Defera500 mg

Defera is an oral iron chelator used to reduce chronic iron overload.

Established / approved uses

• Transfusional iron overload due to thalassemia syndromes (thalassemia major) — Defera is indicated in adults and children when current chelation therapy (e.g., deferoxamine) is inadequate or contraindicated.
• Transfusional iron overload due to sickle cell disease or other anemias — Defera is approved for this use in patients whose prior chelation therapy is inadequate.

Not established

The safety and efficacy of Defera have not been established for iron overload due to myelodysplastic syndrome or Diamond-Blackfan anemia, and it should not be used for these conditions outside of a specialist/clinical-trial setting.

Defera is generally reserved as second-line therapy and, in some regimens, is used in combination with deferoxamine under specialist supervision for patients with severe iron overload.

Each film-coated tablet contains Deferiprone INN 500 mg (also available as 1000 mg tablets and as an oral solution 100 mg/mL in some markets, depending on manufacturer). Excipients vary by brand and formulation.

Defera is a synthetic, orally active, bidentate iron-chelating agent belonging to the hydroxypyridinone class. It is used to remove excess iron from the body in patients who require long-term blood transfusions (for example, in thalassemia major), where transfusions lead to progressive accumulation of iron that can damage the heart, liver, and endocrine glands if untreated.

Defera carries a boxed warning for agranulocytosis, a potentially fatal drop in white blood cells, and requires mandatory regular blood count monitoring throughout treatment.

Iron-chelating agent (antidote for iron overload); hydroxypyridinone class

Mechanism

Deferiprone is a bidentate ligand; three molecules of Deferiprone surround one iron(III) atom (3:1 stoichiometry) to form a stable, neutral complex that is excreted mainly in the urine, with a small amount eliminated in feces. This removes excess iron from tissues and reduces harmful labile iron that would otherwise catalyze free-radical damage.

Pharmacokinetics

• Absorption: Rapidly absorbed after oral dosing; peak plasma concentration reached within about 1 hour (may be delayed with food).
• Metabolism: Extensively metabolized in the liver, mainly by glucuronidation (via UGT1A6) to an inactive glucuronide metabolite.
• Excretion: Predominantly renal, largely as the glucuronide metabolite and the iron complex; elimination half-life is approximately 2-3 hours.

Take Defera by mouth, generally with food, at evenly spaced intervals as prescribed. Swallow tablets whole; use the dosing device provided for oral solution formulations. Do not stop or change the dose without consulting the treating physician, since ongoing blood count monitoring is required throughout treatment.

Clinically significant interactions

• Drugs associated with neutropenia or agranulocytosis (e.g., certain antipsychotics, antithyroid drugs, some antiretrovirals, other cytotoxic/myelosuppressive drugs): co-administration with Defera should generally be avoided; if unavoidable, more frequent absolute neutrophil count monitoring is required (see Contraindications/Precautions for the underlying agranulocytosis risk).
• UGT1A6 inhibitors (e.g., diclofenac, probenecid, silymarin/milk thistle): may reduce metabolism/clearance of Defera and increase exposure; avoid concurrent use where possible.
• Polyvalent cation-containing products (aluminum-, iron-, or zinc-containing antacids or supplements): can chelate with Defera and reduce its absorption; separate administration by at least 4 hours.
• Vitamin C (high-dose): may increase iron availability during chelation; use only under medical supervision if combined with Defera.

Common

• Nausea, vomiting, abdominal pain
• Joint pain (arthralgia)
• Elevated liver enzymes (ALT)
• Reddish-brown discoloration of urine (chromaturia) — a harmless, expected effect of iron excretion
• Headache

Serious (see Precautions and Warnings for full detail)

• Neutropenia and agranulocytosis (potentially fatal — requires immediate discontinuation and evaluation)
• Zinc deficiency
• Hepatic fibrosis (rare, reported with long-term use)

In patients treated for sickle cell disease or other anemias, fever, bone/back pain, sickle cell crisis, sore throat, and upper respiratory infection have also been reported with Defera.

Pregnancy

Defera has shown embryo-fetal harm (fetal loss and malformations) in animal studies at clinically relevant doses, and human data are insufficient to rule out risk; treatment should generally be avoided in pregnancy. Defera should be used during pregnancy only if clearly needed and the potential benefit justifies the potential risk to the fetus, and only under direct physician supervision. Women of reproductive potential should use effective contraception during treatment with Defera and for a period after stopping (per treating physician's advice); male patients are advised to use contraception for a period after stopping treatment.

Lactation

It is not known whether Defera passes into human breast milk. Breastfeeding is generally not recommended during treatment with Defera and for a period after the last dose; a physician should be consulted before breastfeeding.

Boxed warning: Agranulocytosis

Defera can cause agranulocytosis that can lead to serious infection and death; neutropenia may precede agranulocytosis. Absolute neutrophil count (ANC) must be measured before starting Defera and monitored on a mandatory regular schedule (typically weekly) throughout treatment. Patients must be instructed to report any signs or symptoms of infection (fever, sore throat, mouth sores, chills) immediately. Treatment with Defera must be interrupted if neutropenia is confirmed and stopped if agranulocytosis occurs.

Other precautions

• Hepatic effects: Elevated liver enzymes and, rarely, hepatic fibrosis have been reported; liver function should be monitored regularly (e.g., monthly ALT) during treatment with Defera.
• Zinc deficiency: Decreased plasma zinc has been observed; zinc levels should be checked periodically (e.g., annually) and supplementation given if deficient.
• Embryo-fetal toxicity: See Pregnancy and Lactation.
• Iron deficiency: Excessive chelation can cause iron deficiency; serum ferritin and iron indices should be monitored to avoid over-chelation.

Limited data on overdose with Defera are available; neurological symptoms (such as unsteady gait/cerebellar signs, double vision, and slowed movement) have been reported at doses roughly 2.5-3 times the recommended dose, with gradual recovery after stopping. There is no specific antidote for Defera overdose. In case of suspected overdose, seek immediate medical attention or contact emergency services/poison control; treatment is supportive and symptomatic under medical supervision.

Store Defera at room temperature (20-25°C / 68-77°F), with excursions permitted to 15-30°C; protect from moisture and light, and keep the container tightly closed. Keep out of reach of children.

Renal impairment

Data are limited; use Defera with caution and close monitoring in patients with significant renal impairment.

Hepatic impairment

Use Defera with caution and enhanced liver-function monitoring in patients with hepatic impairment, given the risk of transaminase elevation and rare hepatic fibrosis (see Precautions).

Elderly

Clinical experience with Defera in elderly patients is limited, as chronic transfusional iron overload predominantly affects younger patients; use with routine monitoring if prescribed.

Pediatric

See Pediatric Uses.

Treatment with Defera is typically long-term/chronic, continuing for as long as transfusion-related iron overload persists. The treating physician periodically reassesses the need for continued therapy using serum ferritin trends and, where available, organ (cardiac/hepatic) iron measurements, adjusting or stopping Defera as clinically indicated.

Deferiprone belongs to the class of iron-chelating agents (hydroxypyridinone chelators), used as antidotes for chronic iron overload.

Deferiprone is a bidentate iron chelator: three molecules of Deferiprone bind one atom of trivalent iron to form a stable, water-soluble complex that is then excreted, principally in the urine. By binding free and loosely-bound (labile) iron, Deferiprone reduces iron-catalyzed oxidative tissue damage and lowers total body iron burden over time.

The safety and effectiveness of Defera have been established in pediatric patients 8 years of age and older for transfusional iron overload, using the same weight-based dosing as adults (see Dosage and Administration). Some national labels (including in Bangladesh) permit use from 6 years of age when deferoxamine therapy is inadequate or contraindicated, under specialist supervision. Safety and effectiveness of Defera in children younger than the locally approved minimum age have not been established, and mandatory neutrophil monitoring applies equally to pediatric patients.