DEFERASIROX: 11,322 Adverse Event Reports & Safety Profile

Deferasirox is an iron-chelating agent provided as a tablet for oral use. Deferasirox is designated chemically as 4-[3,5-bis(2-hydroxyphenyl)-1H-1,2,4-triazol-1-yl]benzoic acid and has the following structural formula: Deferasirox is a white to slightly yellow color powder. It has a molecular formula C 21 H 15 N 3 O 4 and molecular weight of 373.36 g/mol. It is freely soluble in dimethyl formamide, sparingly soluble in dimethylsulfoxide and practically insoluble in water with a pH of suspension of 4.1. Each deferasirox tablet contains 90 mg, 180 mg or 360 mg deferasirox and contains following Inactive ingredients: colloidal silicon dioxide, croscarmellose sodium, hypromellose, polyethylene glycol, magnesium stearate, microcrystalline cellulose, povidone K30, poloxamer 407, talc and titanium dioxide. Additionally, each 180 mg and 360 mg tablet contains FD&C blue # 2/Indigo Carmine Aluminum Lake; each 180 mg tablet contains iron oxide yellow and each 360 mg tablets contain D&C red #27/Phloxine Aluminum Lake. Image

AND USAGE Deferasirox is an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older. ( 1.1 ) Deferasirox is 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 (Fe) concentration (LIC) of at least 5 mg Fe per gram of dry weight (Fe/g dw) and a serum ferritin greater than 300 mcg/L. Limitations of Use: The safety and efficacy of deferasirox when administered with other iron chelation therapy have not been established. ( 1.3 )

1.1 Treatment of Chronic Iron Overload Due to Blood Transfusions (Transfusional Iron Overload) Deferasirox oral granules 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 oral granules is 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. This indication is approved under accelerated approval based on a reduction of liver iron concentrations (to less than 5 mg Fe/g dw) and serum ferritin levels <span class="opacity-50 text-xs">[see Clinical Studies ( 14 )]</span>. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

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

AND ADMINISTRATION Transfusional Iron Overload: Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m 2 is 14 mg per kg (calculated to nearest whole tablet or nearest whole sachet content for granules) once daily. ( 2.1 )

Ntdt

Syndromes: Initial dose for patients with eGFR greater than 60 mL/min/1.73 m 2 is 7 mg per kg (calculated to nearest whole tablet or nearest whole sachet content for granules) once daily. ( 2.2 ) See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment. ( 2.1 , 2.2 , 2.3 , 2.4 )

2.1 Transfusional Iron Overload JADENU 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: Obtain serum creatinine in duplicate (due to variations in measurements). 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). Obtain urinalyses and serum electrolytes to evaluate renal tubular function <span class="opacity-50 text-xs">[see Dosage and Administration (2.4), Warnings and Precautions (5.1)]</span> . Serum transaminases and bilirubin <span class="opacity-50 text-xs">[see Dosage and Administration (2.4), Warnings and Precautions (5.2)]</span> Baseline auditory and ophthalmic examinations <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10)]</span>

Initiating

Therapy: The recommended initial dose of JADENU 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 or nearest whole sachet content for granules. 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 JADENU, 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 If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction especially if the JADENU dose is greater than 17.5 mg/kg/day [see Adverse Reactions (6.1)] . If the serum ferritin falls below 500 mcg/L, interrupt JADENU therapy to minimize the risk of overchelation, and continue monthly monitoring [see Warnings and Precautions (5.6)] . Evaluate the need for ongoing chelation therapy for patients whose conditions no longer require regular blood transfusions. 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 JADENU 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 JADENU 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 <span class="opacity-50 text-xs">[see Clinical Studies (14)]</span> Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements). 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). Obtain urinalyses and serum electrolytes to evaluate renal tubular function <span class="opacity-50 text-xs">[see Dosage and Administration (2.4), Warnings and Precautions (5.1)]</span>. Serum transaminases and bilirubin <span class="opacity-50 text-xs">[see Dosage and Administration (2.4), Warnings and Precautions (5.2)]</span> Baseline auditory and ophthalmic examinations <span class="opacity-50 text-xs">[see Warnings and Precautions (5.10)]</span>

Initiating

Therapy: The recommended initial dose of JADENU 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 or nearest whole sachet content for granules. 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 JADENU tablets once daily with water or other liquids, preferably at the same time each day. Take JADENU 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 JADENU tablets with aluminum-containing antacid products <span class="opacity-50 text-xs">[see Drug Interactions (7.1)]</span> . For patients who have difficulty swallowing whole tablets, JADENU 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. Take JADENU Sprinkle granules on an empty stomach or with a light meal <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> . Administer JADENU Sprinkle granules by sprinkling the full dose on soft food (e.g., yogurt or applesauce) immediately prior to use and administered orally.

Jadenu

Sprinkle granules should be taken once a day, preferably at the same time each day. Do not take JADENU Sprinkle granules with aluminum-containing antacid products [see Drug Interactions (7.1)] . For patients who are currently on chelation therapy with Exjade tablets for oral suspension and converting to JADENU, the dose should be about 30% lower, rounded to the nearest whole tablet or nearest whole sachet content for granules. The table below provides additional information on dosing conversion to JADENU.

Exjade

Tablets for oral suspension (white round tablet)

Jadenu

Tablets (film coated blue oval tablet)

Jadenu

Sprinkle Granules (white to almost white granules) Transfusion-Dependent Iron Overload Starting Dose 20 mg/kg/day 14 mg/kg/day Titration Increments 5–10 mg/kg 3.5–7 mg/kg Maximum Dose 40 mg/kg/day 28 mg/kg/day Non-Transfusion-Dependent Thalassemia Syndromes Starting Dose 10 mg/kg/day 7 mg/kg/day Titration Increments 5–10 mg/kg 3.5–7 mg/kg Maximum Dose 20 mg/kg/day 14 mg/kg/day

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 JADENU tablets or JADENU Sprinkle granules [see Warnings and Precautions (5.2), Use in Specific Populations (8.7)] . Patients with Baseline Renal Impairment Do not use JADENU 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 40-60 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 JADENU JADENU is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2 <span class="opacity-50 text-xs">[see Contraindications (4)]</span> . For decreases in renal function while receiving JADENU <span class="opacity-50 text-xs">[see Warnings and Precautions (5.1)]</span> , 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–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 JADENU 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 JADENU use. Use the minimum effective JADENU 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 JADENU 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–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 JADENU use. Use the minimum effective JADENU 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 JADENU 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 JADENU tablets or JADENU Sprinkle granules 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 JADENU tablets or JADENU Sprinkle granules 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)] .

Deferasirox tablets for oral suspension are contraindicated in patients with:

• Estimated GFR less than 40 mL/min/1.73 m 2 [see Dosage and Administration ( Error! Hyperlink reference not valid. ), Warnings and Precautions ( Error! Hyperlink reference not valid. )];
• Poor performance status [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )];
• High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy);
• Advanced malignancies [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )];
• Platelet counts less than 50 x 10 9 /L [see Warnings and Precautions ( Error! Hyperlink reference not valid. , Error! Hyperlink reference not valid. )]; Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension [see Warnings and Precautions ( Error! Hyperlink reference not valid. ), Adverse Reactions ( Error! Hyperlink reference not valid. )] .
• Estimated GFR less than 40 mL/min/1.73 m 2 . ( 4 )
• Patients with poor performance status. ( 4 )
• Patients with high-risk myelodysplastic syndrome (MDS). ( 4 )
• Patients with advanced malignancies. ( 4 )
• Patients with platelet counts less than 50 x 10 9 /L. ( 4 )
• Known hypersensitivity to deferasirox or any component of deferasirox tablets for oral suspension. ( 4 )

REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome [see Warnings and Precautions (5.1, 5.6)]

Hepatic

Toxicity and Failure [see Warnings and Precautions (5.2, 5.6)] GI Hemorrhage [see Warnings and Precautions (5.3)]

Bone Marrow

Suppression [see Warnings and Precautions (5.4)] Hypersensitivity [see Warnings and Precautions (5.7)]

Severe Skin

Reactions [see Warnings and Precautions (5.8)]

Skin

Rash [see Warnings and Precautions (5.9)] Auditory and Ocular Abnormalities [see Warnings and Precautions (5.10)] In patients with transfusional iron overload, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, vomiting, nausea, abdominal pain, skin rashes, and increases in serum creatinine. In deferasirox tablets for oral suspension-treated patients with NTDT syndromes, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, rash, and nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals Limited at 1-866-210-9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

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.

Transfusional Iron

Overload A total of 700 adult and pediatric patients were treated with deferasirox tablets for oral suspension (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 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 tablets for oral suspension at the completion of the study.

Table

1 displays adverse reactions occurring in greater than 5% of deferasirox tablets for oral suspension-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 tablets for oral suspension. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

Table

1.

Adverse

Reactions a Occurring in Greater Than 5% of Deferasirox Tablets for Oral Suspension-treated Patients in Study 1, Study 3, and MDS Pool Study 1 (Beta-thalassemia)

Study

3 (Sickle Cell Disease)

Mds

Pool Adverse Reactions Deferasirox Tablets for Oral Suspension N=296 n (%) Deferoxamine N=290 n (%)

Deferasirox

Tablets for Oral Suspension N=132 n (%) Deferoxamine N=63 n (%)

Deferasirox

Tablets for Oral Suspension N=627 n (%)

Abdominal

Pain b 63 (21) 41 (14) 37 (28) 9 (14) 145 (23)

Diarrhea

35 (12) 21 (7) 26 (20) 3 (5) 297 (47)

Creatinine

Increased c 33 (11) 0 (0) 9 (7) 0 89 (14)

Nausea

31 (11) 14 (5) 30 (23) 7 (11) 161 (26)

Vomiting

30 (10) 28 (10) 28 (21) 10 (16) 83 (13)

Rash

25 (8) 9 (3) 14 (11) 3 (5) 83 (13) Abbreviation: MDS, myelodysplastic syndrome. a Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug. b Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’. c Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’. See also Table 2.

In Study

1, a total of 113 (38%) patients treated with deferasirox tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension 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 tablets for oral suspension-treated patients required dose reductions. In this study, 5 patients in the deferasirox tablets for oral suspension group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox tablets for oral suspension permanently discontinued. Four additional patients discontinued deferasirox tablets for oral suspension 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 tablets for oral suspension 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 Study 1 (Beta-thalassemia)

Study

3 (Sickle Cell Disease)

Mds

Pool Laboratory Parameter Deferasirox Tablets for Oral Suspension N=296 n (%) Deferoxamine N=290 n (%)

Deferasirox

Tablets for Oral Suspension N=132 n (%) Deferoxamine N=63 n (%)

Deferasirox

Tablets for Oral Suspension N=627 n (%)

Serum Creatinine

Creatinine increase >33% at 2 consecutive post-baseline visits 113 (38) 41 (14) 48 (36) 14 (22) 229 (37) Creatinine increase >33% and >ULN at 2 consecutive post-baseline visits 7 (2) 1 (0) 3 (2) 2 (3) 126 (20) SGPT/ALT SGPT/ALT >5 x ULN at 2 post-baseline visits 25 (8) 7 (2) 2 (2) 0 9 (1) SGPT/ALT >5 x ULN at 2 consecutive post-baseline visits 17 (6) 5 (2) 5 (4) 0 5 (1) Abbreviations: ALT, alanine transaminase; MDS, myelodysplastic syndrome; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal. Non-Transfusion-Dependent Thalassemia Syndromes In Study 5, 110 patients with NTDT received 1 year of treatment with deferasirox tablets for oral suspension 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 tablets for oral suspension at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [see Clinical Studies (14)] .

Tables

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% in Patients with NTDT Study 5 Study 6 Deferasirox Tablets for Oral Suspension N = 110 n (%) Placebo N = 56 n (%)

Deferasirox

Tablets for Oral Suspension N = 130 n (%) Any adverse reaction 31 (28) 9 (16) 27 (21)

Nausea

7 (6) 4 (7) 2 (2) a Rash 7 (6) 1 (2) 2 (2) a Diarrhea 5 (5) 1 (2) 7 (5) Abbreviation: NTDT, non-transfusion-dependent thalassemia. a The occurrence of nausea, and rash are included for Study 6. There were no additional adverse reactions with a suspected relationship to study drug occurring in greater than 5% of patients in Study 6.

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 tablets for oral suspension-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 Study 5 Study 6 Laboratory Parameter Deferasirox Tablets for Oral Suspension N = 110 n (%) Placebo N = 56 n (%)

Deferasirox

Tablets for Oral Suspension N = 130 n (%) Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline values) 3 (3) 0 2 (2) SGPT/ALT (> 5 x ULN and > 2 x baseline) 1 (1) 1 (2) 2 (2) Abbreviation: ALT, alanine transaminase; NTDT, non-transfusion-dependent thalassemia; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal. 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 tablets for oral suspension-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 tablets for oral suspension 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 tablets for oral suspension dosage starting at 20 mg/kg/day (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 tablets for oral suspension dosage >30 mg/kg/day, 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 when their serum ferritin was <1,000 mcg/L (n=158) had a 6-fold greater rate of renal adverse reactions (incidence rate ration (IRR) = 6, 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 reaction 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 EXJADE (deferasirox) tablets for oral suspension. 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 postapproval use of deferasirox tablets for oral suspension 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), hypersensitivity 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 Gastrointestinal 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), renal tubular disorder (n=1), proteinuria (n=1), hematuria (n=1), upper GI hemorrhage (n=1), vomiting (n=2), abdominal pain (n=1), and hypokalemia (n=1).

AND PRECAUTIONS Acute Kidney Injury: Measure serum creatinine in duplicate before starting therapy. Monitor renal function during deferasirox tablets for oral suspension therapy and reduce dose or interrupt therapy for toxicity. (2.1, 2.4, 5.1)

Hepatic

Toxicity: Monitor hepatic function. Reduce dose or interrupt therapy for toxicity. (5.2) Fatal and Nonfatal Gastrointestinal Bleeding, Ulceration, and Irritation: Risk may be greater in patients who are taking deferasirox tablets for oral suspension in combination with drugs that have known ulcerogenic or hemorrhagic potential. (5.3)

Bone Marrow

Suppression: Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events; monitor blood counts during deferasirox tablets for oral suspension therapy. Interrupt therapy for toxicity. (5.4) Age-related Risk of Toxicity: Monitor elderly and pediatric patients closely for toxicity. (5.5)

Hypersensitivity

Reactions: Discontinue deferasirox tablets for oral suspension for severe reactions and institute medical intervention. (5.7)

Severe Skin

Reactions, including Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Discontinue deferasirox tablets for oral suspension. (5.8)

5.1 Acute Kidney Injury, Including Acute Renal Failure Requiring Dialysis, and Renal Tubular Toxicity Including Fanconi Syndrome Deferasirox tablets for oral suspension are 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/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 <span class="opacity-50 text-xs">[see Use in Specific Populations (8.6)]</span> . For patients with renal impairment (eGFR 40 to 60 mL/min/1.73 m 2 ) reduce the starting dose by 50% <span class="opacity-50 text-xs">[see Dosage and Administration (2.4, 2.5), Use in Specific Populations (8.6)]</span> . Deferasirox tablets for oral suspension 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, adult and pediatric deferasirox tablets for oral suspension-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 tablets for oral suspension 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 tablets for oral suspension, most commonly in pediatric patients with beta-thalassemia and serum ferritin levels less than 1,500 mcg/L <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.4 ), Clinical Pharmacology (12.3) ]</span>. 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.1, 2.2)]</span>. 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 tablets for oral suspension 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 <span class="opacity-50 text-xs">[see Dosage and Administration (2.5), Warnings and Precautions (5.6), Adverse Reactions (6.1, 6.2), Use in Specific Populations (8.4)]</span>.

5.2 Hepatic Toxicity and Failure Deferasirox tablets for oral suspension can cause hepatic injury, fatal in some patients.

In Study

1, 4 patients (1.3%) discontinued deferasirox tablets for oral suspension 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 tablets for oral suspension-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 tablets for oral suspension 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 tablets for oral suspension in the 20 to 40 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 tablets for oral suspension 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 in deferasirox tablets for oral suspension-treated patients, 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 tablets for oral suspension <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox tablets for oral suspension 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 tablets for oral suspension 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) <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> .

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

5.5 Age-Related Risk of Toxicity Elderly Patients Deferasirox tablets for oral suspension have been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. Monitor elderly patients treated with deferasirox tablets for oral suspension more frequently for toxicity <span class="opacity-50 text-xs">[see Use in Specific Populations (8.5)]</span> .

Pediatric Patients

Deferasirox tablets for oral suspension 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 when body iron burden was approaching or in the normal range. Interrupt deferasirox tablets for oral suspension in patients with volume depletion, and resume deferasirox tablets for oral suspension when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox tablets for oral suspension in the 20 to 40 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 suspension in pooled clinical trials (n=158) found a higher rate of renal adverse reactions among patients receiving doses greater than 25 mg/kg/day 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 <span class="opacity-50 text-xs">[see Adverse Reaction (6.1), Use in Specific Populations (8.4)]</span>. If the serum ferritin falls below 1,000 mcg/L at 2 consecutive visits, consider dose reduction, especially if the dose is greater than 25 mg/kg/day <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox tablets for oral suspension 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 tablets for oral suspension in the 20 to 40 mg/kg/day range when the body iron burden is approaching or within the normal range has resulted in life-threatening adverse reactions <span class="opacity-50 text-xs">[see Dosage and Administration (2.1)]</span> . 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 tablets for oral suspension 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 tablets for oral suspension and obtain a confirmatory LIC <span class="opacity-50 text-xs">[see Clinical Studies (14)]</span> .

5.7 Hypersensitivity Deferasirox tablets for oral suspension may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.2)]</span> . If reactions are severe, discontinue deferasirox tablets for oral suspension and institute appropriate medical intervention. Deferasirox tablets for oral suspension are 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 tablets for oral suspension therapy <span class="opacity-50 text-xs">[see Adverse Reactions (6.1, 6.2)]</span> . 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 tablets for oral suspension immediately and do not reintroduce deferasirox tablets for oral suspension therapy.

5.9 Skin Rash Rashes may occur during deferasirox tablets for oral suspension treatment <span class="opacity-50 text-xs">[see Adverse Reactions (6.1)]</span> . For rashes of mild to moderate severity, deferasirox tablets for oral suspension may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with deferasirox tablets for oral suspension. 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 tablets for oral suspension 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 when serum ferritin was less than 1,000 mcg/L <span class="opacity-50 text-xs">[see Warnings and Precautions (5.6)]</span>. Perform auditory and ophthalmic testing (including slit-lamp examinations and dilated fundoscopy) before starting deferasirox tablets for oral suspension treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.

INTERACTIONS Do not take deferasirox tablets for oral suspension with aluminum-containing antacid preparations. (7.1) Deferasirox tablets for oral suspension increases the exposure of the CYP2C8 substrate repaglinide. Consider repaglinide dose reduction and monitor blood glucose levels. (7.3) Avoid the use of deferasirox tablets for oral suspension with CYP1A2 substrate theophylline. (7.4) Deferasirox increases exposure of busulfan. Monitor plasma concentrations of busulfan when coadministered with deferasirox to allow dose adjustment of busulfan as needed. (7.7)

7.1 Aluminum-Containing Antacid Preparations The concomitant administration of deferasirox tablets for oral suspension 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 tablets for oral suspension with aluminum-containing antacid preparations due to the mechanism of action of deferasirox tablets for oral suspension.

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) <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> .

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 tablets for oral suspension 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 tablets for oral suspension are coadministered with other CYP2C8 substrates <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.

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 tablets for oral suspension. Monitor theophylline concentrations and consider theophylline dose modification if you must coadminister theophylline with deferasirox tablets for oral suspension. Closely monitor patients for signs of exposure related toxicity when deferasirox tablets for oral suspension are coadministered with other drugs metabolized by CYP1A2 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span> .

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 tablets for oral suspension with potent UGT inducers (e.g., rifampicin, phenytoin, phenobarbital, ritonavir) may result in a decrease in deferasirox tablets for oral suspension efficacy due to a possible decrease in deferasirox concentration. Avoid the concomitant use of potent UGT inducers with deferasirox tablets for oral suspension. Consider increasing the initial dose of deferasirox tablets for oral suspension 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 tablets for oral suspension due to a possible decrease in deferasirox concentration. If you must coadminister these agents together, consider increasing the initial dose of deferasirox tablets for oral suspension <span class="opacity-50 text-xs">[see Dosage and Administration (2.5), Clinical Pharmacology (12.3)]</span> .

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 <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3)]</span>.