JADAX 90

Indications

• Chronic iron overload due to repeated blood transfusions
• Thalassemia major
• Aplastic anemia
• Sideroblastic anemia

Dosage

Children: For children aged 2 years and above, the initial dose is typically 20 mg/kg once daily, adjusted according to serum ferritin levels. Maximum recommended daily dose is 40 mg/kg.

Adults: Initially 20 mg/kg once daily, adjusted based on serum ferritin levels and clinical response. Maximum dose should not exceed 40 mg/kg daily.

Mechanism of action

Deferasirox binds trivalent (ferric) iron with high affinity, forming a stable complex that is eliminated via the kidneys. It acts as a tridentate ligand, binding iron in a ratio of 2:1, which effectively lowers iron levels in the body. Deferasirox also impacts nuclear factor-kappaB, a key regulator of various cellular processes, which may contribute to its therapeutic effects in certain hematological conditions.

Pharmacodynamics

Deferasirox selectively chelates iron (Fe3+) and exhibits a strong affinity for it. Although it has low affinity for other trace metals such as zinc and copper, its administration can lead to variable decreases in the serum concentrations of these metals. The clinical implications of these decreases are not fully understood, but they may impact overall metal homeostasis.

Pharmacokinetics

Deferasirox is administered orally and is well absorbed from the gastrointestinal tract. Peak plasma concentrations are reached within a few hours after dosing. The drug undergoes extensive metabolism in the liver, primarily through glucuronidation, and is excreted mainly in the feces, with a smaller fraction eliminated via urine. The half-life of deferasirox is approximately 8 to 16 hours, allowing for once-daily dosing.

Adverse effects

• Diarrhoea
• Dizziness
• Headache
• Hot flush
• Nausea
• Skin reactions
• Urine discolouration

Interactions

• Aluminium hydroxide - Severe (decreases exposure)
• Aminophylline - Severe (increases exposure)
• Antipsychotics, second-generation - Severe (increases exposure)
• Clozapine - Severe (increases exposure)
• Meglitinides - Severe (increases exposure)
• Repaglinide - Severe (increases exposure)
• Theophylline - Severe (increases exposure)
• Ritonavir - Moderate (decreases exposure)
• Treprostinil - Moderate (increases exposure)
• Rifampicin - Moderate (decreases exposure)

Precautions

• Diagnosis of Vitamin B12 deficiency should be confirmed before administration
• Should not be given to patients with cardiac dysfunction
• Use with caution in patients with conditions leading to iron overload

Pregnancy

Not recommended during pregnancy due to potential risks.

Breast-feeding

Present in milk but not known to be harmful.

Storage

Store in a cool, dry place, away from light.

Formulations

• Oral suspension
• Tablet

Mechanism of action

Two molecules of deferasirox are capable of binding to 1 atom of iron. Deferasirox works in treating iron toxicity by binding trivalent (ferric) iron (for which it has a strong affinity), forming a stable complex which is eliminated via the kidneys. Exjade (deferasirox) is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain. ... Nuclear factor-kappaB is a key regulator of many cellular processes and its impaired activity has been described in different myeloid malignancies including myelodysplastic syndromes. /Investigators/ evaluated deferasirox activity on nuclear factor-kappaB in myelodysplastic syndromes as a possible mechanism involved in hemoglobin improvement during in vivo treatment. Forty peripheral blood samples collected from myelodysplastic syndrome patients were incubated with 50 muM deferasirox for 18 hr. Nuclear factor-kappaB activity dramatically decreased in samples showing high basal activity as well as in cell lines, whereas no similar behavior was observed with other iron chelators despite a similar reduction in reactive oxygen species levels. Additionally, ferric hydroxyquinoline incubation did not decrease deferasirox activity in K562 cells suggesting the mechanism of action of the drug is independent from cell iron deprivation by chelation. Finally, incubation with both etoposide and deferasirox induced an increase in K562 apoptotic rate. Nuclear factor-kappaB inhibition by deferasirox is not seen from other chelators and is iron and reactive oxygen species scavenging independent. ... ... Iron-induced increase in oxidative stress was also associated with increased phosphorylation of ERK-, p38-, and JNK-mitogen-activated protein kinase (MAPK). Interestingly, deferasirox treatment significantly diminished the phosphorylation of all three MAPK subfamilies. These results suggest that deferasirox may confer a cardioprotective effect against iron induced injury. HIV-1 replication is induced by an excess of iron and iron chelation by desferrioxamine (DFO) inhibits viral replication by reducing proliferation of infected cells. Treatment of cells with DFO and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit expression of proteins that regulate cell-cycle progression, including cycle-dependent kinase 2 (CDK2). Recent studies /have/ shown that CDK2 participates in HIV-1 transcription and viral replication suggesting that inhibition of CDK2 by iron chelators might also affect HIV-1 transcription. Here /investigators/ evaluated the effect of a clinically approved orally effective iron chelator, 4-[3,5-bis-(hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid (ICL670) and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells. Neither ICL670 nor 311 induced cytotoxicity at concentrations that inhibited HIV-1 transcription. The chelators decreased cellular activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2. Neither ICL670A or 311 decreased CDK9 protein level but significantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain. In conclusion, /these/ findings add to the evidence that iron chelators can inhibit HIV-1 transcription by deregulating CDK2 and CDK9. ... Iron depletion improves insulin resistance in patients with nonalcoholic fatty liver disease and diabetes and also stabilizes the hypoxia-inducible factor (HIF)-1, resulting in increased glucose uptake in vitro. This study investigated the effect of iron depletion by deferoxamine on insulin signaling and glucose uptake in HepG2 hepatocytes and in rat liver. In HepG2 c

Pharmacodynamics

Deferasirox is an orally active chelator that is selective for iron (as Fe3+). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Although deferasirox has very low affinity for zinc and copper there are variable decreases in the serum concentration of these trace metals after the administration of deferasirox. The clinical significance of these decreases is uncertain.