KELOSIROX

Deferasirox is an iron-chelating agent provided as a tablet for oral use.

Deferasirox is designated chemically as 4-[3,5-bis(2-hydroxy-phenyl)-1 H -1,2,4-triazol-1-yl] benzoic acid and has the following structural formula: Deferasirox is a white to slightly yellow colour powder.

It has a molecular formula

C 21 H 15 N 3 O and molecular weight of 373.36.

Deferasirox tablets contain 90 mg, 180 mg, or 360 mg deferasirox.

Inactive ingredients include colloidal silicon dioxide, croscarmellose sodium, hydrogenated castor oil, lactose monohydrate, low substituted hydroxy propyl cellulose, microcrystalline cellulose, poloxamer, povidone (K30) and sodium stearyl fumarate.

The film coating contains.hypromellose, titanium dioxide, propylene glycol, talc and iron oxide yellow. structure.

Deferasirox tablets are an iron chelator indicated for the treatment of chronic iron overload due to blood transfusions in patients 2 years of age and older.

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 (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 tablets when administered with other iron chelation therapy have not been established. 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.

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.

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 0-24h, 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.

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.

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.

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.

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 to 16 hours following oral administration.

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.

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.

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.

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% .

The concomitant administration of cholestyramine after a single dose of deferasirox tablets for oral suspension decreased deferasirox AUC inf by 45% .

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

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.

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

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

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.

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 Hepatic Toxicity and Failure GI Hemorrhage Bone Marrow Suppression Hypersensitivity Severe Skin Reactions Skin Rash Auditory and Ocular Abnormalities 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-treated patients with NTDT syndromes, the most frequently occurring (greater than 5%) adverse reactions are diarrhea, rash, and nausea.

To report SUSPECTED ADVERSE

REACTIONS, contact MSN Pharmaceuticals Inc.fda.gov/medwatch. 6.1Clinical 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 contains the same active ingredient as deferasirox tablets for oral suspension.

The following adverse reactions have been reported with deferasirox tablets for oral suspension.

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 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 to 205 weeks.

Six hundred twenty-seven patients with myelodysplastic syndrome (MDS) were enrolled across 5 uncontrolled trials.

These studies varied in duration from 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 Study 1 (Beta-thalassemia) Study 3 (Sickle Cell Disease) MDS Pool Adverse Reactions Deferasirox N=296 n(%) Deferoxamine N=290 n(%) Deferasirox N=132 n(%) Deferoxamine N=63 n(%) Deferasirox N=627 n(%) Abdominal Pain b 63 41 37 9 145 Diarrhea 35 21 26 3 297 Creatinine Increased c 33 0 9 0 89 Nausea 31 14 30 7 161 Vomiting 30 28 28 10 83 Rash 25 9 14 3 83 Abbreviation: MDS, myelodysplastic syndrome. a Adverse reaction frequencies are based on AEs 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 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.

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.

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) .

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.

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.

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 N=296 n(%) Deferoxamine N=290 n(%) Deferasirox N=132 n(%) Deferoxamine N=63 n(%) Deferasirox N=627 n(%) Serum Creatinine Creatinine increase >33% at 2 consecutive post-baseline visits 113 41 48 14 229 Creatinine increase >33% and >ULN at 2 consecutive post-baseline visits 7 1 3 2 126 SGPT/ALT SGPT/ALT >5 x ULN at 2 post-baseline visits 25 7 2 0 9 SGPT/ALT >5 x ULN at 2 consecutive post-baseline visits 17 5 5 0 5 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 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial.

In Study of the patients who completed Study were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year.

Table 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.

Than 5% Patients with NTDT Any adverse reaction Study 5 Study 6 Deferasirox Placebo Deferasirox N = 110 N = 56 N = 130 n (%) n (%) n (%) 31 9 27 Nausea 7 4 2 a Rash 7 1 2 a Diarrhea 5 1 7 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 >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-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 and Study are presented in Table 4 below.

Table 4.

Number (%) of Patients with NTDT with Increases in Serum Creatinine or SGPT/ALT Laboratory Parameter Study 5 Study 6 Deferasirox Placebo Deferasirox N = 110 N = 56 N = 130 n (%) n (%) n (%) Serum creatinine (> 33% increase from baseline and > ULN at ≥ 2 consecutive post-baseline values) 3 0 2 SGPT/ALT (> 5 x ULN and > 2 x baseline) 1 1 2 Abbreviations: ALT, alanine transaminase; NTDT, non-transfusion-dependent thalassemia; SGPT, serum glutamic-pyruvic transaminase; ULN, upper limit of normal.

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.

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 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.

Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported.

In one case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption.

In one pediatric case, a dose of 2-3 times the prescribed dose for 6 days resulted in acute renal failure requiring hemofiltration and acute liver injury/failure, which were reversible with intensive care support.

Single doses of deferasirox up to 80 mg per kg per day with the tablet for oral suspension formulation in iron-overloaded beta-thalassemic patients have been tolerated with nausea and diarrhea noted.

In healthy subjects, single doses of up to 40 mg per kg per day with the tablet for oral suspension formulation were tolerated.

Early signs of acute overdose are digestive effects such as abdominal pain, diarrhea, nausea, and vomiting.

Hepatic and renal disorders have been reported, including cases of liver enzyme and creatinine increased with recovery after treatment discontinuation.

An erroneously administered single dose of 90 mg/kg led to Fanconi syndrome which resolved after treatment.

There is no specific antidote for deferasirox.

In case of overdose, it may be treated with induction of vomiting or gastric lavage, and by symptomatic treatment.

Deferasirox is contraindicated in patients with

Estimated GFR less than 40 mL/min/1.73 m 2; Poor performance status; High-risk myelodysplastic syndromes (this patient population was not studied and is not expected to benefit from chelation therapy); Advanced malignancies; Platelet counts less than 50 x 10 9 /L; Known hypersensitivity to deferasirox or any component of deferasirox.

GFR less than 40 mL/min/1.73 m 2.

Patients with poor performance status.

Patients with high-risk myelodysplastic syndrome (MDS).

Patients with advanced malignancies.

Patients with platelet counts less than 50 x 10 9 /L. Known hypersensitivity to deferasirox or any component of deferasirox.

Initial dose for patients with estimated glomerular filtration rate (eGFR) greater than 60 mL/min/1.73 m is 14 mg per kg (calculated to nearest whole tablet ) once daily.

Initial dose for patients with eGFR greater than 60 mL/min/1.73 m is 7 mg per kg (calculated to nearest whole tablet) once daily.

See full prescribing information for information regarding monitoring, administration, and dose-reductions for organ impairment. 2.1Transfusional Iron Overload Deferasirox tablets 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 Obtain 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.

Serum transaminases and bilirubin

Baseline auditory and ophthalmic examinations 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 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.

Monitor serum ferritin monthly and adjust the dose of deferasirox tablets, if necessary, every 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.

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 deferasirox tablets dose is greater than 17.5 mg/kg/day.

If the serum ferritin falls below 500 mcg/L, interrupt deferasirox tablets therapy to minimize the risk of overchelation, and continue monthly monitoring.

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.

Monitor blood counts, liver function, renal function and ferritin monthly.

Interrupt deferasirox tablets 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. 2.2 Iron Overload in Non-Transfusion-Dependent Thalassemia Syndromes Deferasirox tablets 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 Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements).

Baseline auditory and ophthalmic examinations Initiating Therapy: The recommended initial dose of deferasirox tablets for patients with eGFR greater than 60 mL/min/1.73 m is 7 mg per kg body weight orally once daily.

If the baseline

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

Monitor serum ferritin monthly to assess the patient’s response to therapy and to minimize the risk of overchelation.

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.

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 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.

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.

Restart treatment when the

LIC rises again to more than 5 mg Fe/g dw. 2.3Administration 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.

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.

Tablets for oral suspension (white round tablet) Deferasirox Tablets (film coated yellow oval tablet) Transfusion-Dependent Iron Overload Starting Dose 20 mg/kg/day 14 mg/kg/day Titration Increments to 10 mg/kg 3.5 to 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 to 10 mg/kg 3.5 to 7 mg/kg Maximum Dose 20 mg/kg/day 14 mg/kg/day 2.4Use 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.

Do not use deferasirox tablets in adult or pediatric patients with eGFR less than 40 mL/min/1.73 m 2.

For patients with renal impairment (eGFR to 60 mL/min/1.73 m 2 ), reduce the starting dose by 50% .

Exercise caution in pediatric patients with eGFR between 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. 2.5Dose Modifications for Decrease in Renal Function While on Deferasirox Tablets Deferasirox tablets is contraindicated in patients with eGFR less than 40 mL/min/1.73 m 2.

For decreases in renal function while receiving deferasirox tablets, 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.

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.

Patients (regardless of age): Discontinue therapy for eGFR less than 40 mL/min/1.73 m 2.

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.

Deferasirox 90 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '90' on another side.

They are available in bottles of 30 tablets (NDC 69539-073-30).

They are available in bottles of 1000 tablets (NDC 69539-073-99).

Deferasirox 180 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '180' on another side.

They are available in bottles of 30 tablets (NDC 69539-074-30).

They are available in bottles of 1000 tablets (NDC 69539-074-99).

Deferasirox 360 mg tablets are yellow colored, film coated oval, biconvex tablets with beveled edges debossed with 'D' on one side and '360' on another side.

They are available in bottles of 30 tablets (NDC 69539-075-30).

They are available in bottles of 1000 tablets (NDC 69539-075-99).

Store deferasirox tablets at 20°C to 25°C (68°F to 77°F); excursions are permitted between 15°C to 30°C (59°F to 86°F) .

Protect from moisture.

There are no studies with the use of deferasirox in pregnant women to inform drug-associated risks.

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.

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 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).

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.

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.

In those clinical studies, 173 children (ages to < 12 years) and 119 adolescents (ages 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.

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.

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.

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.

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.

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.

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.

However, due to Novartis Pharmaceuticals Corporation’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

Four hundred thirty-one 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 of these patients were between and 75 years of age while 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.