Pharmacology Update: Deferasirox Tablets for Oral Suspension (Exjade®)
Pharmacology Update
Deferasirox Tablets for Oral Suspension (Exjade®)
By William T. Elliott, MD, FACP, and James Chan, PhD, PharmD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Assistant Clinical Professor of Medicine, University of California, San Francisco; Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationships to this field of study.
Following a priority review, the FDA has approved deferasirox, the first oral iron chelator for the treatment of chronic iron overload due to transfusions. It will be marketed by Novartis Pharmaceuticals as Exjade®.
Indications
Deferasirox is indicated for the treatment of chronic iron overload due to blood transfusions (ages ≥ 2 years).1
Dosage
The recommended initial dose is 20 mg/kg body weight. Treatment should be started if there is evidence of chronic iron overload. These include transfusion of approximately 20 units/40 kg patients (100 mL/kg of packed red blood cells) and serum ferritin > 1000 µg/L.1 After initiation of therapy, serum ferritin should be monitored every month and the dose adjusted every 3 to 6 months as needed. Adjustments should be made in increments of 5 or 10 mg/kg and based on patient's response and therapeutic goal. The dose should not exceed 20 mg/kg.1
Deferasirox should be taken once daily at about the same time on an empty stomach at least 30 minutes before any food. The tablets should not be taken whole or chewed but dispersed in water, orange juice, or apple juice. Aluminum containing antacids should not be taken at the same time. Co-administration with other iron chelators is not recommended due to lack of safety data.1
Deferasirox is supplied as 125 mg, 250 mg, and 500 mg tablets for suspension.
Potential Advantages
Deferasirox is well absorbed after oral administration and is effective in reducing liver iron concentration.1,2 Deferasirox is selective for iron and has little affinity for copper or zinc.1
Potential Disadvantages
Deferasirox is more likely to increase serum creatinine than deferoxamine (38% vs 15% respectively). It is also more likely to cause proteinuria (urine protein/creatinine ratio > 0.6 mg/mg) (18.6% vs 7.25). Drug induced hepatitis has also been reported. Monthly monitoring of serum creatinine, urine protein, and liver function test are recommended.1 Other reported adverse events include hearing loss, ocular (lens opacities, cataracts, increase in intraocular pressure, retinal disorders), and skin rash. Other adverse effects include diarrhea, vomiting, nausea, headache, abdominal pain, pyrexia, and cough. Gastrointestinal side effects, elevation in serum creatinine, and skin rash are dose related.1 Auditory and ophthalmic testing (eg, slit lamp examination and dilated fundoscopy) is recommended every 12 months.1
Comments
Deferasirox is a 3,5-bis (ortho-hydroxy phenyl) triazole.1,2,4 It is well absorbed after oral administration and is the first oral iron chelator approved. Efficacy was demonstrated in a multi-center, open-label randomized study (n = 586).1,3 Chronically transfused patients with b-thalassemia who had hemosiderosis were randomized to a starting dose of 5, 10, 20, or 30 mg/kg once daily of deferasirox or 20 to 60 mg/kg of deferoxamine for at least 5 days per week. Results at 12 months showed 52.9% of deferasirox treated patients and 66.4% of deferoxamine treated patients achieved the primary end point. These include decrease in liver iron concentration of 3 mg iron dry weight for baseline values 10 mg iron/g dry weight, reduction of baseline values between 7 and < 10 to < 7 mg iron/g dry weight, or maintenance or reduction for baseline values < 7 mg iron/dry weight. The 30 mg/kg dose was most effective. The apparent difference in efficacy may be related to under dosing of deferasirox due to underestimation of some baseline liver iron concentrations rather than a true difference between drugs.3 The 2 drugs have different routes of excretion of chelated iron. Deferoxamine-chelated iron from the reticuloendothelial (RE) iron stores is excreted mainly in the urine, and iron chelated from the hepatocytes excreted in the feces. In contrast, with deferasirox, both iron chelated from the RE and hepatocytes stores are excreted in the feces.4 Deferasirox may be more effective than deferoxamine in promoting the excretion of chelatable iron from hepatocellular iron stores.5 The use of serum ferritin for dose adjustment is more practical than ideal as it is only roughly related to liver iron concentration.3 However liver biopsies guided dosing is not practical. Potential for renal and liver toxicity have been reported. Increase in serum creatinine and liver enzymes were more common with deferasirox than deferoxamine. The cost of deferasirox was not available at the time of this review.
Clinical Implications
Iron overload due to frequent blood transfusions is a potentially life-threatening condition. It is common in patients with blood disorders such as thalassemia, sickle cell disease and myelodysplastic syndrome. Current effective therapy is deferoxamine, which requires parenteral administration and usually continuous subcutaneous infusion over 8-12 hours often resulting local side effects and poor adherence. Deferasirox offers the major advantage of oral administration. However long-term safety and relative effectiveness compared to deferoxamine have not been established.
References
1. Exjade Product Information. Novartis Pharmaceutical Corporation. November 2005.
2. Nisbet-Brown E, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: a randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003;361:1597-1602.
3. Exjade (ICL 670, deferasirox) Advisory Committee Summary. www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4177B1_02_a.pdf. Accessed December 6, 2005.
4. Nick H, et al. Development of tridentate iron chelators: from desferrithiocin to ICL670. Curr Med Chem. 2003;10:1065-1076.
5. Capellini MD. Iron-chelating therapy with the new oral agent ICL670 (Exjade). Best Pract Res Clin Haematol. 2005;18:289-298.
Following a priority review, the FDA has approved deferasirox, the first oral iron chelator for the treatment of chronic iron overload due to transfusions. It will be marketed by Novartis Pharmaceuticals as Exjade®.Subscribe Now for Access
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