What are the differences between ferrous sulfate, ferrous gluconate, and ferrous fumarate?

Differences Between Ferrous Sulfate, Ferrous Gluconate, and Ferrous Fumarate

All three ferrous salts are equally effective for treating iron-deficiency anemia, with no formulation demonstrating superior absorption or tolerability in clinical trials—the choice should be based primarily on elemental iron content and cost, with ferrous sulfate remaining the gold-standard first-line option. 1

Elemental Iron Content

The three formulations differ substantially in their concentration of elemental iron per tablet:

• Ferrous sulfate contains approximately 65 mg elemental iron per 324 mg tablet (roughly 20% elemental iron by weight). 2, 3
• Ferrous fumarate contains approximately 106 mg elemental iron per 325 mg tablet (roughly 33% elemental iron by weight), making it the most concentrated formulation. 2, 1
• Ferrous gluconate contains only 37–38 mg elemental iron per 324 mg tablet (roughly 11–12% elemental iron by weight), making it the least concentrated. 2, 4

This means ferrous fumarate delivers the most elemental iron per tablet, while ferrous gluconate delivers the least. 1

Clinical Efficacy

No oral iron formulation has demonstrated superior absorption or clinical efficacy compared to ferrous sulfate in rigorous clinical trials. 1

• All three ferrous salts produce similar increases in hemoglobin, hematocrit, and mean corpuscular volume when equivalent doses of elemental iron are administered. 5, 6
• Ferrous sulfate conventional-release tablets demonstrate the highest iron absorption in laboratory models using human intestinal cells. 7
• Clinical studies comparing ferrous fumarate and ferrous gluconate show equivalent therapeutic responses when adjusted for elemental iron content. 8, 6

Tolerability and Side Effects

There is no strong evidence that any ferrous salt formulation is better tolerated than others—gastrointestinal side effects occur with all three at similar rates. 1, 9

• One small study suggested slightly fewer gastrointestinal complaints with ferrous gluconate compared to ferrous fumarate, but both were associated with side effects. 10
• Another study found ferrous fumarate caused slightly more gastrointestinal symptoms than a controlled-release preparation, but the difference was modest. 5
• A pregnancy study reported that liquid ferrous gluconate produced no side effects or dropouts, while solid ferrous gluconate and ferrous sulfate each caused one dropout. 6
• The British Society of Gastroenterology considers ferrous sulfate, fumarate, and gluconate as equivalent first-line options, with choice based on cost and availability rather than tolerability differences. 10

Cost Considerations

Ferrous sulfate is the most cost-effective option, costing approximately $0.30–$4.50 for 30 tablets, compared to $3.90 for ferrous fumarate and $1.50–$3.30 for ferrous gluconate. 2

Practical Prescribing Recommendations

Start with ferrous sulfate 200 mg (65 mg elemental iron) once daily on an empty stomach—this is the gold-standard, most cost-effective first-line treatment. 1

• If ferrous sulfate is not tolerated, switch to ferrous fumarate or ferrous gluconate as acceptable alternatives, but do not expect improved tolerability based on current evidence. 1, 9
• Adjust the number of tablets based on elemental iron content: to achieve 50–100 mg elemental iron daily, prescribe 1 tablet of ferrous sulfate (65 mg), 1 tablet of ferrous fumarate (106 mg), or 2–3 tablets of ferrous gluconate (37 mg each). 2, 1
• Do not switch between ferrous salts expecting better tolerability—evidence does not support this practice. 1

Dosing Strategy (Applies to All Three Formulations)

Take once daily in the morning on an empty stomach with 250–500 mg vitamin C, avoiding coffee, tea, and calcium-containing foods for 1–2 hours. 1, 9

• Once-daily dosing is superior to multiple daily doses because iron doses ≥60 mg trigger hepcidin elevation that persists 24 hours and blocks absorption of subsequent doses by 35–45%. 1, 9
• If gastrointestinal side effects are intolerable, switch to alternate-day dosing (every other day) rather than switching formulations—this significantly increases fractional absorption and reduces symptoms while maintaining efficacy. 1, 9, 10

Common Pitfalls to Avoid

• Do not prescribe multiple daily doses—this increases side effects without improving absorption due to hepcidin-mediated blockade. 1
• Do not assume ferrous gluconate is "gentler"—it simply contains less elemental iron per tablet, requiring more tablets to achieve therapeutic dosing. 2, 1
• Do not use modified-release or enteric-coated formulations—these release iron beyond the duodenum, reducing absorption efficiency. 2, 7
• Do not discontinue therapy when hemoglobin normalizes—continue for an additional 3 months to restore iron stores. 1, 9

When to Switch to Intravenous Iron

Consider IV iron if oral iron (regardless of formulation) causes intolerable side effects despite dosing adjustments, or if hemoglobin fails to rise after 2–4 weeks of adherent therapy. 1, 9

• IV iron is also indicated in malabsorption syndromes (inflammatory bowel disease, celiac disease, post-bariatric surgery) where oral iron absorption is impaired. 2, 1