Clinical Inquiries

Are any oral iron formulations better tolerated than ferrous sulfate?

McDiarmid T, Johnson ED, Gordon A. J Fam Pract 2002 Jun;51(6):576.

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-based 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 rate 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 non-anemic adult patients taking 50 mg/day elemental iron also found a lower rate 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

Clinical Commentary

The key to iron supplementation for most patients is that, perhaps with the exception of pregnant women, it is an ongoing need. As a result, I prefer a strategy that they can live with for years. Based on recent recommendations from the Centers for Disease Control,(1) my preference is to supplement once a day with iron in whatever form they will take it, while increasing the iron-containing foods in their diet. Most adults can start with the equivalent of 325 mg of ferrous sulfate (60 mg of elemental iron) a day, increasing to twice a day if they are tolerating that with little GI upset or constipation. Children should be given about 3 mg/kg/day. Additional iron can be added to the diet via raisins, sunflower seeds, almonds, and dark leafy greens, which are more acceptable to most people than liver.

(1) Centers for Disease Prevention and Control. Recommendations to prevent and control iron deficiency in the United States. MMWR 1998;47(No. RR-3):1-36.

Recommendations from Others

Wintrobe’s Clinical Hematology9 and Williams Hematology10 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.

Clinical Commentary by Andrea Gordon, MD, at http://www.fpin.org.

Figures

Representative average wholesale prices* for various iron supplement formulations
Iron supplement group Generic or brand name Dosage Cost of 1-month course
Ferrous salts Ferrous sulfate (generic) Tablet: 325 mg po tid $0.63 to $5.11 (90 tabs)
Ferrous fumarate (generic) Tablet: 300 mg (99 mg iron) po bid $1.80 (60 tabs)
Ferrous gluconate (generic) Tablet: 325 mg (36 mg iron) po tid $2.70 to $5.00 (90 tabs)
Controlled-release Slow FE (Novartis) Tablet: 160 mg (50 mg iron) po tid $18.92 (90 tabs)
Ferro-Grad-500 (Abbott) Tablet: 105 mg iron po bid $31.84 (60 tabs)
Polysaccharide–iron complex Niferex-150 (Schwarz Pharma) Capsule: 150 mg iron po qd $10.50 (30 caps)
Carbonyl iron Feosol (SmithKline Beecham) Tablet: 50 mg iron po tid $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.

References

  1. Hallberg L, Ryttinger L, Solvell Lnull Side-effects of oral iron therapy. A double-blind study of different iron compounds in tablet form. 1966. Volume 459. Page(s): 3-10.
  2. Rybo G, Solvell Lnull Side-effect studies on a new sustained release iron preparation. 1971. Volume 8. Page(s): 257-64.
  3. Brock C, Curry H, Hanna C, Knipfer M, Taylor Lnull Adverse effects of iron supplementation: a comparative trial of a wax-matrix iron preparation and conventional ferrous sulfate tablets. 1985. Volume 7. Page(s): 568-73.
  4. Elwood PC, Williams Gnull A comparative trial of slow-release and conventional iron preparations. 1970. Volume 204. Page(s): 812-5.
  5. Jacobs P, Coghlan Pnull Comparative bioavailability of ferric polymaltose and ferrous sulphate in iron-deficient blood donors. 1993. Volume 8. Page(s): 89-95.
  6. Sas G, Nemesanszky E, Brauer H, Scheffer Knull On the therapeutic effects of trivalent and divalent iron in iron deficiency anaemia. 1984. Volume 34. Page(s): 1575-9.
  7. Gordeuk VR, Brittenham GM, Hughes M, Keating LJ, Opplt JJnull High-dose carbonyl iron for iron deficiency anemia: a randomized double-blind trial. 1987. Volume 46. Page(s): 1029-34.
  8. Devasthali SD, Gordeuk VR, Brittenham GM, Bravo JR, Hughes MA, Keating LJnull Bioavailability of carbonyl iron: a randomized, double-blind study. 1991. Volume 46. Page(s): 272-8.
  9. Richard LGnull Wintrobe’s Clinical Hematology. 1999. Page(s): 979-1010. 10th ed. Baltimore: Williams &; Wilkins;.
  10. Fairbanks VF, Beutler Enull Williams Hematology. 2001. Page(s): 447-70. 6th ed. New York: McGraw-Hill;.