Iron

SeriousNon-iron-deficiency anemias (hemolytic, sideroblastic, aplastic, B12/folate deficiency) without concurrent documented iron deficiencyGrade B

Iron supplementation without genuine deficiency causes overload. Hemolysis releases heme-iron.

SeriousIron deficiency not confirmed — anemia without iron studiesGrade B

Empirical iron in non-IDA causes accumulation without benefit. Diagnosis requires ferritin <30 µg/L plus TSAT <20% or elevated sTfR.

SeriousSevere hepatic impairment (Child-Pugh C / decompensated cirrhosis / acute hepatic failure)Grade B

Liver is primary iron storage and hepcidin synthesis organ. Severe hepatic impairment reduces hepcidin production causing iron dysregulation.

SeriousAceruloplasminemia (biallelic CP loss-of-function)Grade C

Without ceruloplasmin ferroxidase activity, iron exported via ferroportin cannot be loaded onto transferrin — it accumulates in brain, liver, and pancreas causing irreversible neurodegeneration. Serum: elevated ferritin, LOW TSAT, LOW ceruloplasmin.

SeriousFirst trimester pregnancy — parenteral iron at high single doses (>500 mg)Grade C

ModerateActive inflammatory bowel disease flare — oral iron specificallyGrade B

Unabsorbed luminal iron worsens mucosal oxidative stress, promotes pathogenic Enterobacteriaceae, and exacerbates colonic inflammation. Oral iron absorption also impaired during active flare via hepcidin.

ModerateChronic kidney disease stage 3b–5 — oral iron as sole therapyGrade B

Uremia reduces intestinal absorption; inflammation-driven hepcidin elevation limits oral iron efficacy.

ModerateIron-refractory iron deficiency anemia (IRIDA — biallelic TMPRSS6 loss-of-function)Grade C

Constitutively elevated hepcidin blocks ferroportin.

ModerateFerroportin disease type 4A (SLC40A1 loss-of-function)Grade C

Iron trapped in macrophages; paradoxically elevated ferritin with low/normal TSAT.

ModerateImmunocompromised patients with active infection, febrile neutropenia (ANC <500/µL), or bacteremiaGrade C

Severely impaired innate immunity cannot contain iron-fuelled pathogen proliferation. IV iron transiently creates NTBI and suppresses neutrophil/macrophage killing for 24–48h.

ModerateHypotension (systolic BP <90 mmHg, MAP <65 mmHg) — IV ironGrade C

All IV iron formulations produce vasodilatory infusion reactions. Patients with active hypotension have minimal hemodynamic reserve.

ModerateHyperferritinemia-cataract syndrome / neuroferritinopathy (FTL 5' UTR mutations)Grade C

Constitutive L-ferritin overproduction independent of iron status. Ferritin 1,000–5,000 ng/mL with NORMAL TSAT.

SeriousFluoroquinolone antibiotics (ciprofloxacin, levofloxacin, moxifloxacin, norfloxacin)Grade B

Chelation: iron complexes with fluoroquinolone carboxyl and ketone groups forming insoluble chelates in GI lumen.

SeriousTetracycline antibiotics (doxycycline, minocycline, tetracycline, demeclocycline)Grade B

Bidirectional chelation: iron-tetracycline complex formation reduces antibiotic absorption by 50–90%; tetracyclines simultaneously reduce iron absorption

SeriousMycophenolate mofetilGrade B

Iron chelates mycophenolic acid in GI tract, reducing immunosuppressant AUC by ~35% — clinically significant risk of acute rejection in solid organ transplant recipients.

SeriousDeferasirox / Deferoxamine (iron chelators)Grade B

Iron chelators bind supplemental iron directly, neutralizing therapeutic intent of supplementation and potentially generating reactive chelator-iron complexes at supraphysiologic iron concentrations.

SeriousMycophenolate mofetil (MMF) / mycophenolic acidGrade B

Iron chelates mycophenolic acid (MPA) in the GI lumen, reducing MMF oral bioavailability (AUC) by approximately 35% in transplant pharmacokinetic studies. In solid organ transplant recipients where precise immunosuppression is required to prevent acute rejection, this degree of…

SeriousDeferasirox / deferoxamine / deferiprone (iron chelators)Grade B

Iron chelators are specifically designed to bind free iron. Concurrent iron supplementation directly neutralizes chelation therapy by providing additional iron substrate.

ModerateLevothyroxineGrade B

Iron forms insoluble ferric-thyroxine complex in GI tract; reduces levothyroxine absorption by 9–21%.

ModerateLevodopa / carbidopaGrade B

Iron chelates levodopa in GI tract; studies show ~30–50% reduction in levodopa AUC with co-administration.

ModerateMethyldopaGrade B

Iron chelates methyldopa reducing absorption; may reduce antihypertensive efficacy.

ModerateAntacids (calcium carbonate, magnesium hydroxide, aluminum hydroxide) and PPIsGrade B

Antacids raise gastric pH reducing ferric→ferrous conversion (ferric iron near-insoluble above pH 3); PPIs abolish gastric acid essential for non-heme iron solubilization.

ModerateDimercaprol (BAL, British Anti-Lewisite)Grade B

Iron-dimercaprol complexes are highly toxic to kidneys; Dimercaprol mobilizes iron from stores and the iron-BAL complex causes acute tubular necrosis.

ModerateProton pump inhibitors (omeprazole, lansoprazole, pantoprazole, esomeprazole)Grade B

Gastric acid required for ferric → ferrous reduction at brush border (DCYTB/CYBRD1 pathway); elevated gastric pH (PPIs raise pH >4) reduces ferric iron solubility and DMT1-mediated absorption by 30–50%.

ModerateAntacids (calcium carbonate, magnesium hydroxide, aluminum hydroxide)Grade B

Alkaline pH reduces ferric iron solubility; calcium directly competes with iron at DMT1/divalent metal transporter.

ModerateCalcium supplementsGrade B

Calcium and iron compete at DMT1 (SLC11A2) and potentially at ferroportin-mediated basolateral export.

ModerateZinc (supplements)Grade B

Competitive inhibition at shared intestinal DMT1 transporter — iron and zinc compete for the same duodenal uptake pathway.

ModerateCalcium (supplements and dairy)Grade B

Calcium directly inhibits both heme and non-heme iron absorption at the duodenal level — the only inhibitor of heme iron absorption. Effect is significant even at physiologic dietary calcium intakes.

ModerateProton pump inhibitors (omeprazole, pantoprazole, esomeprazole)Grade B

Gastric acid is required to reduce dietary/supplemental Fe³⁺ to absorbable Fe²⁺ at duodenal brush border.

ModerateProton pump inhibitors (omeprazole, lansoprazole, pantoprazole, esomeprazole, rabeprazole)Grade B

Gastric acid required for ferric → ferrous reduction at brush border (DCYTB/CYBRD1 pathway); elevated gastric pH (PPIs raise pH >4) reduces ferric iron solubility and DMT1-mediated absorption by 30–50%.

ModerateBisphosphonates (alendronate, risedronate, ibandronate)Grade C

Iron chelates bisphosphonates reducing their already-low oral bioavailability (~1%); theoretical reduction in anti-resorptive efficacy

ModerateMycophenolate mofetil (MMF)Grade C

Iron may form complexes with mycophenolic acid reducing MMF bioavailability; interaction documented in transplant literature.

ModerateBisphosphonates (alendronate, risedronate, ibandronate, zoledronate oral)Grade C

Iron chelates bisphosphonate hydroxyl groups reducing oral bioavailability; concomitant GI irritation compounds tolerability issues

ModeratePhosphate binders (sevelamer, calcium acetate, lanthanum carbonate)Grade C

Phosphate binders chelate divalent metals including iron in GI lumen; reduces oral iron absorption.

ModerateCholestyramine and bile acid sequestrants (colesevelam, colestipol)Grade C

Anion exchange resins adsorb iron in GI lumen reducing absorption; interaction extends to all oral formulations

ModerateCholestyramine / Colestipol (bile acid sequestrants)Grade C

Anion exchange resins bind iron in GI lumen, reducing absorption.

ModerateQT-prolonging drugs (amiodarone, sotalol, haloperidol, class IA/III antiarrhythmics, ondansetron, azithromycin, fluoroquinolones with cardiac risk)Grade C

However, IV iron formulations — particularly ferumoxytol (FDA black box warning) — can cause acute hemodynamic instability, hypotension, and cardiovascular collapse via complement activation-related pseudoallergy (CARPA) and direct vasodilatory effects. Hemodynamic…

ModerateQT-prolonging drugs (amiodarone, sotalol, class IA antiarrhythmics, haloperidol, ondansetron, azithromycin, hydroxychloroquine, droperidol)Grade C

However, IV iron formulations — particularly ferumoxytol (FDA black box warning) — can cause acute hemodynamic instability via complement activation-related pseudoallergy (CARPA) and direct vasodilatory effects. Infusion-related hypotension in patients already on QT-prolonging…

ModerateQT-prolonging drugs (amiodarone, sotalol, class IA/III antiarrhythmics, haloperidol, ondansetron, azithromycin, hydroxychloroquine, droperidol)Grade C

IV iron formulations — particularly ferumoxytol (FDA black box warning) — can cause acute hemodynamic instability via CARPA and direct vasodilatory effects. Infusion-related hypotension in patients on QT-prolonging drugs creates additive arrhythmic risk: reflex tachycardia,…

ModerateCYP3A4 substrates (cyclosporine, tacrolimus, midazolam, simvastatin, atorvastatin, sildenafil, fentanyl, carbamazepine, many others)Grade D

Iron undergoes no CYP3A4-mediated biotransformation; Exception: oral iron chelates cyclosporine in GI lumen reducing cyclosporine bioavailability — this is a GI chelation interaction, not CYP3A4-mediated.

ModerateCYP3A4 substrates (cyclosporine, tacrolimus, midazolam, simvastatin, atorvastatin, sildenafil, fentanyl, carbamazepine, diltiazem, itraconazole,…Grade D

Iron undergoes no CYP3A4-mediated biotransformation; Exception: oral iron chelates cyclosporine in the GI lumen reducing cyclosporine bioavailability — this is a GI chelation interaction, not CYP3A4-mediated (see cyclosporine entry).

ModerateCYP3A4 substrates (cyclosporine, tacrolimus, midazolam, simvastatin, atorvastatin, sildenafil, fentanyl, carbamazepine, itraconazole)Grade D

Iron undergoes no CYP3A4-mediated biotransformation; Exception: oral iron chelates cyclosporine in the GI lumen — this is GI chelation, not CYP3A4-mediated (see cyclosporine entry).

MinorCalcium supplements (calcium carbonate, calcium citrate)Grade B

Calcium competitively inhibits DMT1-mediated iron transport; 300–600 mg Ca²⁺ reduces non-heme iron absorption by ~30–60% in single-meal studies

MinorZinc supplementsGrade B

Zinc and iron share DMT1 as a common transporter; zinc reduces non-heme iron absorption by ~30–40% when >25 mg zinc co-administered

MinorEntacapone (COMT inhibitor)Grade C

Entacapone is a catechol compound that chelates iron (and other metals); in vitro data show complex formation.

MinorCholestyramine (and other bile acid sequestrants: colestipol, colesevelam)Grade C

Anion exchange resins bind iron in GI tract, reducing absorption; effect less well-characterized than with fat-soluble vitamins but clinically documented

MinorCyclosporineGrade C

IV iron sucrose/FCM modestly increases plasma cyclosporine levels in transplant recipients (likely displacement from macrophage uptake pathways altering distribution); pharmacokinetic interaction, not chelation

MinorH2-receptor antagonists (famotidine, ranitidine, cimetidine)Grade C

Moderate gastric acid suppression impairs ferric iron reduction; quantitatively less impact than PPIs (pH typically 3–5 vs >4 with PPIs)

MinorHMG-CoA reductase inhibitors / statins (simvastatin, atorvastatin, rosuvastatin)Grade D

No direct PK interaction (iron undergoes no CYP-mediated biotransformation). Theoretical: iron overload amplifies ROS-mediated lipid peroxidation.

MinorMetforminGrade D

No established direct pharmacokinetic interaction (iron not CYP-metabolized; metformin not a chelation target).

MinorStatins (simvastatin, atorvastatin, rosuvastatin, pravastatin, lovastatin)Grade D

No direct pharmacokinetic interaction (iron undergoes no CYP-mediated biotransformation; statins are not iron chelation targets at physiological concentrations).

MinorHMG-CoA reductase inhibitors / statins (simvastatin, atorvastatin, rosuvastatin, pravastatin)Grade D

No direct pharmacokinetic interaction (iron undergoes no CYP-mediated biotransformation; statins are not iron chelation targets).