increased inci-
dence and severity of infection: conversely, iron-deficiency
anaemia may offer some protection against infections. The
topic has been reviewed and although there is no evidence
that small amounts of iron supplements or iron-fortified food
in normal people will render them more prone to infection
there is some evidence that in populations with a high preva-
lence of endemic infectious disease such as malaria, iron ther
apy may be followed by a higher incidence of infectious
complications or by a flare-up of existing low-grade disease.
Therefore, the routine use of iron supplements in such com-
munities has been questioned , however, an increasing
number of studies have failed to demonstrate a detrimental
effect.
Interference with diagnostic tests. Although studies in
vitro have demonstrated that iron (ferrous sulphate) will cause
a false-positive result in the Hemoccult test for blood in fae-
ces, this does not occur in vivo in persons receiving oral iron
therapy.An explanation for the difference in these findings
is that hydrogen peroxide in the Hemoccult developer con-
verts ferrous ions in solution to ferric ions which cause oxi-
dation in the test. whereas in vivo the iron is probably
eliminated in the faeces in the form of non-reactive insoluble
iron precipitates
Porphyria. Erythropoietic protoporphyria was exacerbated
by oral iron therapy in four patients: a further patient had a
variable reaction to iron being able to tolerate it on some oc-
casions but suffering from exacerbation of porphyria on oth-
ers.
Interactions
Iron salts are not well absorbed by mouth, and ad-
ministration with food may further impair their ab-
sorption.
Compounds containing calcium and magnesium, in-
cluding antacids and mineral supplements, and bi-
carbonates, carbonates, oxalates or phosphates.
may also impair the absorption of iron by the forma-
tion of insoluble complexes. Similarly the absorp-
tion of both iron salts and tetracyclines is diminished
when they are taken concomitantly by mouth. If
treatment with both drugs is required, a time interval
of about 2 to 3 hours should be allowed between
them. A suitable interval is also advised if an iron
supplement is required in patients receiving trien-
tine. Zinc salts may decrease the absorption of iron.
Some agents, such as ascorbic acid and citric acid.
may actually increase the absorption of iron.
The response to iron may be delayed in patients re-
ceiving concomitant parenteral chloramphenicol
therapy.
Iron salts can also decrease the absorption of other
drugs and thus reduce their bioavailability and clin-
ical effect. Drugs so affected included bisphospho-
nates, fluoroquinolones, levodopa, methyldopa,
penicillamine and tetracycline. Iron salts may re-
duce the efficacy of thyroxine.
Interactions with parenteral iron are mentioned un-
der Iron Dextran.
Pharmacokinetics
Iron is irregularly and incompletely absorbed from
the gastro-intestinal tract, the main sites of absorp-
tion being the duodenum and jejunum. Absorption
is aided by the acid secretion of the stomach and by
some dietary acids (such as ascorbic acid) and is
more readily affected when the iron is in the ferrous
state or is part of the haem complex (haem-iron).
Absorption is also increased in conditions of iron
deficiency or in the fasting state but is decreased if
the body stores are overloaded. Only about 5 to 15%
of the iron ingested in food is normally absorbed.
Following absorption the majority of iron is bound
to transferrin and transported to the bone marrow
where it is incorporated into haemoglobin: the re-
mainder is contained within the storage forms, ferri-
tin or haemosiderin, or as myoglobin. with smaller
amounts occurring in haem-containing enzymes or
in plasma bound to transferrin.
Only very small amounts of iron are excreted as the
majority released after the destruction of the haemo-
globin molecule is reused. This conservation of
body iron, and lack of an excretory mechanism for
excess iron, is the reason for the development of iron
overload with excessive iron therapy or repeated
transfusions.
Human Requirements
The body contains about 4 g of iron most of which
is present as haemoglobin.
Apart from haemorrhage, iron is mainly lost from
the body in the faeces, urine, from skin, and sweat,
but the total loss is very small. Iron is also lost in
small amounts in breast milk and in menstrual
blood. In healthy men and postmenopausal women
the loss is replaced by the absorption of about I mg
of iron daily; about 1.5 to 2 mg needs to be absorbed
daily by premenopausal women. In childhood and
adolescence, the need is proportionately greater be-
cause of growth. Iron absorption is variable but is
usually between 5 and 15% and therefore a dietary
allowance containing the equivalent of about 10 mg
of iron daily is usually sufficient for men and post-
menopausal women; up to 15 mg daily may be nec-
essary for premenopausal women with normal
menstrual blood losses: some authorities recom-
mend higher amounts or supplements during preg-
nancy. For further details concerning dietary
requirements, see below and for a discussion of pro-
phylactic iron given during pregnancy, see Iron-
deficiency Anaemia, under Uses and Administra-
tion, below.
Good dietary sources of haem-iron are animal prod-
ucts such as meat and fish; non-haem-iron is also
found in animal products and in vegetable products
such as legumes and some leafy vegetables, but
some vegetable products with a high iron content
also contain phosphates or phytates which inhibit
absorption by the formation of unabsorbable com-
plexes.
In the United Kingdom, dietary reference values (DRV)' and
in the United States, recommended dietary allowances
(RDA) have been published for iron.
In the UK the estimated average requirement (EAR) for adult
males and postmenopausal females is 6.7 mg daily and the
reference nutrient intake (RNI) is 8.7 mg daily; for premeno-
pausal females, but without heavy menstrual blood losses, the
EAR and RNI are 11.4 and 14.8 mg daily respectively.
Amounts for infants, children, and adolescents, which are
proportionately higher than those for adults, are also given.
No increase is considered necessary during pregnancy or lac-
tation.
In the USA the RDA for adult males and postmenopausal fe-
males is 10 mg daily and that for premenopausal women is
15 mg. Amounts for infants, children, and adolescents, again
proportionately higher than for adults, arc also provided. No
increase is considered necessary during lactation although an
increase to 30 mg during pregnancy is considered warranted.'
The Food and Agriculture Organization of the United Nations
together with the World Health Organization has also pub-
lished guidelines concerning iron requirements and these take
into account many factors including bioavailability of iron in
the diet.
Uses and Administration
Iron is an essential constituent of the body, being
necessary for haemoglobin formation and for the
oxidative processes of living tissues. Iron deficiency
results in defective erythropoiesis and anaemia. Iron
and iron salts should only be given for the treatment
or prophylaxis of iron-deficiency anaemias (see be-
low). They should not be given for the treatment of
other types of anaemia except where iron deficiency
Table 1. Approximate amounts of different iron
salts that supply 60mg of elemental iron.
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Iron Salt Amount
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Ferrous ascorbate (anhydrous) 437 mg
Ferrous aspartate (tetrahydrate) 422 mg
Ferrous carbonate (anhydrous) 125 mg
Ferrous chloride (tetrahydrate) 214 mg
Ferrous fumarate (anhydrous) 183 mg
Ferrous gluceptate (anhydrous) 544 mg
Ferrous gluconate (dihydrate) 518 mg
Ferrous lactate (trihydrate) 310 mg
Ferrous oxalate (dihydrate) 193 mg
Ferrous succinate (anhydrous) 185 mg
Ferrous sulphate (dried) 186 mg
Ferrous sulphate (hyptahydrate) 300 mg
Ferrous tartrate (hemipentahydrate) 268 mg
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is also present. Iron-deficiency anaemias respond
readily to iron therapy but the underlying cause of
the anaemia should be determined and treated.
The preferred route for the administration of iron is
by mouth, usually as soluble ferrous salts, which are
better absorbed than ferric salts. The usual adult
dose for the treatment of iron-deficiency anaemia is
100 to 200 mg of iron daily in divided doses. The
usual adult prophylactic dose is 60 to 120 mg of iron
daily. There are various recommendations for chil-
dren's doses and up to 2 mg of iron per kg body-
weight three times daily for treatment and I mg per
kg daily for prophylaxis of iron-deficiency anaemia
has been employed. Therapy is generally continued
until haemoglobin concentrations reach normal val-
ues, which may take some weeks, and then for a fur-
ther 3 months or more to restore body-iron stores.
Further information concerning the dosage of iron
salts and compounds used is provided in the individ-
ual monographs; this information, however, tends to
reflect the amounts of iron contained in different
salt? or available commercial preparations and
therefore, in some instances, may not be within the
general range of iron dosages as quoted above.
Some oral preparations of iron are presented in
modified-release dosage forms and these prepara-
tions are claimed to result in reduced gastro-intesti-
nal side-effects and have the advantage of once-
daily dosing. The preparations are designed to re-
lease the iron gradually along the gut but in some
instances the iron may not have been released until
the preparation reaches a part of the gut where ab-
sorption is poor thus resulting in sub-optimal
dosing.
Iron can also be given parenterally in circumstances
where oral therapy cannot be undertaken and such
use is typified by iron dextran.
Anoxic seizures. Recent findings of a reduction in the fre-
quency of breath-holding episodes in children treated with
iron suggest that there might be a relationship between anoxic
seizures and iron deficiency.
Iron-deficiency anaemia. Iron deficiency eventually re-
sults in anaemia, usually of a microcytic. hypochro-
mic type, and because iron requirements are increased during
infancy, puberty, pregnancy, and menstruation, such anaemias
are most common in women and children. Although any un-
derlying cause for the iron deficiency should be sought and
treated, most iron-deficiency anaemias respond well to treat-
ment with oral iron. The usual dose is sufficient of a ferrous
salt to supply about 100 to 200 mg of elemental iron daily.
with the aim of increasing haemoglobin concentrations by O.1
to 0.2 g per 100 mL per day or 2 g per 100 mL over 3 to 4
weeks.- Treatment is continued for about 3 months once hae-
moglobin concentrations have returned to the normal range.
in order to aid replenishment of iron stores. Parenteral iron
therapy is rarely indicated. Prophylactic administration may
be justifiable in certain groups, such as in pregnancy and in
pre-school children, but there is some debate as to its value,
and its use in the former has declined. (For the possible
problems associated with iron supplementation in those who
are not deficient, sec under Precautions, above.) Usual pro-
phylactic doses provide about 60 to 120 mg of elemental iron
daily. Intermittent iron supplementation is under study.