Exjade (deferasirox) is an iron chelating agent. Exjade tablets for oral suspension contain 125 mg, 250 mg, or 500 mg deferasirox. Deferasirox is designated chemically as 4-[3,5-Bis (2-hydroxyphenyl)-1H-1,2,4-triazol-1yl]-benzoic acid and its structural formula is

Deferasirox is a white to slightly yellow powder. Its molecular formula is C₂₁H₁₅N₃O₄ and its molecular weight is 373.4.

Inactive Ingredients: Lactose monohydrate (NF), crospovidone (NF), povidone (K30) (NF), sodium lauryl sulphate (NF), microcrystalline cellulose (NF), silicon dioxide (NF), and magnesium stearate (NF).

Last updated on RxList: 2/17/2010

Exjade (deferasirox) is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. In these patients, Exjade has been shown to reduce liver iron concentration and serum ferritin levels. Clinical trials to demonstrate increased survival or to confirm clinical benefit have not been completed [see Clinical Studies].

Individualize the decision to initiate Exjade therapy based on consideration of the anticipated clinical benefit and risks of the therapy, taking into consideration factors such as the life expectancy and comorbidities of the patient [see WARNINGS AND PRECAUTIONS and CONTRAINDICATIONS].

The safety and efficacy of Exjade when administered with other iron chelation therapy have not been established.

Dosing Information

Prior to starting therapy, obtain baseline serum ferritin and iron levels. The risk for toxicity may be increased when Exjade is given to patients with low iron burden or with serum ferritin levels that are only slightly elevated [see Dose Modifications].

The recommended initial daily dose of Exjade is 20 mg/kg body weight.

Take Exjade once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. Do not chew tablets or swallow them whole. Do not take Exjade with aluminum-containing antacid products. Calculate doses (mg/kg per day) to the nearest whole tablet. Completely disperse tablets by stirring in water, orange juice, or apple juice until a fine suspension is obtained. Disperse doses of < 1 g in 3.5 ounces of liquid and doses of ≥ 1 g in 7.0 ounces of liquid. After swallowing the suspension, resuspend any residue in a small volume of liquid and swallow.

Individualize the decision to remove accumulated iron based on anticipated clinical benefit and risks of Exjade therapy. In patients who are in need of iron chelation therapy, it is recommended that therapy with Exjade (deferasirox) be started when a patient has evidence of chronic iron overload, such as the transfusion of approximately 100 mL/kg of packed red blood cells (approximately 20 units for a 40-kg patient) and a serum ferritin consistently > 1000 mcg/L.

Dose Modifications

Exjade may require dose adjustment, interruption or cessation of the therapy due to toxicity or any of the following [see WARNINGS AND PRECAUTIONS, Geriatric Use]:

Based on Serum Ferritin

After commencing initial therapy, monitor serum ferritin every month and adjust the dose of Exjade if necessary every 3-6 months based on serum ferritin trends. Make dose adjustments in steps of 5 or 10 mg/kg and tailor adjustments to the individual patient's response and therapeutic goals (maintenance or reduction of body iron burden). In patients not adequately controlled with doses of 30 mg/kg (e.g., serum ferritin levels persistently above 2500 mcg/L and not showing a decreasing trend over time), doses of up to 40 mg/kg may be considered. Doses above 40 mg/kg are not recommended.

If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade.

Based on Serum Creatinine

For adults, reduce the daily dose of Exjade by 10 mg/kg if a rise in serum creatinine to > 33% above the average of the pretreatment measurements is seen at 2 consecutive visits, and cannot be attributed to other causes. For pediatric patients, reduce the dose by 10 mg/kg if serum creatinine levels rise above the age-appropriate upper limit of normal at 2 consecutive visits.

Concomitant UGT inducers or Cholestyramine

Concomitant use of UGT inducers or cholestyramine decreases deferasirox systemic exposure (AUC). Avoid the concomitant use of cholestyramine or potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) with Exjade. If you must co-administer these agents together, consider increasing the initial dose of Exjade to 30 mg/kg, and monitor serum ferritin levels and clinical responses for further dose modification [see DRUG INTERACTIONS].

Dosage Forms And Strengths

125 mg tablets

Off-white, round, flat tablet with beveled edge and imprinted with “J” and “125” on one side and “NVR” on the other.

250 mg tablets

Off-white, round, flat tablet with beveled edge and imprinted with “J” and “250” on one side and “NVR” on the other.

500 mg tablets

Off-white, round, flat tablet with beveled edge and imprinted with “J” and “500” on one side and “NVR” on the other.

Storage And Handling

Exjade is provided as 125 mg, 250 mg, and 500 mg tablets for oral suspension.

125 mg

Off-white, round, flat tablet with beveled edge and imprinted with “J” and “125” on one side and “NVR” on the other.

Bottles of 30 tablets……………………………..(NDC 0078-0468-15)

250 mg

Off-white, round, flat tablet with beveled edge and imprinted with “J” and “250” on one side and “NVR” on the other.

Bottles of 30 tablets……………………………..(NDC 0078-0469-15)

500 mg

Off-white, round, flat tablet with beveled edge and imprinted with “J” and “500” on one side and “NVR” on the other.

Bottles of 30 tablets……………………………..(NDC 0078-0470-15)

Store Exjade tablets at 25°C (77°F); excursions are permitted to 15–30°C (59–86°F) [see USP Controlled Room Temperature]. Protect from moisture.

Manufactured by: Novartis Pharma Stein AG Stein, Switzerland. Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936.

Last updated on RxList: 2/17/2010

Clinical Trials Experience

The following adverse reactions are also discussed in other sections of the labeling:

Renal Failure [see WARNINGS AND PRECAUTIONS]. Hepatic Failure [see WARNINGS AND PRECAUTIONS]. Fatal and non-fatal Gastrointestinal Bleedings [see WARNINGS AND PRECAUTIONS]. Cytopenias [see WARNINGS AND PRECAUTIONS].

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

A total of 700 adult and pediatric patients were treated with Exjade (deferasirox) for 48 weeks in premarketing studies. These included 469 patients with ß-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were < 16 years of age. In the sickle cell disease population, 89% of patients were Black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 ß-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88-205 weeks.

Table 1 displays adverse reactions occurring in > 5% of Exjade-treated β-thalassemia patients (Study 1) and sickle cell disease patients (Study 3) with a suspected relationship to study drug. Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to Exjade. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

Table 1: Adverse Reactions Occurring in > 5% of Exjade-treated Patients in Study 1 and Study 3*

Preferred Term	Study 1 (β-Thalassemia)		Study 3 (Sickle Cell Disease)
	EXJADE N=296 n (%)	Deferoxamine N=290 n (%)	EXJADE N=132 n (%)	Deferoxamine N=63 n (%)
Abdominal Pain**	63 (21.3)	41 (14.1)	37 (28.0)	9 (14.3)
Diarrhea	35 (11.8)	21 (7.2)	26 (19.7)	3 (4.8)
Creatinine Increased***	33 (11.1)	0 (0)	9 (6.8)	0
Nausea	31 (10.5)	14 (4.8)	30 (22.7)	7 (11.1)
Vomiting	30 (10.1)	28 (9.7)	28 (21.2)	10 (15.9)
Rash	25 (8.4)	9 (3.1)	14 (10.6)	3 (4.8)
*Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug. ** Includes ‘abdominal pain', ‘abdominal pain lower', and ‘abdominal pain upper' which were reported as adverse events. *** Includes ‘blood creatinine increased' and ‘blood creatinine abnormal' which were reported as adverse events. Also see Table 2.

In Study 1, a total of 113 (38%) patients treated with Exjade had increases in serum creatinine > 33% above baseline on 2 separate occasions (Table 2) and 25 (8%) patients required dose reductions. Increases in serum creatinine appeared to be dose related [see WARNINGS AND PRECAUTIONS]. In this study, 17 (6%) patients treated with Exjade developed elevations in SGPT/ALT levels > 5 times the upper limit of normal at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued Exjade therapy [see WARNINGS AND PRECAUTIONS]. An additional 2 patients, who did not have elevations in SGPT/ALT > 5 times the upper limit of normal, discontinued Exjade because of increased SGPT/ALT. Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).

In Study 3, a total of 48 (36%) patients treated with Exjade had increases in serum creatinine > 33% above baseline on 2 separate occasions (Table 2) [see WARNINGS AND PRECAUTIONS]. Of the patients who experienced creatinine increases in Study 3, 8 Exjade-treated patients required dose reductions. In this study, 5 patients in the Exjade group developed elevations in SGPT/ALT levels > 5 times the upper limit of normal at 2 consecutive visits and 1 patient subsequently had Exjade permanently discontinued. Four additional patients discontinued Exjade due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash.

Table 2: Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1 and Study 3

Laboratory Parameter	Study 1 (β-Thalassemia)		Study 3 (Sickle Cell Disease)
	EXJADE N=296 n (%)	Deferoxamine N=290 n (%)	EXJADE N=132 n (%)	Deferoxamine N=63 n (%)
Serum Creatinine
Creatinine increase > 33% and postbaseline visits	113 (38.2)	41 ( 14.1)	48 (36.4)	14 (22.2)
Creatinine increase > 33% and > ULN at 2 consecutive postbaseline visits	7 (2.4)	1 (0.3)	3 (2.3)	2 (3.2)
SGPT/ALT
SGPT/ALT > 5 x ULN at 2 postbaseline visits	25 (8.4)	7 (2.4)	2 (1.5)	0
SGPT/ALT > 5 x ULN at 2 consecutive postbaseline visits	17 (5.7)	5 (1.7)	5 (3.8)	0

Proteinuria

In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio > 0.6 mg/mg) occurred in 18.6% of Exjade-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1. Although no patients were discontinued from Exjade in clinical studies up to 1 year due to proteinuria, monthly monitoring is recommended. The mechanism and clinical significance of the proteinuria are uncertain.

Other Adverse Reactions

In the population of more than 5,000 patients who have been treated with Exjade during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, pharyngolaryngeal pain, early cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, and renal tubulopathy (Fanconi's syndrome). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.

Postmarketing Experience

The following adverse reactions have been spontaneously reported during postapproval use of Exjade. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

Skin and subcutaneous tissue disorders: leukocytoclastic vasculitis, urticaria, alopecia

Immune system disorders: hypersensitivity reactions (including anaphylaxis and angioedema).

The concomitant administration of Exjade and aluminum-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminum than for iron, do not administer Exjade with aluminum-containing antacid preparations.

Effect of Deferasirox on Drug Metabolizing Enzymes

Deferasirox inhibits human CYP3A4, CYP2C8, CYP1A2, CYP2A6, CYP2D6, and CYP2C19 in vitro. The clinical significance of deferasirox inhibition of CYP1A2, CYP2A6, CYP2D6, and CYP2C19 is unknown.

Interaction with Agents Metabolized by CYP3A4

In healthy volunteers, the concomitant administration of Exjade and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam peak concentration by 23 % and exposure by 17%. In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in CYP3A4 substrate concentration and potential loss of effectiveness, use caution when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents).

Interaction with Agents Metabolized by CYP2C8

In a healthy volunteer study, the concomitant administration of Exjade (30 mg/kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) resulted in an increase in repaglinide systemic exposure (AUC) to 2.3-fold of control and an increase in Cmax of 62%. If Exjade and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Exercise caution when Exjade and other CYP2C8 substrates like paclitaxel are co-administered.

Interaction with Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism

In a healthy volunteer study, the concomitant administration of Exjade (single dose of 30 mg/kg) and the potent UDP-glucuronosyltransferase (UGT) inducer rifampicin (600 mg/day for 9 days) resulted in a decrease of deferasirox systemic exposure (AUC) by 44%. Therefore, the concomitant use of Exjade with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in Exjade efficacy.

Avoid the concomitant use of potent UGT inducers with Exjade. If you must co-administer these agents together, consider increasing the initial dose of Exjade to 30 mg/kg and monitor serum ferritin levels and clinical responses for further dose modification [see DOSAGE AND ADMINISTRATION].

Interaction with Cholestyramine

The concomitant use of Exjade with cholestyramine may result in a decrease in Exjade efficacy. In healthy volunteers, the administration of cholesytramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC). Avoid the concomitant use of cholestyramine with Exjade. If you must coadminister these agents together, consider increasing the initial dose of Exjade to 30 mg/kg and monitor serum ferritin levels and clinical responses for further dose modification [see DOSAGE AND ADMINISTRATION].

Last updated on RxList: 2/17/2010

Included as part of the PRECAUTIONS section.

Renal

Acute renal failure, fatal in some patients and requiring dialysis in others, has been reported following the postmarketing use of Exjade (deferasirox). Most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. Monitor serum creatinine and/or creatinine clearance in patients who: are at increased risk of complications, have preexisting renal conditions, are elderly, have comorbid conditions, or are receiving medicinal products that depress renal function. Closely monitor the renal function of patients with creatinine clearances between 40 and less than 60 mL/min, particularly in situations where patients have additional risk factors that may further impair renal function such as concomitant medications, dehydration, or severe infections.

Assess serum creatinine and/or creatinine clearance in duplicate before initiating therapy to establish a reliable pretreatment baseline, due to variations in measurements. Monitor serum creatinine and/or creatinine clearance monthly thereafter. In patients with additional renal risk factors (see above), monitor serum creatinine and/or creatinine clearance weekly during the first month after initiation or modification of therapy and monthly thereafter.

Consider dose reduction, interruption, or discontinuation for increases in serum creatinine. If there is a progressive increase in serum creatinine beyond the age-appropriate upper limit of normal, interrupt Exjade use. Once the creatinine has returned to within the normal range, therapy with Exjade may be reinitiated at a lower dose followed by gradual dose escalation, if the clinical benefit is expected to outweigh potential risks [see Dose Modifications].

In the clinical studies, for increases of serum creatinine on 2 consecutive measures ( > 33% in patients > 15 years of age or > 33% and greater than the age-appropriate upper limit of normal in patients < 15 years of age), the daily dose of Exjade was reduced by 10 mg/kg. Patients with baseline serum creatinine above the upper limit of normal were excluded from clinical studies.

In the clinical studies, Exjade-treated patients experienced dose-dependent increases in serum creatinine. These increases occurred at a greater frequency compared to deferoxamine-treated patients (38% vs. 14%, respectively, in Study 1 and 36% vs 22%, respectively, in Study 3). Most of the creatinine elevations remained within the normal range [see ADVERSE REACTIONS]. There have also been reports of renal tubulopathy in patients treated with Exjade. The majority of these patients were children and adolescents with ß-thalassemia and serum ferritin levels < 1500 mcg/L.

Hepatic Dysfunction and Failure

In Study 1, 4 patients discontinued Exjade because of hepatic abnormalities (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). There have been postmarketing reports of hepatic failure, some with a fatal outcome, in patients treated with Exjade. Most of these events occurred in patients greater than 55 years of age. Most reports of hepatic failure involved patients with significant comorbidities, including liver cirrhosis and multiorgan failure. Serum transaminases and bilirubin should be monitored before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.

Gastrointestinal

Fatal GI hemorrhages, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts, have been reported. Non-fatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving Exjade [see ADVERSE REACTIONS]. Physicians and patients should remain alert for signs and symptoms of GI ulceration and hemorrhage during Exjade therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. Use caution when administering Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.

Cytopenias

There have been postmarketing reports (both spontaneous and from clinical trials) of cytopenias, including agranulocytosis, neutropenia and thrombocytopenia, in patients treated with Exjade. Some of these patients died. The relationship of these episodes to treatment with Exjade is uncertain. Most of these patients had preexisting hematologic disorders that are frequently associated with bone marrow failure [see ADVERSE REACTIONS]. Monitor blood counts regularly. Consider interrupting treatment with Exjade in patients who develop unexplained cytopenia. Reintroduction of therapy with Exjade may be considered, once the cause of the cytopenia has been elucidated.

Hypersensitivity

Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving Exjade, with the onset of the reaction occurring in the majority of cases within the first month of treatment [see ADVERSE REACTIONS]. If reactions are severe, discontinue Exjade and institute appropriate medical intervention.

Rash

Rashes may occur during Exjade (deferasirox) treatment. For rashes of mild to moderate severity, Exjade may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, Exjade may be interrupted. Reintroduction at a lower dose with escalation may be considered in combination with a short period of oral steroid administration. Erythema multiforme has been reported during Exjade treatment.

Co-morbidities

Clinical trials to demonstrate increased survival or to confirm clinical benefit have not been completed. Exjade has been shown to decrease serum ferritin and liver iron concentration in clinical trials. Consider the importance of these factors as well as individual patient factors and the prognosis associated with any underlying conditions before initiation of Exjade therapy [see CONTRAINDICATIONS].

In postmarketing experience, there have been reports of serious adverse reactions, some with a fatal outcome, in patients taking Exjade therapy, predominantly when the drug was administered to patients with advanced age, complications from underlying conditions or very advanced disease. Most of these deaths occurred within six months of Exjade initiation and generally involved worsening of the underlying condition. The reports do not rule out the possibility that Exjade may have contributed to the deaths.

Special Senses

Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) have been reported at a frequency of < 1% with Exjade therapy in the clinical studies. Auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) are recommended before starting Exjade treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, consider dose reduction or interruption.

Laboratory Tests

Measure serum ferritin monthly to assess response to therapy and to evaluate for the possibility of overchelation of iron. If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Exjade [see DOSAGE AND ADMINISTRATION].

In the clinical studies, the correlation coefficient between the serum ferritin and LIC was 0.63. Therefore, changes in serum ferritin levels may not always reliably reflect changes in LIC.

Perform laboratory monitoring of renal and hepatic function [see WARNINGS AND PRECAUTIONS].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

A 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg per day (0.48 times the MRHD (Maximum Recommended Human Dose) on a mg/m² basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg per day (0.81 times the MRHD on a mg/m² basis) in males and 300 mg/kg per day (1.21 times the MRHD on a mg/m² basis) in females.

Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in-vivo oral rat micronucleus tests.

Deferasirox at oral doses up to 75 mg/kg per day (0.6 times the MRHD on a mg/m² basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies with Exjade in pregnant women. Administration of deferasirox to animals during pregnancy and lactation resulted in decreased offspring viability and an increase in renal anomalies in male offspring at exposures that were less than the recommended human exposure. Exjade should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In embryofetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to (100 mg/kg/day in rats and 50 mg/kg/day in rabbits) 0.8 times the MRHD (Maximum Recommended Human Dose) on a mg/m² basis. These doses resulted in maternal toxicity but no fetal harm was observed.

In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses (10, 30, and 90 mg/kg/day) 0.08, 0.2, and 0.7 times the MRHD on a mg/m² basis. Maternal toxicity, loss of litters, and decreased offspring viability occurred at 0.7 times the MRHD on a mg/m² basis, and increases in renal anomalies in male offspring occurred at 0.2 times the MRHD on a mg/m² basis.

Nursing Mothers

It is not known whether Exjade is excreted in human milk. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Of the 700 patients who received Exjade during clinical studies, 292 were pediatric patients 2 - < 16 years of age with various congenital and acquired anemias, including 52 patients age 2 - < 6 years, 121 patients age 6 - < 12 years and 119 patients age 12 - < 16 years. Seventy percent of these patients had β-thalassemia. Children between the ages of 2 - < 6 years have a systemic exposure to Exjade approximately 50% of that of adults [see CLINICAL PHARMACOLOGY]. However, the safety and efficacy of Exjade in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults [see Clinical Studies, INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION].

Growth and development were within normal limits in children followed for up to 5 years in clinical trials.

Geriatric Use

Four hundred and thirty-one (431) patients ≥ 65 years of age have been studied in clinical trials of Exjade. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Closely monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for Exjade toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment

Exjade has not been studied in patients with renal impairment [see WARNINGS AND PRECAUTIONS].

Hepatic Impairment

Exjade has not been studied in patients with hepatic impairment.

Last updated on RxList: 2/17/2010

Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. Single doses up to 80 mg/kg/day in iron overloaded β-thalassemic patients have been tolerated with nausea and diarrhea noted. In healthy volunteers, single doses of up to 40 mg/kg/day were tolerated. There is no specific antidote for Exjade. In case of overdose, induce vomiting and employ gastric lavage.

Exjade is contraindicated in patients with:

• creatinine clearance < 40 mL/min or serum creatinine > 2 times the age-appropriate upper limit of normal;
• poor performance status and high-risk myelodysplastic syndromes or advanced malignancies [see WARNINGS AND PRECAUTIONS];
• platelet counts < 50 x 10⁹/L;
• known hypersensitivity to deferasirox or any component of Exjade.

Last updated on RxList: 2/17/2010

Mechanism of Action

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.

Pharmacodynamics

Pharmacodynamic effects tested in an iron balance metabolic study showed that deferasirox (10, 20 and 40 mg/kg per day) was able to induce a mean net iron excretion (0.119, 0.329 and 0.445 mg Fe/kg body weight per day, respectively) within the clinically relevant range (0.1-0.5 mg/kg per day). Iron excretion was predominantly fecal.

Pharmacokinetics

Absorption

Exjade is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5-4 hours. The Cmax and AUC of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3-2.3 after multiple doses. The absolute bioavailability (AUC) of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (AUC) of deferasirox was variably increased when taken with a meal.

Distribution

Deferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults.

Metabolism

Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalyzed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). Deconjugation of glucuronide metabolites in the intestine and subsequent reabsorption (enterohepatic recycling) was confirmed in a healthy volunteer study in which the administration of cholestyramine 12 g twice daily (strongly binds to deferasirox and its conjugates) 4 and 10 hours after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC) by interfering with the enterohepatic recycling of deferasirox.

Excretion

Deferasirox and metabolites are primarily (84% of the dose) excreted in the feces. Renal excretion of deferasirox and metabolites is minimal (8% of the administered dose). The mean elimination half-life (t½) ranged from 8-16 hours following oral administration.

Pharmacokinetics in Special Populations

Pediatric: Following oral administration of single or multiple doses, systemic exposure of adolescents and children to deferasirox was less than in adult patients. In children < 6 years of age, systemic exposure was about 50% lower than in adults.

Geriatric: The pharmacokinetics of deferasirox have not been studied in geriatric patients (65 years of age or older).

Gender: Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males.

Renal Insufficiency: Deferasirox is minimally (8%) excreted via the kidney.

Hepatic Impairment: Deferasirox is principally excreted by glucuronidation and is minimally (8%) metabolized by oxidative cytochrome P450 enzymes. Exjade treatment has been initiated in patients with baseline liver transaminase levels up to 5 times the upper limit of the normal range. The pharmacokinetics of deferasirox were not influenced by such transaminase levels.

QT Prolongation

The effect of 20 and 40 mg/kg per day of deferasirox on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo- and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female volunteers age 18-65 years. No evidence of prolongation of the QTc interval was observed in this study.

Clinical Studies

The primary efficacy study, Study 1, was a multicenter, open-label, randomized, active comparator control study to compare Exjade (deferasirox) and deferoxamine in patients with β-thalassemia and transfusional hemosiderosis. Patients ≥ 2 years of age were randomized in a 1:1 ratio to receive either oral Exjade at starting doses of 5, 10, 20 or 30 mg/kg once daily or subcutaneous Desferal (deferoxamine) at starting doses of 20 to 60 mg/kg for at least 5 days per week based on LIC (liver iron concentration) at baseline (2-3, > 3-7, > 7-14 and > 14 mg Fe/g dry weight). Patients randomized to deferoxamine who had LIC values < 7 mg Fe/g dry weight were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol.

Patients were to have a liver biopsy at baseline and end of study (after 12 months) for LIC. The primary efficacy endpoint was defined as a reduction in LIC of ≥ 3 mg Fe/g dry weight for baseline values ≥ 10 mg Fe/g dry weight, reduction of baseline values between 7 and < 10 to < 7 mg Fe/g dry weight, or maintenance or reduction for baseline values < 7 mg Fe/g dry weight.

A total of 586 patients were randomized and treated, 296 with Exjade and 290 with deferoxamine. The mean age was 17.1 years (range, 2-53 years); 52% were females and 88% were Caucasian. The primary efficacy population consisted of 553 patients (Exjade n=276; deferoxamine n=277) who had LIC evaluated at baseline and 12 months or discontinued due to an adverse event. The percentage of patients achieving the primary endpoint was 52.9% for Exjade and 66.4% for deferoxamine. The relative efficacy of Exjade to deferoxamine cannot be determined from this study.

In patients who had an LIC at baseline and at end of study, the mean change in LIC was -2.4 mg Fe/g dry weight in patients treated with Exjade and -2.9 mg Fe/g dry weight in patients treated with deferoxamine.

Reduction of LIC and serum ferritin was observed with Exjade doses of 20 to 30 mg/kg per day. Exjade doses below 20 mg/kg per day failed to provide consistent lowering of LIC and serum ferritin levels (Figure 1). Therefore, a starting dose of 20 mg/kg per day is recommended [see DOSAGE AND ADMINISTRATION].

Figure 1: Changes in Liver Iron Concentration and Serum Ferritin Following EXJADE (5-30 mg/kg per day) in Study 1

Study 2 was an open-label, noncomparative trial of efficacy and safety of Exjade given for 1 year to patients with chronic anemias and transfusional hemosiderosis. Similar to Study 1, patients received 5, 10, 20, or 30 mg/kg per day of Exjade based on baseline LIC.

A total of 184 patients were treated in this study: 85 patients with β-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). 19% of patients were < 16 years of age and 16% were ≥ 65 years of age. There was a reduction in the absolute LIC from baseline to end of study (-4.2 mg Fe/g dry weight).

Study 3 was a multicenter, open-label, randomized trial of the safety and efficacy of Exjade relative to deferoxamine given for 1 year in patients with sickle cell disease and transfusional hemosiderosis. Patients were randomized to Exjade at doses of 5, 10, 20, or 30 mg/kg per day or subcutaneous deferoxamine at doses of 20-60 mg/kg per day for 5 days per week according to baseline LIC.

A total of 195 patients were treated in this study: 132 with Exjade and 63 with deferoxamine. 44% of patients were < 16 years of age and 91% were Black. At end of study, the mean change in LIC (as measured by magnetic susceptometry by a superconducting quantum interference device) in the per protocol-1 (PP-1) population, which consisted of patients who had at least one postbaseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving Exjade (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54).

Last updated on RxList: 2/17/2010

Advise patients to take Exjade once daily on an empty stomach at least 30 minutes prior to food, preferably at the same time every day. Instruct patients to completely disperse the tablets in water, orange juice, or apple juice, and drink the resulting suspension immediately. After the suspension has been swallowed, resuspend any residue in a small volume of the liquid and swallow. Advise patients not to chew or swallow the tablets whole.

Advise patients not to chew tablets or swallow them whole.

Advise patients who experience diarrhea or vomiting to maintain adequate hydration.

Caution patients not to take aluminum-containing antacids and Exjade simultaneously.

Because auditory and ocular disturbances have been reported with Exjade, conduct auditory testing and ophthalmic testing before starting Exjade treatment and thereafter at regular intervals [see WARNINGS AND PRECAUTIONS].

Caution patients experiencing dizziness to avoid driving or operating machinery [see ADVERSE REACTIONS].

Caution patients about the potential for the development of GI ulcers or bleeding when taking Exjade in combination with drugs that have ulcerogenic or hemorrhagic potential, such as NSAIDs, corticosteroids, oral bisphosphonates, or anticoagulants.

Caution patients about potential loss of effectiveness of drugs metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptive agents) when Exjade is administered with these drugs.

Caution patients about potential loss of effectiveness of Exjade when administered with drugs that are potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). Based on serum ferritin levels and clinical response, consider increases in the dose of Exjade when concomitantly used with potent UGT inducers.

Perform careful monitoring of glucose levels when repaglinide is used concomitantly with Exjade. An interaction between Exjade and other CYP2C8 substrates like paclitaxel cannot be excluded.

Advise patients that blood tests will be performed because EXJADE may affect your kidneys, liver, or blood. The blood tests will be performed every month or more frequently if you are at increased risk of complications (e.g., pre-existing kidney condition, are elderly, have multiple medical conditions, or are taking medicine that affects your organs). There have been reports of severe kidney and liver problems, blood disorders, stomach bleeds and death in patients taking Exjade.

Skin rashes may occur during Exjade treatment and if severe treatment should be interrupted. Serious allergic reactions (which include swelling of the throat) have been reported in patients taking EXJADE, usually within the first month of treatment. If reactions are severe, advise patients to stop taking EXJADE and contact their doctor immediately.

Certain patients should not receive Exjade. These include patients with creatinine clearance < 40 mL/min or serum creatinine > 2 times the age-appropriate upper limit of normal, patients with poor performance status and high-risk myelodysplastic syndromes or advanced malignancies, patients with platelet counts < 50 x 109/L, and those with hypersensitivity to deferasirox or any component of Exjade.

Last updated on RxList: 2/17/2010

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

DEFERASIROX TABLET - FOR ORAL SUSPENSION

(deaf-ur-ES-ur-ox)

COMMON BRAND NAME(S): Exjade

USES: This medication is used to treat ongoing high levels of iron in the body caused by multiple blood transfusions. Deferasirox can be taken by mouth and belongs to a class of drugs known as iron chelating agents. It works by reacting with iron, allowing the body to pass extra iron out in the stool.

Frequent blood transfusions are often needed in certain types of blood diseases (e.g., thalassemia, sickle cell disease, anemia). Blood transfusions have very helpful benefits, but they can cause the body to hold on to too much iron. This extra iron can build up in various organs and cause problems such as heart failure, liver disease and diabetes. Getting rid of extra iron can decrease the risk of these diseases.

HOW TO USE: Stir the tablet(s) into water, orange juice or apple juice until the tablets have completely broken apart and are well mixed into the liquid. If your dose is less than 1 gram, stir the tablets into about 1/2 cup (3.5 ounces) of liquid. If your dose is more than 1 gram, use about 1 cup (7 ounces) of liquid. Drink all of the mixture immediately, then add more liquid to the empty container and stir to get any drug that may remain. Drink all of this rinsing liquid immediately.

Take this medication on an empty stomach at least 30 minutes before food, usually once daily or as directed by your doctor. Do not chew the tablets or swallow them whole. Always mix this medication into liquid as directed.

Certain antacids that contain aluminum may decrease the amount of medication that your body can absorb. If you take an antacid, wait at least 2 hours after taking this medication.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time each day. Dosage is based on your medical condition, body size and response to therapy.

SIDE EFFECTS: Nausea, vomiting, diarrhea, dizziness, headache, fever and abdominal pain may occur. If any of these effects persist or worsen, notify your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if any of these unlikely but serious side effects occur: trouble sleeping, hearing loss, unusual feelings of restlessness/high energy (hyperactivity), vision changes.

This drug may rarely cause serious liver disease. If you notice any of the following unlikely but very serious side effects, tell your doctor immediately: persistent nausea/vomiting, severe stomach/abdominal pain, dark urine, yellowing of eyes/skin.

This drug may rarely cause serious (even fatal) kidney or blood problems. The risk may be increased with serious blood diseases, kidney problems, or in older adults. Careful monitoring by your doctor may decrease your risk. Tell your doctor immediately if you notice any of the following symptoms: change in amount of urine, easy bleeding/bruising, signs of infection (e.g., fever, persistent sore throat), unusual tiredness.

A very serious allergic reaction to this drug is unlikely, but seek immediate medical attention if it occurs. Symptoms of a serious allergic reaction may include: rash, itching, swelling, severe dizziness, trouble breathing.

Deferasirox can commonly cause a mild rash that is usually not serious. However, you may not be able to tell it apart from a rare rash that could be a sign of a severe allergic reaction. Therefore, seek immediate medical attention if you develop any rash.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking deferasirox, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney problems, liver problems.

This drug may make you dizzy; use caution engaging in activities requiring alertness such as driving or using machinery. Limit alcoholic beverages.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, elderly people may be at greater risk for side effects while using this drug. Caution is advised when using this drug in the elderly because they may be more sensitive to its effects.

This medication should be used only when clearly needed during pregnancy. Discuss the risks and benefits with your doctor.

It is not known whether this drug passes into breast milk. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medication because very serious interactions may occur: other medications that remove iron from your body (e.g., deferoxamine).

If you are currently using the medication listed above, tell your doctor or pharmacist before starting deferasirox.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: antacids, any form of vitamin/mineral supplement.

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., serum ferritin, blood counts, liver and kidney function tests) will be performed before starting and while you are receiving treatment with this medication to monitor your progress or check for side effects. Hearing and eye exams may also be performed. Consult your doctor for more details.

MISSED DOSE: If you miss a dose, use it as soon as you remember. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

STORAGE: Store at room temperature at 77 degrees F (25 degrees C) away from light and moisture. Brief storage between 59-86 degrees F (15-30 degrees C) is permitted. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.