Why Isn’t Iron Replacement Working? My Top 4 Reasons

Oral iron replacement is one of the most common ways to manage iron deficiency anemia. While it seems straightforward—take a pill, replace the iron—patients often struggle to reach therapeutic goals. One of the biggest reasons is poor absorption. Here are four common culprits that can explain why oral iron replacement isn’t working and hemoglobin is not responding.

1. Taking Iron With Supplements

Iron is best absorbed on an empty stomach, but many times our polypharmacy patients have numerous medications and supplements to take. Calcium carbonate is a supplement that is frequently prescribed and often taken by our patients to increase calcium intake. This supplement can raise the pH of the stomach and ultimately reduce the absorption of iron, as it needs an acidic environment for adequate absorption.

2. Drug-Drug Interactions

Iron is a prime candidate for interactions. Proton pump inhibitors (PPIs) like omeprazole reduce stomach acid, which is essential for converting ferric iron into the more absorbable ferrous form. Antacids and H2 blockers have similar effects. On the other hand, iron itself can reduce the absorption of drugs like levothyroxine, bisphosphonates, and certain antibiotics (tetracyclines, fluoroquinolones). This creates a two-way street of therapeutic failures.

3. Underlying GI Disorders

Certain conditions inherently reduce iron absorption. Celiac disease, inflammatory bowel disease, bariatric surgery, and atrophic gastritis are common examples (and excellent board exam nuggets). In these cases, no matter how well a patient takes their supplement, the damaged or altered intestinal lining can’t effectively absorb the mineral. Recognizing the underlying pathology is key before simply increasing the oral dose. In many of these cases, it may be necessary to do IV iron replacement.

4. Nonadherence and Tolerability Issues

GI side effects like constipation, nausea, and abdominal discomfort frequently lead patients to skip doses or stop iron altogether. Even if patients are prescribed the right drug at the right dose, missed doses and self-adjusted regimens can mimic poor absorption. A pharmacist’s role in uncovering this adherence piece is often the missing link.

If a patient isn’t responding to oral iron replacement, it’s rarely just “bad luck.” Think through administration timing, drug interactions, gut health, adherence, and stomach acid issues before jumping to IV iron therapy. A careful medication review and patient conversation can save time, money, and unnecessary procedures.

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Written By Eric Christianson

September 17, 2025

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