What is the appropriate treatment for a patient with hemochromatosis or iron overload, specifically considering the use of Deferasirox (iron chelator)?

Deferasirox for Iron Overload in Hemochromatosis

Primary Recommendation

Phlebotomy remains the first-line treatment for hemochromatosis; deferasirox should only be considered as a second-line option when phlebotomy is not feasible, and it is contraindicated in patients with advanced liver disease. 1

When to Consider Deferasirox

Deferasirox may be appropriate in specific clinical scenarios where phlebotomy cannot be performed: 1

• Inaccessible veins preventing regular phlebotomy access 1
• Severe needle phobia that prevents compliance with phlebotomy 1
• Concomitant anemia (though this should prompt investigation for other causes, as anemia is not characteristic of hemochromatosis) 1
• Life-threatening cardiac iron overload, particularly in juvenile hemochromatosis 1
• Hemodynamic instability where bloodletting would cause harm 1

Critical Contraindications and Warnings

Absolute contraindications per FDA labeling: 2

• Estimated GFR <40 mL/min/1.73 m² 2
• Advanced liver disease or cirrhosis (deferasirox can cause hepatic failure) 1, 2
• Poor performance status 2
• Platelet count <50 × 10⁹/L 2
• Known hypersensitivity to deferasirox 2

The European Association for the Study of the Liver explicitly contraindicates deferasirox in cirrhotic patients due to risk of hepatic failure. 1

Dosing Protocol

Starting dose: 10 mg/kg/day orally once daily 1, 3, 2, 4

• The FDA-approved starting dose for transfusional iron overload is 14 mg/kg/day, but phase I/II trials in hemochromatosis patients showed that 10 mg/kg/day is most appropriate due to better tolerability 2, 4
• Calculate dose to the nearest whole tablet 2
• Doses of 15 mg/kg/day caused more adverse events (increased ALT and creatinine) in hemochromatosis patients 4

Target ferritin levels: 1, 3, 2

• During induction: Reduce ferritin to 50 μg/L 1, 3
• During maintenance: Keep ferritin between 50-100 μg/L 1, 3
• Interrupt therapy if ferritin falls below 500 μg/L 2

Efficacy data: Deferasirox at 10 mg/kg/day reduced median serum ferritin by 75% over 48 weeks to <250 ng/mL in hemochromatosis patients 1, 4

Mandatory Monitoring Requirements

Before initiating therapy, obtain: 2

• Serum creatinine in duplicate (due to measurement variations) and calculate eGFR 2
• Urinalysis and serum electrolytes to evaluate renal tubular function 2
• Serum transaminases and bilirubin 2
• Baseline auditory and ophthalmic examinations 2
• Serum ferritin level 2

During therapy, monitor monthly: 2

• Serum ferritin (adjust dose every 3-6 months based on trends) 2
• Renal function (serum creatinine, eGFR) 2
• Liver function tests (ALT, AST, bilirubin) 2
• Complete blood count 2

Common and Serious Adverse Effects

Most common adverse effects (>5%): 2

• Diarrhea, nausea, vomiting, abdominal pain 2
• Skin rashes 2
• Increases in serum creatinine 2

Serious adverse effects requiring immediate action: 2

• Acute kidney injury including acute renal failure requiring dialysis and Fanconi syndrome 2
• Hepatic toxicity and failure 2
• Gastrointestinal hemorrhage (risk increased with concurrent NSAIDs or anticoagulants) 2
• Bone marrow suppression (neutropenia, agranulocytosis, thrombocytopenia) 2
• Severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS) 2

Important Clinical Pitfalls to Avoid

Never use deferasirox in cirrhotic patients - this is explicitly contraindicated by the European Association for the Study of the Liver due to risk of hepatic failure 1

Avoid overchelation - target ferritin of 50 μg/L to prevent iron deficiency; interrupt therapy if ferritin falls below 500 μg/L 1, 3, 2

Do not combine with aluminum-containing antacids 2

Monitor for drug interactions: 2

• Increases exposure of repaglinide (consider dose reduction) 2
• Increases exposure of busulfan (monitor plasma concentrations) 2
• May increase theophylline levels (avoid concurrent use) 2

Refer to specialized centers - patients requiring chelation therapy should be managed by clinicians with expertise in iron disorders 1

Regulatory Status and Evidence Quality

Deferasirox is NOT approved by the European Medicines Agency for treatment of hemochromatosis - it is used off-label in this indication 1, 3

The FDA has approved deferasirox only for transfusional iron overload in patients ≥2 years of age, not for hereditary hemochromatosis 2

Evidence quality is weak - long-term safety and efficacy data beyond 1 year in hemochromatosis patients is lacking 1

Alternative Chelation Options

If deferasirox is not suitable, consider: 1

• Deferoxamine (parenteral) - limited experience in hemochromatosis but shown to be safe in 3 patients; can be combined with mini-phlebotomies in patients with hemodynamic instability 1, 5
• Deferiprone (oral) - very limited experience; 3 hemochromatosis patients with severe cardiac iron overload developed hematological toxicity (2 with agranulocytosis, 1 fatal) 1

Erythrocytapheresis is superior to phlebotomy when available, reducing treatment frequency and allowing faster iron removal 1