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Are any oral iron formulations better tolerated than ferrous sulfate? (Clinical inquiries: from the family practice inquiries network).

EVIDENCE-BASED ANSWER Ferrous salt preparations (ferrous sulfate, ferrous gluconate, and ferrous fumarate) are equally tolerable. (Grade of recommendation: A, based on randomized controlled trial.) Controlled-release iron preparations cause less nausea and epigastric pain than conventional ferrous sulfate (grade of recommendation: A, based on randomized controlled trials), although the discontinuation rates between the 2 iron formulations were similar. Ferrous sulfate remains the standard first-line treatment of iron-deficiency anemia given its general tolerability, effectiveness, and low cost.

EVIDENCE SUMMARY A randomized, double-blinded, placebo-controlled study in 1496 subjects examined side-effect rates of 3 iron salt formulations using equal dosages of elemental iron (Table). (1) Gastrointestinal (GI) side-effect rates were not significantly different. The side-effect rate in the ferrous sulfate group (23%) was significantly different from that of the placebo group (14%); thus, for every 11 patients treated with ferrous sulfate, 1 patient would have GI side effects attributable to the iron salt (number needed to harm [NNH] = 11).

Two formulations--controlled-release iron preparations and polysaccharide-iron complexes--decrease the amount of iron presented to the proximal GI tract. Three large randomized trials assessed tolerability of controlled-release iron preparations compared with ferrous sulfate. (2-4) The only double-blinded study found a lower rote of nausea and epigastric pain in the controlled-release iron formulation among 1376 blood donors receiving 200 mg/day elemental iron (3.3% vs 6.4%, P < .05, NNH = ~32). (2) A nonblinded randomized trial of 543 nonanemic adult patients taking 50 mg/day elemental iron also found a lower rote of stomach-related side effects in the controlled-release group (12.2% vs 27.2%, P < .001, NNH = ~7). (3) However, none of the 3 studies showed a difference in the discontinuation rates between the 2 iron formulations. Comparative constipation rates among the trials were conflicting.

Two small, nonblinded, randomized trials of polysaccharide-iron complexes reported conflicting results. A study of 159 subjects found fewer subjects discontinuing the polysaccharide-iron complex taken with meals than ferrous sulfate taken on an empty stomach. (5) A study of 60 subjects taking both preparations on an empty stomach found no difference in side-effect rates. (6) Two small, randomized, blinded studies found no difference in rates of GI side effects between carbonyl iron and ferrous sulfate. (7,8)


Wintrobe's Clinical Hematology (a) and Williams Hematology (10) recommend ferrous sulfate as the standard oral iron preparation, and assert that claims of improved tolerability of one oral iron preparation over another have not been substantiated.
Representative average wholesale prices *
for various iron supplement formulations

supplement          Generic or
  group             brand name           Dosage

Ferrous salts      Ferrous sulfate     Tablet: 325 mg
                   (generic)           po tid

                   Ferrous fumarate    Tablet: 300 mg
                   (generic)           (99 mg iron) po bid

                   Ferrous gluconate   Tablet: 325 mg
                   (generic)           (36 mg iron) po tid

Controlled         Slow FE             Tablet: 160 mg
release            (Novartis)          (50 mg iron) po tid

                   Ferro-Grad-500      Tablet: 105 mg iron
                   (Abbott)            po bid

Polysaccharide-    Niferex-150         Capsule: 150 mg
iron complex       (Schwarz Pharma)    iron po qd

Carbonyl iron      Feosol              Tablet: 50 mg
                   (SmithKline         iron po tid

supplement         Cost of 1-month
  group              course

Ferrous salts      $0.63 to $5.11
                   (90 tabs)

                   $1.80 (60 tabs)

                   $2.70 to $5.00
                   (90 tabs)

Controlled         $18.92 (90 tabs)

                   $31.84 (60 tabs)

Polysaccharide-    $10.50 (30 caps)
iron complex

Carbonyl iron      $18.38 (90 tabs)

* 2001 Drug Topics, Red Book. Daily dosages given here deliver
150 to 210 mg of elemental iron and are for comparison
of average costs. Actual dosage should be adjusted according
to the calculated need for iron replacement and the results
of laboratory monitoring.


(1.) Hallberg L, Ryttinger L, Solvell L. Side-effects of oral iron therapy. A double-blind study of different iron compounds in tablet form. Acta Med Scand Suppl 1966; 459:3-10.

(2.) Rybo G, Solvell L. Side-effect studies on a new sustained release iron preparation. Scand J Haematol 1971; 8:257-64.

(3.) Brick C, Curry H, Hanna C, Knipfer M, Taylor L. Adverse effects of iron supplementation a comparative trial of a wax-matrix iron preparation and conventional ferrous sulfate tablets. Clin Ther 1985;7:568-73.

(4.) Elwood PC, Williams G. A comparative trial of slow-release and conventional iron preparations. Practitioner 1970; 204:812-5.

(5.) Jacobs P, Coghlan P. Comparative bioavailability of ferric polymaltose and ferrous sulphate in iron-deficient blood donors. J Clin Apheresis 1993; 8:89-95.

(6.) Sas G, Nemesanszky E, Brauer H, Scheffer K. On the therapeutic effects of trivalent and divalent iron in iron deficiency anaemia. Arzneimittel-Forschung 1984; 34:1575-9.

(7.) Gordeuk VR, Brittenham GM, Hughes M, Keating LJ, Opplt JJ. High-dose carbonlyl iron for iron deficiency anemia: a randomized double-blind trial. Am J Clin Nutr 1987; 46:1029-34.

(8.) Devasthali SD, Gordeuk VR, Brittenham GM, Bravo JR, Hudges MA, Keating LJ. Bioavailability of carbonyl iron: a randomized, double-blind study Eur J Haematol 1991; 46:272-8.

(9.) Richard LG. Wintrobe's Clinical Hematology. 10th ed. Baltimore: Williams &; Wilkins; 1999:979-1010.

(10.)Fairbanks VF, Beutler F., Williams Hematology. 6th ed New York: McGraw-Hill: 2001:447-70.
Todd McDiarmid, MD
Moses Cone Family Practice Residency
Greensboro, NC

E. Diane Johnson, MLS
J. Otto Lottes Health Sciences Library
University of Missouri-Columbia

Clinical Commentary by Andrea Gordon, MD, at
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Author:McDiarmid, Todd; Johnson, E. Diane
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Jun 1, 2002
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