What medications can be used to reduce iron (Fe) overload in a patient with haemochromatosis who cannot undergo phlebotomy (venesection)?

Medications for Iron Overload in Haemochromatosis When Phlebotomy is Contraindicated

Iron chelation therapy should be initiated when phlebotomy is not possible, with deferasirox (oral) as the primary second-line option at a starting dose of 10 mg/kg/day, though it requires careful risk-benefit consideration and should not be used in patients with advanced liver disease. 1

Primary Chelation Options

Deferasirox (Oral - First Choice Among Chelators)

Deferasirox represents the most studied chelation option in haemochromatosis and is effective at reducing iron burden, but evidence remains weak and it is not approved by the European Medicines Agency for this indication. 1

Dosing and efficacy:

• Start at 10 mg/kg/day based on phase I/II trials showing this dose reduced median serum ferritin by 75% over 48 weeks to <250 ng/mL 1, 2
• The 15 mg/kg/day dose caused more adverse events without substantially better efficacy 1, 2
• Target serum ferritin of 50 μg/L during iron depletion, maintaining 50-100 μg/L thereafter 1

Critical contraindications and warnings:

• Absolutely contraindicated in patients with advanced liver disease (Child-Pugh C) 1, 3
• Contraindicated if eGFR <40 mL/min/1.73 m² 3
• Can cause acute renal failure, hepatic failure, and gastrointestinal hemorrhage (FDA black box warnings) 3
• Requires dose reduction in moderate hepatic impairment (Child-Pugh B) 3

Mandatory monitoring:

• Serum creatinine in duplicate and eGFR before starting 3
• Serum transaminases and bilirubin every 2 weeks for first month, then monthly 3
• Weekly renal function monitoring for first month in patients with baseline renal impairment 3
• Monthly serum ferritin 3

Common adverse effects:

• Gastrointestinal: diarrhea, nausea (dose-dependent) 1, 2
• Renal impairment (8 patients had serum creatinine >33% above baseline in trials) 2
• Hepatotoxicity (6 patients had ALT >3× baseline in trials) 2

Deferoxamine (Parenteral - Alternative Option)

Deferoxamine via subcutaneous infusion can be considered, particularly in patients with advanced disease who poorly tolerate phlebotomy or have cardiac iron overload. 1

• Very limited evidence in haemochromatosis (shown safe in only 3 patients) 1
• FDA-approved for chronic iron overload due to transfusion-dependent anemias 4
• Can be combined with mini-phlebotomies in patients with hemodynamic instability or low baseline hemoglobin 1
• Poor compliance is a major limitation due to parenteral administration 5

Deferiprone (Oral - Use With Extreme Caution)

Deferiprone has very limited evidence in haemochromatosis and carries significant hematological toxicity risk, including fatal agranulocytosis. 1

• In a retrospective cohort, all 3 haemochromatosis patients with severe cardiac iron overload developed hematological toxicity (2 with agranulocytosis, one fatal; 1 with neutropenia) 1
• May be considered for combination therapy in juvenile haemochromatosis with life-threatening cardiac iron overload 1
• Should only be prescribed by specialists with clinical expertise 1

Clinical Scenarios for Chelation Therapy

Chelation should be considered in the following situations where phlebotomy cannot be performed: 1

• Inaccessible veins
• Severe needle phobia
• Concomitant anemia (though anemia is not characteristic of haemochromatosis and warrants investigation for other causes) 1
• Life-threatening cardiac iron overload (typically in juvenile haemochromatosis) 1
• Conditions where bloodletting would cause harm 1

Special Considerations

Juvenile Haemochromatosis

Combined chelation therapy with deferiprone and deferoxamine has been described for life-threatening cardiac iron overload, though phlebotomy remains first-line when possible. 1

Pregnancy

All iron chelation drugs are contraindicated in pregnancy. 1

Referral Requirement

Patients requiring chelation therapy should be referred to specialized centers with expertise in iron disorders for evaluation and treatment. 1

Critical Pitfalls to Avoid

• Never use deferasirox in cirrhotic patients - this is explicitly contraindicated and can cause hepatic failure 1, 3
• Do not assume anemia is from haemochromatosis - it suggests another underlying condition requiring investigation 1
• Avoid overchelation - target ferritin of 50 μg/L, not lower, to prevent iron deficiency 1
• Monitor renal function intensively - acute renal failure is a major risk with deferasirox 3
• Recognize that chelation is off-label - deferasirox is not EMA-approved for haemochromatosis 1