What is the best iron preparation for intravenous infusion in an adult patient with restless leg syndrome and iron deficiency or insufficiency?

Best Iron Preparation for Restless Leg Syndrome Infusion

For adults with RLS requiring intravenous iron therapy, ferric carboxymaltose (Injectafer) is the preferred formulation, receiving the only strong recommendation with moderate certainty of evidence from the American Academy of Sleep Medicine. 1

Strength of Recommendation by IV Iron Formulation

The 2025 AASM guidelines provide a clear hierarchy of IV iron preparations based on evidence quality:

First-Line: Ferric Carboxymaltose (Strong Recommendation)

• Ferric carboxymaltose receives a strong recommendation with moderate certainty of evidence, making it the only IV iron formulation with this level of support 1
• The evidence base includes 5 randomized controlled trials demonstrating clinically significant improvements in disease severity, sleep quality, and quality of life with moderate effect sizes 1
• Adverse events leading to study withdrawal did not meet clinical significance, with the main risks being hypophosphatemia and dizziness 1
• Standard dosing is 1,000 mg IV, which can be given as a single dose or split into two 750 mg doses separated by at least 7 days 2

Second-Line Options (Conditional Recommendations)

• Low molecular weight iron dextran receives only a conditional recommendation with very low certainty of evidence, based on just 1 observational study 1
• Ferumoxytol similarly receives only a conditional recommendation with very low certainty of evidence, based on 1 RCT without a placebo arm 1

Not Recommended for General RLS Population

• Iron sucrose failed to show clinically significant benefit over placebo in high-quality studies for general RLS patients 1
• Iron sucrose only receives a conditional recommendation specifically for patients with end-stage renal disease who have ferritin <200 ng/mL and transferrin saturation <20% 1

Why Ferric Carboxymaltose is Superior

The pharmacologic properties explain the superiority:

• Slow-release, higher-dose formulations (ferric carboxymaltose, ferumoxytol, low molecular weight iron dextran) enable H-ferritin binding and macrophage iron uptake necessary for CNS penetration 1, 3
• Fast-release, low-dose formulations like iron sucrose lack the necessary pharmacology to deliver iron effectively to the central nervous system 1
• This CNS penetration is critical because brain iron deficiency is the leading pathophysiologic concept in RLS 1

When to Use IV Iron vs. Oral Iron

The decision algorithm based on iron studies:

Ferritin ≤75 ng/mL or Transferrin Saturation <20%

• Either oral ferrous sulfate OR IV ferric carboxymaltose can be used as first-line 1, 4, 3
• Oral iron (ferrous sulfate 65 mg elemental iron daily) receives a conditional recommendation with moderate certainty 1, 3
• IV ferric carboxymaltose is preferred if rapid response is needed or oral iron is not tolerated 3

Ferritin 75-100 ng/mL

• Use IV iron ONLY (not oral iron) in this range 1, 4, 3
• Oral iron is poorly absorbed when ferritin >50-75 ng/mL, making it ineffective 1, 3
• This is a critical pitfall to avoid—many clinicians incorrectly prescribe oral iron in this range 4

Ferritin >100 ng/mL

• Iron supplementation is generally not indicated based on current evidence 3

Critical Testing Requirements Before Treatment

All patients with clinically significant RLS must have serum ferritin and transferrin saturation checked before initiating any iron therapy 1, 4, 3:

• Blood should be drawn in the morning after fasting 1, 4
• Patients must avoid all iron-containing supplements and foods for at least 24 hours before blood draw 1, 4, 3
• Testing while on supplements will give falsely elevated results and lead to inappropriate treatment decisions 4, 3

Common Pitfalls to Avoid

Don't Use General Population Iron Thresholds

• RLS requires higher ferritin thresholds (≥75 ng/mL) than the general population (<15-30 ng/mL) 4, 3
• Using standard anemia cutoffs will miss the majority of RLS patients who would benefit from iron therapy 4
• Brain iron deficiency occurs even when serum iron appears normal by general standards 4

Don't Assume All IV Iron Formulations Are Equivalent

• Only ferric carboxymaltose has strong evidence in RLS 1
• Iron sucrose lacks efficacy except in dialysis patients 1, 3
• The pharmacologic differences between formulations are clinically meaningful 1, 3

Don't Forget to Monitor for Hypophosphatemia

• Check serum phosphate levels in patients requiring repeat courses of treatment, especially if within 3 months 1, 2
• Symptomatic hypophosphatemia is a known risk with ferric carboxymaltose 2
• Treat hypophosphatemia as medically indicated before repeating iron infusion 2

Practical Administration Details

For ferric carboxymaltose (Injectafer) 2:

• Administer as undiluted slow IV push over 15 minutes (for 1,000 mg dose) or diluted in up to 250 mL normal saline over at least 15 minutes 2
• For IV push, give at approximately 100 mg (2 mL) per minute 2
• Observe patients for at least 30 minutes after administration for hypersensitivity reactions 2
• Treatment may be repeated if iron deficiency recurs 2

Evidence Quality Considerations

The strength of the ferric carboxymaltose recommendation is based on:

• Multiple recent RCTs (5 studies) with consistent findings 1
• Moderate certainty of evidence using GRADE methodology 1
• Clinically significant improvements in disease severity, sleep quality, and quality of life 1
• Acceptable safety profile with no significant increase in study withdrawals due to adverse events 1
• Recent research confirms rapid response (as early as day 8) in responders 5
• Long-term efficacy demonstrated at 52 weeks in patients with iron deficiency anemia 6