What are the recommended treatments for an adult with restless‑legs syndrome and peripheral iron deficiency (serum ferritin ≤75 ng/mL or 75‑100 ng/mL with transferrin saturation <20%)?

Treatment Recommendations for Low Serum Ferritin in RLS Patients

For adults with RLS and ferritin ≤75 ng/mL or transferrin saturation <20%, initiate either oral ferrous sulfate (325-650 mg daily containing 65 mg elemental iron) or intravenous ferric carboxymaltose (1000 mg single dose) as first-line iron therapy, with IV ferric carboxymaltose receiving the strongest evidence (strong recommendation, moderate certainty) and oral iron receiving conditional support. 1, 2

Iron Supplementation Algorithm Based on Laboratory Values

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

• Start with either oral ferrous sulfate OR IV ferric carboxymaltose as first-line options 1, 2
• Oral ferrous sulfate: 325-650 mg daily (65 mg elemental iron), taken every day or every other day to optimize absorption 2, 3
• IV ferric carboxymaltose: 1000 mg as a single infusion—this is the only IV iron formulation with strong recommendation and moderate certainty of evidence 1, 2
• Oral iron is possibly effective but has poor absorption when ferritin exceeds 50-75 ng/mL, making it less reliable in the upper range of this threshold 2
• Common side effects of oral iron include constipation, which may limit tolerability and adherence 2

Ferritin 75-100 ng/mL (with adequate transferrin saturation)

• Use IV iron ONLY—oral iron is not recommended in this range 1, 2
• IV ferric carboxymaltose 1000 mg is the preferred formulation due to its slow-release, higher-dose pharmacology that enables H-ferritin binding and macrophage iron uptake necessary for CNS penetration 2
• Oral iron is poorly absorbed when ferritin is in this range and will not effectively correct the brain iron deficiency that drives RLS pathophysiology 2

Ferritin >100 ng/mL

• Iron supplementation is generally not indicated based on current evidence 2
• Focus on other RLS management strategies, including addressing exacerbating factors and considering gabapentinoid therapy 1, 4

Critical Testing Requirements Before Treatment

• Check serum ferritin AND transferrin saturation in ALL patients with clinically significant RLS—this is a mandatory good practice statement 1, 5
• Blood must be drawn in the morning after avoiding all iron-containing supplements and foods for at least 24 hours prior to the draw 1, 2, 5
• Transferrin saturation <20% identifies functional iron deficiency even when ferritin appears adequate, revealing patients who need supplementation despite seemingly normal ferritin levels 5
• Ferritin can be falsely elevated by inflammation, making transferrin saturation essential for accurate assessment 5
• Also check renal function (creatinine, eGFR) to identify chronic kidney disease, which requires different treatment algorithms 5
• Obtain a complete blood count to assess for overt anemia requiring more aggressive iron repletion 5

Why IV Ferric Carboxymaltose is Superior to Other IV Formulations

• Ferric carboxymaltose is the ONLY IV iron with strong recommendation and moderate certainty of evidence, based on 5 randomized controlled trials demonstrating clinically significant improvements in disease severity, sleep quality, and quality of life 2, 6
• Low molecular weight iron dextran receives only conditional recommendation with very low certainty (based on 1 observational study) 1, 2
• Ferumoxytol receives only conditional recommendation with very low certainty (based on 1 RCT without placebo arm) 1, 2
• Iron sucrose is NOT recommended for general RLS patients—it failed to show clinically significant benefit over placebo in high-quality studies 2
• Iron sucrose receives conditional recommendation ONLY for end-stage renal disease patients with ferritin <200 ng/mL and transferrin saturation <20% 1, 2, 4
• The pharmacology of slow-release, higher-dose formulations (ferric carboxymaltose) enables the necessary CNS iron delivery, unlike fast-release formulations like iron sucrose 2

Timeline for Response and Monitoring

• IV ferric carboxymaltose may require 12 weeks to reach full efficacy—improvement at 4 weeks may be nonsignificant, but becomes significant by week 12 7
• For oral iron, reassess symptoms and repeat iron studies after 3 months of therapy 2, 8
• If oral iron is not tolerated or ineffective after 3 months, switch to IV ferric carboxymaltose 2
• Monitor serum ferritin and transferrin saturation every 6-12 months during ongoing therapy, as RLS symptoms may recur if iron stores decline below therapeutic thresholds 2, 9
• Check serum phosphate levels in patients requiring repeat courses of IV iron, especially if within 3 months, to monitor for hypophosphatemia 2

Integration with Other RLS Management

Before Starting Iron Therapy

• Address exacerbating factors: discontinue or minimize alcohol, caffeine, antihistaminergic medications (e.g., diphenhydramine), serotonergic antidepressants, and antidopaminergic medications 1, 4
• Treat untreated obstructive sleep apnea if present 1, 4

Concurrent Pharmacologic Therapy

• Gabapentinoids (gabapentin, gabapentin enacarbil, pregabalin) are first-line pharmacologic therapy for RLS and can be initiated concurrently with iron supplementation 1, 4, 3
• Approximately 70% of patients treated with gabapentinoids have much or very much improved RLS symptoms versus 40% with placebo 3
• Iron supplementation and gabapentinoids address different aspects of RLS pathophysiology and are complementary, not mutually exclusive 1, 4

Medications to Avoid

• Do NOT use dopamine agonists (pramipexole, ropinirole, rotigotine) as first-line therapy due to 7-10% annual incidence of augmentation—a paradoxical worsening of symptoms 1, 2, 3
• Avoid cabergoline, bupropion, carbamazepine, clonazepam, and valproic acid, which lack evidence or have significant safety concerns 1, 4

Special Populations

Pediatric Patients

• Initiate iron supplementation when ferritin is <50 ng/mL (lower threshold than adults) 1, 2
• Oral ferrous sulfate receives conditional recommendation with very low certainty of evidence in children 1, 4
• Monitor for constipation, which is a common side effect limiting tolerability 2

Pregnancy

• Iron supplementation is particularly important given pregnancy-specific RLS prevalence (22%, especially in third trimester) 2, 3
• Safety profile favors oral formulations throughout gestation 2
• Consider pregnancy-specific safety profiles when selecting any RLS treatment 1

End-Stage Renal Disease

• Use IV iron sucrose (not ferric carboxymaltose) if ferritin <200 ng/mL AND transferrin saturation <20% 1, 2, 4
• Higher ferritin threshold (200 ng/mL) reflects altered iron metabolism in ESRD 1, 2
• Consider vitamin C supplementation to enhance iron utilization 1, 4

Common Pitfalls to Avoid

• Do NOT use general population ferritin cutoffs (<15-30 ng/mL) for RLS—RLS requires higher thresholds (≤75 ng/mL for adults, <50 ng/mL for children) because brain iron deficiency occurs at higher serum levels than systemic iron deficiency 2, 6
• Do NOT assume all IV iron formulations are equivalent—only ferric carboxymaltose has strong evidence; iron sucrose lacks efficacy except in dialysis patients 2
• Do NOT test iron studies while the patient is taking supplements—wait at least 24 hours after the last iron-containing product 1, 2
• Do NOT forget to check BOTH ferritin AND transferrin saturation—transferrin saturation <20% may reveal functional iron deficiency even with "adequate" ferritin 1, 5
• Do NOT increase oral iron dose indefinitely if ineffective—switch to IV ferric carboxymaltose after 3 months of failed oral therapy 2
• Screen for hemochromatosis before initiating iron therapy in patients with elevated baseline transferrin saturation or ferritin, or suggestive family history 9