Is ferrous sulfate (iron supplement) 325 mg twice a day (BID) an appropriate treatment for iron deficiency anemia?

Ferrous Sulfate 325 mg BID Is NOT the Optimal Dosing Strategy

Current evidence strongly supports once-daily dosing of 50-100 mg elemental iron (equivalent to one 200 mg ferrous sulfate tablet containing 65 mg elemental iron) rather than 325 mg twice daily, as higher doses and multiple daily doses reduce iron absorption and increase side effects without improving outcomes. 1

Why 325 mg BID Is Suboptimal

Absorption Physiology

• Oral doses of 60 mg elemental iron stimulate hepcidin levels, reducing subsequent iron absorption by 35-45%, making the overall absorption from 60 mg once daily similar to 60 mg twice daily 1
• Ferrous sulfate 325 mg contains approximately 105 mg elemental iron 1, meaning 325 mg BID delivers 210 mg elemental iron daily—far exceeding the amount that can be effectively absorbed
• Alternate day dosing leads to significantly increased fractional iron absorption compared with daily dosing 1, suggesting that more frequent dosing is counterproductive

Evidence-Based Dosing Recommendations

The British Society of Gastroenterology (2021) recommends:

• Once daily dosing of 50-100 mg elemental iron taken in the fasting state as the best compromise option for initial treatment 1
• This translates to one ferrous sulfate 200 mg tablet (65 mg elemental iron) once daily 1

For patients with inflammatory bowel disease:

• No more than 100 mg elemental iron per day is recommended, as unabsorbed iron may exacerbate disease activity 1

Monitoring and Expected Response

• Hemoglobin should rise by at least 10 g/L after 2 weeks of daily oral iron therapy 1
• Failure to achieve this response indicates non-compliance, malabsorption, continued bleeding, or need for alternative therapy 1
• Treatment should continue for approximately 3 months after hemoglobin normalization to replenish iron stores 1

When Higher or More Frequent Dosing May Be Considered

Tolerance-Based Adjustments

• If the patient tolerates once-daily dosing well and shows suboptimal response after 2-4 weeks, consider increasing to 325 mg once daily (105 mg elemental iron) 1
• If oral iron is not tolerated, reduce to one tablet every other day rather than increasing frequency 1

Alternative Approaches for Poor Response

• Switch to alternate-day dosing (which paradoxically improves absorption) 1
• Consider ferric maltol (30 mg twice daily) for patients intolerant to traditional iron salts 1
• Intravenous iron should be considered when oral iron is contraindicated, ineffective, or not tolerated 1

Common Pitfalls to Avoid

• Do not assume that doubling the dose doubles the benefit—iron absorption is saturable and hepcidin-regulated 1
• Modified-release preparations (including 325 mg formulations) are less suitable for prescribing as they release iron beyond the duodenum where absorption is optimal 1
• Side effects are dose-dependent, so 325 mg BID will likely cause more gastrointestinal adverse effects than lower doses 1
• The absence of hemoglobin rise after 2 weeks strongly predicts subsequent treatment failure (sensitivity 90.1%, specificity 79.3%) 1

Practical Recommendation

Start with ferrous sulfate 200 mg (65 mg elemental iron) once daily on an empty stomach, monitor hemoglobin at 2-4 weeks, and adjust based on response and tolerance rather than empirically prescribing 325 mg BID. 1