Deferiprone

Approved Indications:

• Transfusional Iron Overload in Thalassemia Syndromes:
• Indicated in patients with transfusion-dependent thalassemia (TDT) when other iron chelation therapies are inadequate or contraindicated.
• Approved as monotherapy or in combination with other chelators (e.g., deferoxamine) for enhanced iron removal.
• Iron Overload in Non-transfusion Dependent Thalassemia (NTDT):
• In select patients requiring iron chelation due to elevated liver iron or ferritin.
• Friedreich’s Ataxia (FA):
• Investigational use for reducing iron accumulation in the brain and improving neurological outcomes.

Clinically Accepted Off-label Uses:

• Iron overload in:
• Sickle cell anemia
• Myelodysplastic syndromes (MDS)
• Aplastic anemia
• Hereditary hemochromatosis (when phlebotomy is not suitable)
• Cardiac siderosis: effective in myocardial iron removal when used alone or with deferoxamine.

Route: Oral only

Adults and Children ≥6 Years:

• Initial Dose:
• 75 mg/kg/day, divided into three doses (25 mg/kg per dose) orally, usually every 8 hours.
• Dose Adjustments:
• May increase to 100 mg/kg/day in patients not adequately chelated, with close monitoring.
• Maximum recommended dose: 100 mg/kg/day.
• Combination Therapy:
• Deferiprone + Deferoxamine may be used sequentially or concurrently (e.g., deferiprone orally and deferoxamine by subcutaneous infusion on alternate nights).

Renal Impairment:

• Use with caution; no standard adjustment, but monitor renal function periodically.

Hepatic Impairment:

• Caution is advised in patients with hepatic dysfunction; monitor ALT, AST, bilirubin.

Elderly:

• No specific adjustments; monitor for increased sensitivity and organ function decline.

Pediatrics (<6 years):

• Not generally recommended unless benefit outweighs risk; limited safety data available.

Deferiprone is an orally active bidentate iron chelator that binds to ferric iron (Fe³⁺) in a 3:1 molar ratio (three molecules of deferiprone per one iron ion). It facilitates iron removal primarily from non-transferrin-bound iron pools, including cardiac and hepatic iron stores, by forming stable complexes that are then excreted predominantly in the urine. Deferiprone has high affinity for cardiac iron, making it particularly useful in preventing or treating iron-induced cardiomyopathy.

Absorption:

• Rapidly absorbed from the gastrointestinal tract; peak plasma concentration occurs within 1–2 hours post-dose.
• Oral bioavailability: ~90%.

Distribution:

• Widely distributed; plasma protein binding: ~2–5%.

Metabolism:

• Primarily metabolized by phase II glucuronidation (via UGT1A6) to an inactive 3-O-glucuronide.

Elimination:

• Excreted mainly via urine (~75–90% as metabolites and iron-bound complexes).
• Elimination half-life: ~1.5–4 hours.

• Pregnancy:
• FDA Category D. Animal studies show fetal toxicity. Use only when benefits justify potential risks. Effective contraception is advised during treatment and for at least 6 months after discontinuation.
• Lactation:
• Unknown if deferiprone is excreted in breast milk. Breastfeeding is contraindicated due to potential risk to the infant.

• Primary Class: Iron chelating agent
• Subclass: Oral bidentate iron chelator

• Hypersensitivity to deferiprone or any of its components
• History of agranulocytosis or recurrent neutropenia
• Current neutropenia (ANC <1.5 × 10⁹/L)
• Pregnancy and breastfeeding
• Severe renal or hepatic impairment (relative contraindication)

• Agranulocytosis/Neutropenia:
• Most serious risk. Perform weekly absolute neutrophil count (ANC) monitoring during therapy. Discontinue immediately if neutropenia or infection develops.
• Hepatotoxicity:
• Monitor ALT, AST, and bilirubin every 1–3 months. Use with caution in hepatic impairment.
• Zinc Deficiency:
• Deferiprone may chelate zinc; monitor serum zinc periodically and supplement if needed.
• Arthropathy:
• Joint pain and swelling may occur; reversible upon discontinuation.
• Ferritin Monitoring:
• Monitor serum ferritin monthly to assess chelation efficacy and adjust dosing accordingly.
• Combination Therapy Risks:
• Increased risk of side effects when used with deferoxamine; close clinical supervision is necessary.

Very Common (≥10%):

• Nausea
• Vomiting
• Abdominal pain
• Arthralgia
• Reddish/brown discoloration of urine (from iron complex excretion)

Common (1–10%):

• Neutropenia
• Diarrhea
• Headache
• Elevated liver enzymes
• Increased ALT/AST
• Fatigue

Rare (<1%):

• Agranulocytosis (life-threatening)
• Leukopenia
• Rash
• Zinc deficiency
• Neurologic symptoms (in overdose or misuse)

Timing:

• GI symptoms typically occur early in treatment.
• Hematologic complications may develop at any time—require continuous monitoring.

• Cytotoxic Drugs (e.g., clozapine, carbamazepine):
• Increased risk of agranulocytosis—avoid concurrent use.
• Aluminum-containing antacids:
• May interfere with deferiprone absorption—avoid simultaneous administration.
• Zinc Supplements:
• May be chelated by deferiprone; if required, administer separately and monitor zinc levels.
• No significant CYP450 interactions identified.

• Updated EMA Guidance:
• Recommends stricter hematologic monitoring due to rare but serious cases of agranulocytosis.
• NCCN and Thalassemia International Federation (2024):
• Deferiprone remains a key agent in managing cardiac iron overload, especially when combined with deferoxamine.
• Ongoing Research:
• Investigating deferiprone in neurodegenerative diseases (e.g., Friedreich’s ataxia) and Parkinson’s due to its ability to cross the blood-brain barrier and chelate iron in neural tissue.

• Tablets and Oral Solution:
• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture and light.
• Keep bottle tightly closed after opening.
• Oral Solution (once opened):
• Stable for up to 35 days if stored properly.
• Handling Precautions:
• No need for special handling beyond standard hygiene. Avoid contact with eyes and mucosa.