1.1 Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload)

Deferasirox tablets are indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older.

1.2 Treatment of Chronic Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

Deferasirox tablets are indicated for the treatment of chronic iron overload in patients 10 years of age and older with non-transfusion-dependent thalassemia (NTDT) syndromes and with a liver iron concentration (LIC) of at least 5 milligrams of iron per gram of liver dry weight (mg Fe/g dw) and a serum ferritin greater than 300 mcg/L.

1.3 Limitations of Use

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

2.1 Transfusional Iron Overload

Deferasirox therapy should only be considered when a patient has evidence of chronic transfusional iron overload. The evidence should include the transfusion of at least 100 mL/kg of packed red blood cells (e.g., at least 20 units of packed red blood cells for a 40 kg person or more in individuals weighing more than 40 kg), and a serum ferritin consistently greater than 1,000 mcg/L.

Prior to starting therapy, or increasing dose, evaluate:

• Serum ferritin level

• Baseline renal function:

o Obtain serum creatinine in duplicate (due to variations in measurements).

o Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).

o Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.1)] .

• Serum transaminases and bilirubin [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.2)]

• Baseline auditory and ophthalmic examinations [see Warnings and Precautions ( 5.10)]

Initiating Therapy:

The recommended initial dose of deferasirox tablets for patients 2 years of age and older with eGFR greater than 60 mL/min/1.73 m 2 is 14 mg per kg body weight orally, once daily. Calculate doses (mg per kg per day) to the nearest whole tablet. Changes in weight of pediatric patients over time must be taken into account when calculating the dose.

During Therapy:

• Monitor serum ferritin monthly and adjust the dose of deferasirox, if necessary, every 3 to 6 months based on serum ferritin trends.

• Use the minimum effective dose to achieve a trend of decreasing ferritin.

• Make dose adjustments in steps of 3.5 or 7 mg per kg and tailor adjustments to the individual patient’s response and therapeutic goals.

• In patients not adequately controlled with doses of 21 mg per kg (e.g., serum ferritin levels persistently above 2,500 mcg/L and not showing a decreasing trend over time), doses of up to 28 mg per kg may be considered. Doses above 28 mg per kg are not recommended [see Warnings and Precautions ( 5.6)] .

• Adjust dose based on serum ferritin levels

o If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction especially if the deferasirox dose is greater than 17.5 mg/kg/day [see Adverse Reactions ( 6.1)] .

o If the serum ferritin falls below 500 mcg/L, interrupt deferasirox therapy to minimize the risk of overchelation, and continue monthly monitoring [see Warnings and Precautions ( 5.6)] .

o Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions.

o Use the minimum effective dose to maintain iron burden in the target range [see Warnings and Precautions ( 5.6)] .

• Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions ( 5.1, 5.2, 5.4)] .

• Interrupt deferasirox for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration ( 2.4, 2.5), Warnings and Precautions ( 5.1), Use in Specific Populations ( 8.4), Clinical Pharmacology ( 12.3)] .

2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

Deferasirox therapy should only be considered when a patient with NTDT syndrome has an LIC of at least 5 mg Fe/g dw and a serum ferritin greater than 300 mcg/L.

Prior to starting therapy, obtain:

• LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy

• Serum ferritin level on at least 2 measurements 1-month apart [see Clinical Studies ( 14)]

• Baseline renal function:

o Obtain serum creatinine in duplicate (due to variations in measurements).

o Calculate the estimated glomerular filtration rate (eGFR). Use a prediction equation appropriate for adult patients (e.g., CKD-EPI, MDRD method) and in pediatric patients (e.g., Schwartz equations).

o Obtain urinalyses and serum electrolytes to evaluate renal tubular function [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.1)] .

• Serum transaminases and bilirubin [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.2)]

• Baseline auditory and ophthalmic examinations [see Warnings and Precautions ( 5.10)]

Initiating Therapy:

• The recommended initial dose of deferasirox for patients with eGFR greater than 60 mL/min/1.73 m 2  is 7 mg per kg body weight orally once daily. Calculate doses (mg per kg per day) to the nearest whole tablet.

• If the baseline LIC is greater than 15 mg Fe/g dw, consider increasing the dose to 14 mg/kg/day after 4 weeks.

During Therapy:

• Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions ( 5.6)] . Interrupt treatment when serum ferritin is less than 300 mcg/L and obtain an LIC to determine whether the LIC has fallen to less than 3 mg Fe/g dw.

• Use the minimum effective dose to achieve a trend of decreasing ferritin.

• Monitor LIC every 6 months.

• After 6 months of therapy, if the LIC remains greater than 7 mg Fe/g dw, increase the dose of deferasirox to a maximum of 14 mg/kg/day. Do not exceed a maximum of 14 mg/kg/day.

• If after 6 months of therapy, the LIC is 3 to 7 mg Fe/g dw, continue treatment with deferasirox at no more than 7 mg/kg/day.

• When the LIC is less than 3 mg Fe/g dw, interrupt treatment with deferasirox and continue to monitor the LIC.

• Monitor blood counts, liver function, renal function and ferritin monthly [see Warnings and Precautions ( 5.1, 5.2, 5.4)] .

• Increase monitoring frequency for pediatric patients who have acute illness, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal [see Dosage and Administration ( 2.4, 2.5), Warnings and Precautions ( 5.1), Use in Specific Populations ( 8.4), Clinical Pharmacology ( 12.3)] .

Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.

2.3 Administration

Swallow deferasirox tablets once daily with water or other liquids, preferably at the same time each day. Take deferasirox tablets on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories). Examples of light meals include 1 whole wheat English muffin, 1 packet jelly (0.5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. turkey on whole wheat bread w/ lettuce, tomato, and 1 packet mustard). Do not take deferasirox tablets with aluminum-containing antacid products [see Drug Interactions ( 7.1)] .

For patients who have difficulty swallowing whole tablets, deferasirox tablets may be crushed and mixed with soft foods (e.g., yogurt or applesauce) immediately prior to use and administered orally. Commercial crushers with serrated surfaces should be avoided for crushing a single 90 mg tablet. The dose should be immediately and completely consumed and not stored for future use.

For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox tablets, the dose should be about 30% lower, rounded to the nearest whole tablet. The table below provides additional information on dosing conversion to deferasirox tablets.



                                           

2.4 Use in Patients With Baseline Hepatic or Renal Impairment

Patients with Baseline Hepatic Impairment

Mild (Child-Pugh A) Hepatic Impairment: No dose adjustment is necessary.

Moderate (Child-Pugh B) Hepatic Impairment: Reduce the starting dose by 50%.

Severe (Child-Pugh C) Hepatic Impairment: Avoid deferasirox tablets [see Warnings and Precautions ( 5.2), Use in Specific Populations ( 8.7)] .

Patients with Baseline Renal Impairment

Do not use deferasirox in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m 2 [ see Dosage and Administration ( 2.5), Contraindications ( 4)].

For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2), reduce the starting dose by 50% [see Use in Specific Populations ( 8.6)] .

Exercise caution in pediatric patients with eGFR between 40 and 60 mL/minute/1.73 m 2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations ( 8.6)] .

2.5 Dose Modifications for Decreases in Renal Function While on Deferasirox Tablets

Deferasirox tablets are contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2[see Contraindications ( 4)] .

For decreases in renal function while receiving deferasirox tablets [see Warnings and Precautions (5.1)], modify the dose as follows:

Transfusional Iron Overload

Adults:

• If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg.



Pediatric Patients (ages 2 years to 17 years):

• Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week.

• Interrupt deferasirox tablets for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions ( 5.1)] .

• In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox tablets use. Use the minimum effective deferasirox tablets dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic-therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox tablets to prevent severe and irreversible renal injury [see Warnings and Precautions ( 5.1)] .

All Patients (regardless of age):

•  Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2 [see Contraindications ( 4)] .

Non-Transfusion-Dependent Thalassemia Syndromes

Adults:

• If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, interrupt therapy if the dose is 3.5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg.

Pediatric Patients (ages 10 years to 17 years):

• Reduce the dose by 3.5 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat the eGFR within 1 week.

• Increase monitoring frequency for pediatric patients who have acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake. Consider dose interruption until oral intake and volume status are normal. Avoid use of other nephrotoxic drugs [see Warnings and Precautions ( 5.1)] .

• In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox tablets use. Use the minimum effective deferasirox tablets dose and monitor renal function more frequently, by evaluating tubular and glomerular function. Titrate dosing based on renal injury. Consider dose reduction or interruption and less nephrotoxic therapies until improvement of renal function. If signs of renal tubular or glomerular injury occur in the presence of other risk factors such as volume depletion, reduce or interrupt deferasirox tablets to prevent severe and irreversible renal injury [see Warnings and Precautions ( 5.1)].

All Patients (regardless of age):

• Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2[see Contraindications ( 4)].

2.6 Dose Modifications Based on Concomitant Medications

UDP-glucuronosyltransferases (UGT) Inducers

Concomitant use of UGT inducers decreases systemic exposure. Avoid the concomitant use of strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir). If you must administer deferasirox tablets with a strong UGT inducer, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration ( 2.1, 2.2), Drug Interactions ( 7.5)] .

Bile Acid Sequestrants

Concomitant use of bile acid sequestrants decreases systemic exposure. Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol). If you must administer deferasirox tablets with a bile acid sequestrant, consider increasing the initial dose by 50%, and monitor serum ferritin levels and clinical responses for further dose modification [see Dosage and Administration ( 2.1, 2.2), Drug Interactions ( 7.6)] .

5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis and Renal Tubular Toxicity Including Fanconi Syndrome

Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2. Exercise caution in pediatric patients with eGFR between 40 and 60 mL/min/1.73 m 2. If treatment is needed, use the minimum effective dose and monitor renal function frequently. Individualize dose titration based on improvement in renal injury [see Use in Specific Populations ( 8.6)] . For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2) reduce the starting dose by 50% [see Dosage and Administration ( 2.4, 2.5), Use in Specific Populations ( 8.6)] .

Deferasirox can cause acute kidney injury including renal failure requiring dialysis that has resulted in fatal outcomes. Based on postmarketing experience, most fatalities have occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, adults and pediatric deferasirox-treated patients with no preexisting renal disease experienced dose-dependent mild, non-progressive increases in serum creatinine and proteinuria. Preexisting renal disease and concomitant use of other nephrotoxic drugs may increase the risk of acute kidney injury in adult and pediatric patients. Acute illnesses associated with volume depletion and overchelation may increase the risk of acute kidney injury in pediatric patients. In pediatric patients, small decreases in eGFR can result in increases in deferasirox exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox tablets for oral suspension exposure, unless the dose is reduced or interrupted. Renal tubular toxicity, including acquired Fanconi syndrome, has been reported in patients treated with deferasirox, most commonly in pediatric patients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L [see Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1, 6.2), Use in Specific Populations ( 8.4), Clinical Pharmacology ( 12.3)] .

Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. Obtain serum electrolytes and urinalysis in all patients to evaluate renal tubular function [see Dosage and Administration ( 2.1, 2.2)] .

Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden. Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt deferasirox during acute illnesses, which can cause volume depletion such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently. Promptly correct fluid deficits to prevent renal injury. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1, 6.2), Use in Specific Populations ( 8.4)] .

5.2 Hepatic Toxicity and Failure

Deferasirox can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure [see Adverse Reactions ( 6.1)] .

Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox-treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume-depleting event. Interrupt  deferasirox therapy when acute liver injury or acute kidney injury is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving deferasirox in the 14 to 28 mg/kg/day range and when iron burden is approaching normal. Use the minimum effective dose to achieve and maintain a low iron burden [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.6), Adverse Reactions ( 6.1)] .

Measure transaminases [aspartate transaminase (AST) and alanine transaminase (ALT)] and bilirubin in all patients before the initiation of treatment and every 2 weeks during the first month and at least monthly thereafter. Consider dose modifications or interruption of treatment for severe or persistent elevations.

Avoid the use of deferasirox in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment [see Dosage and Administration ( 2.4), Use in Specific Populations ( 8.7)] . Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.

5.3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation

GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox [see Adverse Reactions ( 6.1)] . Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. The risk of GI hemorrhage may be increased when administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants. There have been reports of ulcers complicated with GI perforation (including fatal outcome) [see Adverse Reactions ( 6.2)] .

5.4 Bone Marrow Suppression

Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk. Monitor blood counts in all patients. Interrupt treatment with deferasirox in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox is contraindicated in patients with platelet counts below 50 x 10 9/L.

5.5 Age-Related Risk of Toxicity

Elderly Patients

Deferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with deferasirox more frequently for toxicity [see Use in Specific Populations ( 8.5)] .

Pediatric Patients

Deferasirox has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting. These events were frequently associated with volume depletion or with continued deferasirox tablets for oral suspension doses in the 20 to 40 mg/kg/day range equivalent to 14 to 28 mg/kg/day deferasirox when body iron burden was approaching or in the normal range. Interrupt deferasirox in patients with volume depletion, and resume deferasirox when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox in the 14 to 28 mg/kg/day range when iron burden is approaching the normal range. Use the minimum effective dose to achieve and maintain a low iron burden [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.6), Use in Specific Populations ( 8.4)] .

5.6 Overchelation

For patients with transfusional iron overload, measure serum ferritin monthly to assess the patient’s response to therapy and minimize the risk of overchelation. An analysis of pediatric patients treated with deferasirox tablets for oral suspensionin pooled clinical trials (n = 158), found a higher rate of renal adverse reactions among patients receiving doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox while their serum ferritin values were less than 1,000 mcg/L. Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. Use the minimum effective dose to maintain a low-iron burden [see Adverse Reactions ( 6.1), Use in Specific Populations ( 8.4)].

If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the deferasirox dose is greater than 17.5 mg/kg/day [see Adverse Reactions ( 6.1)] .

If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox and continue monthly monitoring. Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range. Continued administration of deferasirox in the 14 to 28 mg/kg/day range, when the body iron burden is approaching or within the normal range can result in life-threatening adverse reactions [see Dosage and Administration ( 2.1)].

For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment. Interrupt deferasirox administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt deferasirox and obtain a confirmatory LIC [see Clinical Studies ( 14)].

5.7 Hypersensitivity

Deferasirox may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment [see Adverse Reactions ( 6.2)] . If reactions are severe, discontinue deferasirox and institute appropriate medical intervention. Deferasirox is contraindicated in patients with known hypersensitivity to deferasirox products and should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock.

5.8 Severe Skin Reactions

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) which could be life-threatening or fatal have been reported during deferasirox therapy [see Adverse Reactions ( 6.1, 6.2)] . Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue deferasirox immediately and do not reintroduce deferasirox therapy.

5.9 Skin Rash

Rashes may occur during deferasirox treatment [see Adverse Reactions ( 6.1)] .

For rashes of mild to moderate severity, deferasirox may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.

5.10 Auditory and Ocular Abnormalities

Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of less than 1% with deferasirox therapy in the clinical studies. The frequency of auditory adverse reactions was increased among pediatric patients, who received deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when serum ferritin was less than 1,000 mcg/L [see Warnings and Precautions ( 5.6)] .

Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting deferasirox treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.

6.1 Clinical Trials Experience

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. Deferasirox was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with deferasirox tablets. Deferasirox tablets contains the same active ingredient as deferasirox tablets for oral suspension. The following adverse reactions have been reported with deferasirox tablets for oral suspension.

Transfusional Iron Overload

A total of 700 adult and pediatric patients were treated with deferasirox for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian, and 292 patients were less than 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 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88 to 205 weeks.

Six hundred twenty-seven (627) patients with myelodysplastic syndrome (MDS) were enrolled across 5 uncontrolled trials. These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (Adverse Events (AEs) 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%). Among 47 patients enrolled in the study of 5-year duration, 10 remained on deferasirox at the completion of the study.

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

Table 1. Adverse Reactions a Occurring in > 5% of Deferasirox-treated Patients in Study 1, Study 3, and MDS Pool

In Study 1, a total of 113 (38%) patients treated with deferasirox had increases in serum creatinine greater than 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 ( 5.1)] . In this study, 17 (6%) patients treated with deferasirox developed elevations in serum glutamic-pyruvic transaminase (SGPT)/ALT levels greater than 5 times the upper limit of normal (ULN) at 2 consecutive visits. Of these, 2 patients had liver biopsy proven drug-induced hepatitis and both discontinued deferasirox therapy [see Warnings and Precautions ( 5.2)] . An additional 2 patients, who did not have elevations in SGPT/ALT greater than 5 times the ULN, discontinued deferasirox 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 deferasirox had increases in serum creatinine greater than 33% above baseline on 2 separate occasions (Table 2) [see Warnings and Precautions ( 5.1)] .

Of the patients who experienced creatinine increases in Study 3, 8 deferasirox-treated patients required dose reductions. In this study, 5 patients in the deferasirox group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox permanently discontinued. Four additional patients discontinued due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash.

In the MDS pool, in the first year, a total of 229 (37%) patients treated with deferasirox had increases in serum creatinine greater than 33% above baseline on 2 consecutive occasions (Table 2) and 8 (3.5%) patients permanently discontinued [see Warnings and Precautions ( 5.1)] . A total of 5 (0.8%) patients developed SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits. The most frequent adverse reactions that led to discontinuation included increases in serum creatinine, diarrhea, nausea, rash, and vomiting. Death was reported in the first year in 52 (8%) of patients [see Clinical Studies ( 14)].

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

                                                                   

Non-Transfusion-Dependent Thalassemia Syndromes

In Study 5, 110 patients with NTDT received 1 year of treatment with deferasirox 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 6, 130 of the patients who completed Study 5 were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies ( 14)] . Table 3 and 4 display the frequency of adverse reactions in patients with NTDT. Adverse reactions with a suspected relationship to study drug were included in Table 3 if they occurred at ≥ 5% of patients in Study 5.

Table 3. Adverse Reactions Occurring in Greater Than 5% Patients with NTDT

                                                

In Study 5, 1 patient in the placebo 10 mg/kg/day group experienced an ALT increase to greater than 5 times ULN and greater than 2 times baseline (Table 4). Three deferasirox-treated patients (all in the 10 mg/kg/day group) had 2 consecutive serum creatinine level increases greater than 33% from baseline and greater than ULN. Serum creatinine returned to normal in all 3 patients (in 1 spontaneously and in the other 2 after drug interruption). Two additional cases of ALT increase and 2 additional cases of serum creatinine increase were observed in the 1-year extension of Study 5. The number (%) of patients with NTDT with increase in serum creatinine or SGPT/ALT in Study 5 and Study 6 are presented in Table 4 below .

Table 4. Number (%) of Patients with NTDT with Increases in Serum Creatinine or SGPT/ALT

Proteinuria

In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) occurred in 18.6% of deferasirox-treated patients compared to 7.2% of deferoxamine-treated patients in Study 1 [see Warnings and Precautions ( 5.1)].

Other Adverse Reactions

In the population of more than 5,000 patients with transfusional iron overload, who have been treated with deferasirox 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, laryngeal pain, cataract, hearing loss, GI hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi syndrome), and acute pancreatitis (with and without underlying biliary conditions). Adverse reactions occurring in 0.01% to 0.1% of patients included optic neuritis, esophagitis, erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS). Adverse reactions, which most frequently led to dose interruption or dose adjustment during clinical trials were rash, GI disorders, infections, increased serum creatinine, and increased serum transaminases.

Pooled Analysis of Pediatric Clinical Trial Data

A nested case control analysis was conducted within a deferasirox tablets for oral suspension pediatric-pooled clinical trial dataset to evaluate the effects of dose and serum ferritin level, separately and combined, on kidney function. Among 1213 children (aged 2 to 15 years) with transfusion-dependent thalassemia, 162 cases of acute kidney injury (eGFR < 90 mL/min/1.73 m 2) and 621 matched-controls with normal kidney function (eGFR > 120 mL/min/1.73 m 2) were identified. The primary findings were:

— A 26% increased risk of acute kidney injury was observed with each 5 mg/kg increase in daily deferasirox dosage equivalent to 3.5 mg/kg deferasirox, starting at 20 mg/kg/day equivalent to 14 mg/kg/day deferasirox (95% confidence interval (CI): 1.08 to 1.48).

— A 25% increased risk for acute kidney injury was observed with each 250 mcg/L decrease in serum ferritin starting at 1250 mcg/L (95% CI: 1.01 to 1.56).

— Among pediatric patients with a serum ferritin < 1,000 mcg/L, those who received deferasirox dosage > 30 mg/kg/day, equivalent to 21 mg/kg/day deferasirox compared to those who received lower dosages, had a higher risk for acute kidney injury (Odds ratio (OR) = 4.47, 95% CI: 1.25 to 15.95), consistent with overchelation.

In addition, a cohort-based analysis of ARs was conducted in the deferasirox tablets for oral suspension pediatric pooled clinical trial data. Pediatric patients who received deferasirox tablets for oral suspension dose > 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when their serum ferritin was < 1,000 mcg/L (n = 158), had a 6-fold greater rate of renal adverse reactions (Incidence Rate Ratio (IRR) = 6.00, 95% CI: 1.75 to 21.36), and a 2-fold greater rate of dose interruptions (IRR = 2.06, 95% CI: 1.33 to 3.17) compared to the time-period prior to meeting these simultaneous criteria. Adverse reactions of special interest (cytopenia, renal, hearing, and GI disorders) occurred 1.9-fold more frequently when these simultaneous criteria were met, compared to preceding time-periods (IRR = 1.91, 95% CI: 1.05 to 3.48) [see Warnings and Precautions ( 5.6)] .

Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's JADENU (desferasirox) tablets and granules. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

6.2 Postmarketing Experience

The following adverse reactions have been spontaneously reported during post-approval use of deferasirox in the transfusional iron overload setting. 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: Stevens-Johnson syndrome (SJS), leukocytoclastic vasculitis, urticaria, alopecia, toxic epidermal necrolysis (TEN)

Immune System Disorders: hypersensitivity reactions (including anaphylactic reaction and angioedema)

Renal and Urinary Disorders: acute renal failure, tubulointerstitial nephritis

Hepatobiliary Disorders: hepatic failure

GI Disorders: GI perforation

Blood and Lymphatic System Disorders: worsening anemia

5-Year Pediatric Registry

In a 5-year observational study, 267 pediatric patients 2 to < 6 years of age (at enrollment) with transfusional hemosiderosis received deferasirox. Of the 242 patients who had pre-and post-baseline eGFR measurements, 116 (48%) patients had a decrease in eGFR of ≥ 33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days. Adverse reactions leading to permanent discontinuation from the study included liver injury (n = 11), vomiting (n = 2), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper GI hemorrhage (n = 1), abdominal pain (n = 1), and hypokalemia (n = 1).

7.1 Aluminum-Containing Antacid Preparations

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

7.2 Agents Metabolized by CYP3A4

Deferasirox may induce CYP3A4 resulting in a decrease in CYP3A4 substrate concentration when these drugs are coadministered. Closely monitor patients for signs of reduced effectiveness when deferasirox is administered with drugs metabolized by CYP3A4 (e.g., alfentanil, aprepitant, budesonide, buspirone, conivaptan, cyclosporine, darifenacin, darunavir, dasatinib, dihydroergotamine, dronedarone, eletriptan, eplerenone, ergotamine, everolimus, felodipine, fentanyl, hormonal contraceptive agents, indinavir, fluticasone, lopinavir, lovastatin, lurasidone, maraviroc, midazolam, nisoldipine, pimozide, quetiapine, quinidine, saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, tolvaptan, tipranavir, triazolam, ticagrelor, and vardenafil) [see Clinical Pharmacology ( 12.3)] .

7.3 Agents Metabolized by CYP2C8

Deferasirox inhibits CYP2C8 resulting in an increase in CYP2C8 substrate (e.g., repaglinide and paclitaxel) concentration when these drugs are coadministered. If deferasirox and repaglinide are used concomitantly, consider decreasing the dose of repaglinide and perform careful monitoring of blood glucose levels. Closely monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other CYP2C8 substrates [ see Clinical Pharmacology ( 12.3)] .

7.4 Agents Metabolized by CYP1A2

Deferasirox inhibits CYP1A2 resulting in an increase in CYP1A2 substrate (e.g., alosetron, caffeine, duloxetine, melatonin, ramelteon, tacrine, theophylline, tizanidine) concentration when these drugs are coadministered. An increase in theophylline plasma concentrations could lead to clinically significant theophylline induced CNS or other adverse reactions. Avoid the concomitant use of theophylline or other CYP1A2 substrates with a narrow therapeutic index (e.g., tizanidine) with deferasirox. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with deferasirox. Closely monitor patients for signs of exposure related toxicity when deferasirox is coadministered with other drugs metabolized by CYP1A2 [see Clinical Pharmacology ( 12.3)] .

7.5 Agents Inducing UDP-glucuronosyltransferase (UGT) Metabolism

Deferasirox is a substrate of UGT1A1 and to a lesser extent UGT1A3. The concomitant use of deferasirox with strong UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of strong UGT inducers with deferasirox. Consider increasing the initial dose of deferasirox if you must coadminister these agents together [see Dosage and Administration ( 2.5), Clinical Pharmacology ( 12.3)] .

7.6 Bile Acid Sequestrants

Avoid the concomitant use of bile acid sequestrants (e.g., cholestyramine, colesevelam, colestipol) with deferasirox due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of deferasirox [see Dosage and Administration ( 2.5), Clinical Pharmacology ( 12.3)] .

7.7 Busulfan

Increased exposure of busulfan was observed with concomitant use with deferasirox. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed [see Clinical Pharmacology ( 12.3)] .

8.1 Pregnancy

Administration of deferasirox to rats during pregnancy resulted in decreased offspring viability and an increase in renal anomalies in male offspring at doses that were about or less than the recommended human dose on a mg/m 2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on an mg/m 2 basis. Deferasirox should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies had a background risk of birth defect, loss, or other adverse outcomes. However, the background risk in the U.S. general population of major birth defects is 2% to 4% and of miscarriage is 15% to 20% of clinically recognized pregnancies.

Data

Animal Data

In embryo-fetal 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 (1.2 times the maximum recommended human dose (MRHD) on an mg/m 2 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 of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m 2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m 2 basis), and increases in renal anomalies in male offspring occurred at

30 mg/kg/day (0.3 times the MRHD on a mg/m 2 basis).

8.2 Lactation

Risk Summary

No data are available regarding the presence of deferasirox or its metabolites in human milk, the effects of the drug on the breastfed child, or the effects of the drug on milk production. 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 a breastfeeding child from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.

8.3 Females and Males of Reproductive Potential

Contraception

Counsel patients to use non-hormonal method(s) of contraception since deferasirox can render hormonal contraceptives ineffective [see Drug Interactions ( 7.2)] .

8.4 Pediatric Use

Transfusional Iron Overload

The safety and effectiveness of deferasirox have been established in pediatric patients 2 years of age and older for the treatment of transfusional iron overload [see Dosage and Administration ( 2.1)] .

Safety and effectiveness have not been established in pediatric patients less than 2 years of age for the treatment of transfusional iron overload.

Pediatric approval for treatment of transfusional iron overload was based on clinical studies of 292 pediatric patients 2 years to less than 16 years of age with various congenital and acquired anemias. Seventy percent of these patients had beta-thalassemia [see Indications and Usage ( 1), Dosage and Administration ( 2.1), Clinical Studies ( 14)] . In those clinical studies, 173 children (ages 2 to < 12 years) and 119 adolescents (ages 12 to < 17 years) were exposed to deferasirox.

Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes

The safety and effectiveness of deferasirox have been established in patients 10 years of age and older for the treatment of chronic iron overload with non-transfusion-dependent thalassemia (NTDT) syndromes [see Dosage and Administration ( 2.2)].

Safety and effectiveness have not been established in patients less than 10 years of age with chronic iron overload in NTDT syndromes.

Pediatric approval for treatment of NTDT syndromes with liver iron (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight and a serum ferritin greater than 300 mcg/L was based on 16 pediatric patients treated with deferasirox therapy (10 years to less than 16 years of age) with chronic iron overload and NTDT. Use of deferasirox in these age groups is supported by evidence from adequate and well-controlled studies of deferasirox in adult and pediatric patients [see Indications and Usage ( 1.2), Dosage and Administration ( 2.2), Clinical Studies ( 14)].

In general, risk factors for deferasirox-associated kidney injury include preexisting renal disease, volume depletion, overchelation, and concomitant use of other nephrotoxic drugs. Acute kidney injury, and acute liver injury and failure has occurred in pediatric patients. In a pooled safety analysis, pediatric patients with higher deferasirox exposures had a greater probability of renal toxicity and decreased renal function, resulting in increased deferasirox exposure and progressive renal toxicity/kidney injury. Higher rates of renal AEs have been identified among pediatric patients receiving deferasirox tablets for oral suspension doses greater than 25 mg/kg/day equivalent to 17.5 mg/kg/day deferasirox when their serum ferritin values were less than 1,000 mcg/L [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.1, 5.6), Adverse Reactions ( 6.1, 6.2)] .

Monitoring recommendations for all pediatric patients with Transfusional Iron Overload and NTDT

It is recommended that serum ferritin be monitored every month to assess the patient’s response to therapy and to minimize the risk of overchelation [see Warnings and Precautions ( 5.6)] . 

Monitor renal function by estimating GFR using an eGFR prediction equation appropriate for pediatric patients and evaluate renal tubular function. Monitor renal function more frequently in pediatric patients in the presence of renal toxicity risk factors, including episodes of dehydration, fever and acute illness that may result in volume depletion or decreased renal perfusion. Use the minimum effective dose [see Warnings and Precautions ( 5.1)] .

Interrupt deferasirox in pediatric patients with transfusional iron overload, and consider dose interruption in pediatric patients with non-transfusion-dependent iron overload, for acute illnesses, which can cause volume depletion, such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor more frequently. Resume therapy as appropriate, based on assessments of renal function, when oral intake and volume status are normal. Evaluate the risk benefit profile of continued deferasirox use in the setting of decreased renal function. Avoid use of other nephrotoxic drugs [see Dosage and Administration ( 2.5), Warnings and Precautions ( 5.1)] .

Juvenile Animal Toxicity Data

Renal toxicity was observed in adult mice, rats, and marmoset monkeys administered deferasirox at therapeutic doses. In a neonatal and juvenile toxicity study in rats, deferasirox was administered orally from postpartum Day 7 through 70, which equates to a human age range of term neonate through adolescence. Increased renal toxicity was identified in juvenile rats compared to adult rats at a dose based on mg/m 2 approximately 0.4 times the recommended dose of 20 mg/kg/day. A higher frequency of renal abnormalities was noted when deferasirox was administered to non-iron overloaded animals compared to iron overloaded animals.



Additional pediatric use information is approved for Novartis Pharmaceuticals Corporation's JADENU (deferasirox) tablets and granules. However, due to Novartis Pharmaceuticals Corporation's marketing exclusivity rights, this drug product is not labeled with that information.

8.5 Geriatric Use

Four hundred thirty-one (431) patients greater than or equal to 65 years of age were studied in clinical trials of deferasirox in the transfusional iron overload setting. Two hundred twenty-five (225) of these patients were between 65 and 75 years of age while 206 were greater than or equal to 75 years of age. 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. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

In elderly patients, including those with MDS, individualize the decision to remove accumulated iron based on clinical circumstances and the anticipated clinical benefit and risks of deferasirox tablets for oral suspension therapy.

8.6 Renal Impairment

Deferasirox is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2[see Contraindications ( 4)] . For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2), reduce the starting dose by 50% [see Dosage and Administration ( 2.4), Clinical Pharmacology ( 12.3)] .

Exercise caution in pediatric patients with an eGFR between 40 and 60 mL/min/1.73 m 2 [see Dosage and Administration ( 2.4)] .

If treatment is needed, use the minimum effective dose with enhanced monitoring of glomerular and renal tubular function. Individualize dose titration based on improvement in renal injury [see Dosage and Administration ( 2.4, 2.5)] .

Deferasirox can cause glomerular dysfunction, renal tubular toxicity, or both, and can result in acute renal failure. Monitor all patients closely for changes in eGFR and renal tubular dysfunction during deferasirox treatment. If either develops, consider dose reduction, interruption or discontinuation of deferasirox until glomerular or renal tubular function returns to baseline [see Dosage and Administration ( 2.4, 2.5), Warnings and Precautions ( 5.1)] .

8.7 Hepatic Impairment

Avoid use in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, reduce the starting dose by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration [see Dosage and Administration ( 2.4), Warnings and Precautions ( 5.2), Clinical Pharmacology ( 12.3)] .

12.1 Mechanism of Action

Deferasirox is an orally active chelator that is selective for iron (as Fe 3+). 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.

12.2 Pharmacodynamics

Pharmacodynamic effects tested in an iron balance metabolic study with the tablet for oral suspension formulation showed that deferasirox (10, 20, and 40 mg per 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 to 0.5 mg per kg per day). Iron excretion was predominantly fecal.

An analysis of pooled pediatric clinical trial data found a statistically significant relationship between exposure and the probability of renal toxicity (increase in serum creatinine and urinary protein), resulting in a decrease in renal function. Decreases in renal function resulted in an increase in deferasirox exposure which may increase the probability of renal toxicity.

Cardiac Electrophysiology

At the maximum approved recommended dose, deferasirox does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Absorption

Based on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (T max) of about 1.5 to 4 hours. In healthy subjects, deferasirox showed comparable T max. The maximal concentrations(C max) and area under the curve (AUC 0  to 24 h, AUC τ) 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 to 2.3 after multiple doses with the tablet for oral suspension formulation.

Tablets

The absolute bioavailability [as measured by area under the curve over time to infinity (AUC inf)] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUC inf) of deferasirox tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUC inf of deferasirox tablets (i.e., 360 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however the mean C max was increased by 30%. The 30% increase in C max observed with deferasirox tablets is not clinically meaningful.

The administration of deferasirox tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUC inf and C max were similar to that under fasting conditions. The administration of deferasirox tablets with a high-fat meal (approximately 1,000 calories with fat content greater than 50% of total calories), increased AUC inf by 18% and C max by 29% compared to that under fasting conditions [see Dosage and Administration ( 2.3)] .

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 (V ss) 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 subjects 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 inf) 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 dose). The mean elimination half-life (t 1/2) ranged from 8 to 16 hours following oral administration.

Drug Interactions

Midazolam: The concomitant administration of deferasirox tablets for oral suspension and CYP3A4 probe substrate midazolam resulted in a decrease of midazolam C max by 23% and AUC inf by 17%. In the clinical setting, this effect may be more pronounced, as the study was not adequately designed to conclusively assess the potential induction of CYP3A4 by deferasirox [see Drug Interactions ( 7.2)] .

Repaglinide: The concomitant administration of deferasirox tablets for oral suspension (30 mg per kg/day for 4 days) and the CYP2C8 probe substrate repaglinide (single dose of 0.5 mg) increased repaglinide AUC inf to 2.3-fold and C max of 1.6-fold [see Drug Interactions ( 7.3)] .

Theophylline: The concomitant administration of deferasirox tablets for oral suspension (repeated dose of 30 mg per kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an approximate doubling of the theophylline AUC inf and elimination half-life. The single dose C max was not affected, but an increase in theophylline C max is expected to occur with chronic dosing [see Drug Interactions ( 7.4) ].

Rifampicin: The concomitant administration of deferasirox tablets for oral suspension (single dose of 30 mg per kg) and the strong uridine diphosphate glucuronosyltransferase (UGT) inducer rifampicin (600 mg per day for 9 days) decreased deferasirox AUC inf by 44% [see Drug Interactions ( 7.5)] .

Cholestyramine: The concomitant administration of cholestyramine after a single dose of deferasirox tablets for oral suspension decreased deferasirox AUC inf by 45% [see Drug Interactions ( 7.6)] .

Busulfan: Concomitant administration of deferasirox and busulfan resulted in an increase of busulfan exposure (AUC).

In vitro Studies : Deferasirox inhibited human CYP2A6, CYP2D6, and CYP2C19 in vitro.

Deferasirox is not a substrate of P-glycoprotein, MRP1 or MRP2.

Pharmacokinetics in Specific 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 less than 6 years of age, systemic exposure was about 50% lower than in adults.

Sex: The apparent clearance is 17.5% lower in females compared to males.

Renal Impairment: Compared to patients with MDS and eGFR greater than 60 mL/min/1.73 m 2, patients with MDS and eGFR 40 to 60 mL/min/1.73 m 2 (n = 34) had approximately 50% higher mean deferasirox trough plasma concentrations.

Hepatic Impairment: In a single dose (20 mg/kg) study in patients with varying degrees of hepatic impairment, deferasirox exposure was increased compared to patients with normal hepatic function. The average total (free and bound) AUC inf of deferasirox increased 16% in 6 patients with mild (Child-Pugh A) hepatic impairment, and 76% in 6 patients with moderate (Child-Pugh B) hepatic impairment compared to 6 patients with normal hepatic function. The impact of severe (Child-Pugh C) hepatic impairment was assessed in only 1 patient.

13.1 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/day (0.7 times the MRHD on an mg/m 2 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/day (1.2 times the MRHD on a mg/m 2 basis) in males and 300 mg/kg/day (1.7 times the MRHD on a mg/m 2 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/day (0.9 times the MRHD on a mg/m 2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.