Deferasorox

Prior to starting therapy, obtain:

LIC by liver biopsy or by an FDA-cleared or approved method for identifying patients for treatment with deferasirox therapy Serum ferritin level on at least 2 measurements 1-month apart [see Clinical Studies (14)] Baseline renal function: Obtain serum creatinine in duplicate (due to variations in measurements).

Calculate the estimated glomerular filtration rate (eGFR). , Schwartz equations). 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 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.

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. 4) ] . 3) ]. Restart treatment when the LIC rises again to more than 5 mg Fe/g dw. 3 Administration Take deferasirox oral granules on an empty stomach or with a light meal (contains less than 7% fat content and approximately 250 calories).

5 ounces), and skim milk (8 fluid ounces) or a turkey sandwich (2 oz. 3) ] . , yogurt or applesauce) immediately prior to use and administered orally. Deferasirox oral granules should be taken once a day, preferably at the same time each day.

1) ] . For patients who are currently on chelation therapy with deferasirox tablets for oral suspension and converting to deferasirox oral granules, the dose should be about 30% lower, rounded to the nearest whole sachet content for granules.

The table below provides additional information on dosing conversion to deferasirox granules. 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%. 7) ]. 5) , Contraindications (4) ] . 6) ] . 73 m 2 . If treatment is needed, use the minimum effective dose and monitor renal function frequently. 6) ] . 73 m 2 [see Contraindications (4) ]. 1) ] , modify the dose as follows: Transfusional Iron Overload Adults: If the serum creatinine increases by 33% or more above the average baseline measurement, repeat the serum creatinine within 1 week, and if still elevated by 33% or more, reduce the dose by 7 mg per kg.

Pediatric Patients (ages 2 years to 17 years):

Reduce the dose by 7 mg per kg if eGFR decreases by greater than 33% below the average baseline measurement and repeat eGFR within 1 week. Interrupt deferasirox oral granules 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. 1) ]. In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox oral granules use.

Use the minimum effective deferasirox oral granules 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.

1) ]. 73 m 2 [see Contraindications (4) ]. 5 mg per kg, or reduce by 50% if the dose is 7 or 14 mg per kg. 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. 1) ]. In the setting of decreased renal function, evaluate the risk benefit profile of continued deferasirox oral granules use. Use the minimum effective deferasirox oral granules 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. 1) ]. 73 m 2 [see Contraindications (4) ] . 6 Dose Modifications Based on Concomitant Medications UDP-glucuronosyltransferases (UGT) Inducers Concomitant use of UGT inducers decreases systemic exposure.

, rifampicin, phenytoin, phenobarbital, ritonavir). 5) ] . Bile Acid Sequestrants Concomitant use of bile acid sequestrants decreases systemic exposure. , cholestyramine, colesevelam, colestipol). 6) ] .

These studies varied in duration from 1 to 5 years. The discontinuation rate across studies in the first year was 46% (Adverse Events (AEs) 20%, withdrawal of consent 10%, death 8%, other 4%, lab abnormalities 3%, and lack of efficacy 1%).

Among 47 patients enrolled in the study of 5-year duration, 10 remained on deferasirox at the completion of the study. Table 1 displays adverse reactions occurring in greater than 5% of deferasirox-treated beta-thalassemia patients (Study 1), sickle cell disease patients (Study 3), and patients with MDS (MDS pool).

Abdominal pain, nausea, vomiting, diarrhea, skin rashes, and increases in serum creatinine were the most frequent adverse reactions reported with a suspected relationship to deferasirox. Gastrointestinal symptoms, increases in serum creatinine, and skin rash were dose related.

Table 1. Adverse Reactions a Occurring in >5% of Deferasirox-treated Patients in Study 1, Study 3, and MDS Pool 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 (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 AEs reported regardless of relationship to study drug. ’ 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.

1) ] . In this study, 17 (6%) patients treated with deferasirox developed elevations in serum glutamic-pyruvic transaminase (SGPT)/ALT levels greater than 5 times the upper limit of normal (ULN) at 2 consecutive visits. 2)] . An additional 2 patients, who did not have elevations in SGPT/ALT greater than 5 times the ULN, discontinued deferasirox because of increased SGPT/ALT.

Increases in transaminases did not appear to be dose related. Adverse reactions that led to discontinuations included abnormal liver function tests (2 patients) and drug-induced hepatitis (2 patients), skin rash, glycosuria/proteinuria, Henoch Schönlein purpura, hyperactivity/insomnia, drug fever, and cataract (1 patient each).

1) ] . Of the patients who experienced creatinine increases in Study 3, 8 deferasirox-treated patients required dose reductions. In this study, 5 patients in the deferasirox group developed elevations in SGPT/ALT levels greater than 5 times the ULN at 2 consecutive visits and 1 patient subsequently had deferasirox permanently discontinued.

Four additional patients discontinued due to adverse reactions with a suspected relationship to study drug, including diarrhea, pancreatitis associated with gallstones, atypical tuberculosis, and skin rash. 1) ] . 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 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 (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 5 or 10 mg/kg/day and 56 patients received placebo in a double-blind, randomized trial. In Study 6, 130 of the patients who completed Study 5 were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year [ see Clinical Studies (14)].

Table 3 and 4 display the frequency of adverse reactions in patients with NTDT. Adverse reactions with a suspected relationship to study drug were included in Table 3 if they occurred at ≥ 5% of patients in Study 5. Table 3. Adverse Reactions Occurring in Greater Than 5% Patients with NTDT Any adverse reaction Study 5 Study 6 Deferasirox N=110 n (%) Placebo N=56 n (%) Deferasirox N=130 n (%) 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 >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 5, Study 6 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 N = 110 n (%) Placebo N= 56 n (%) Deferasirox 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) Abbreviations: 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. 1) ] . 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).

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.

73 m 2 ) were identified. 48). 56). 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. 17) compared to the time-period prior to meeting these simultaneous criteria.

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

2 Postmarketing Experience The following adverse reactions have been spontaneously reported during post-approval use of deferasirox in the transfusional iron overload setting. Because these reactions are reported voluntarily from a population of uncertain size, in which patients may have received concomitant medication, it is not always possible to reliably estimate frequency or establish a causal relationship to drug exposure.

Skin and Subcutaneous Tissue Disorders:

Stevens-Johnson syndrome (SJS), leukocytoclastic vasculitis, urticaria, alopecia, toxic epidermal necrolysis (TEN) Immune System Disorders: hypersensitivity reactions (including anaphylactic reaction and angioedema) Renal and Urinary Disorders: acute renal failure, tubulointerstitial nephritis Hepatobiliary Disorders: hepatic failure GI Disorders: GI perforation Blood and Lymphatic System Disorders: worsening anemia 5-Year Pediatric Registry In a 5-year observational study, 267 pediatric patients 2 to < 6 years of age (at enrollment) with transfusional hemosiderosis received deferasirox.

Of the 242 patients who had pre- and post-baseline eGFR measurements, 116 (48%) patients had a decrease in eGFR of ≥ 33% observed at least once. Twenty-one (18%) of these 116 patients with decreased eGFR had a dose interruption, and 15 (13%) of these 116 patients had a dose decrease within 30 days.

Adverse reactions leading to permanent discontinuation from the study included liver injury (n = 11), vomiting (n = 2), renal tubular disorder (n = 1), proteinuria (n = 1), hematuria (n = 1), upper GI hemorrhage (n = 1), abdominal pain (n = 1), and hypokalemia (n = 1).

In pediatric patients, small decreases in eGFR can result in increases in deferasirox exposure, particularly in younger patients with body surface area typical of patients less than age 7 years. This can lead to a cycle of worsening renal function and further increases in deferasirox tablets for oral suspension exposure, unless the dose is reduced or interrupted.

3) ] . Evaluate renal glomerular and tubular function before initiating therapy or increasing the dose. Use prediction equations validated for use in adult and pediatric patients to estimate GFR. 2) ] . Monitor all patients for changes in eGFR and for renal tubular toxicity weekly during the first month after initiation or modification of therapy and at least monthly thereafter.

Dose reduction or interruption may be considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated. Monitor serum ferritin monthly to evaluate for overchelation. Use the minimum dose to establish and maintain a low iron burden.

Monitor renal function more frequently in patients with preexisting renal disease or decreased renal function. In pediatric patients, interrupt deferasirox during acute illnesses, which can cause volume depletion such as vomiting, diarrhea, or prolonged decreased oral intake, and monitor renal function more frequently.

Promptly correct fluid deficits to prevent renal injury. 4) ] . 2 Hepatic Toxicity and Failure Deferasirox can cause hepatic injury, fatal in some patients. 3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients).

Hepatic toxicity appears to be more common in patients greater than 55 years of age. 1)] . Acute liver injury and failure, including fatal outcomes, have occurred in pediatric deferasirox-treated patients. Liver failure occurred in association with acute kidney injury in pediatric patients at risk for overchelation during a volume-depleting event.

Interrupt deferasirox therapy when acute liver injury or acute kidney injury is suspected and during volume depletion. Monitor liver and renal function more frequently in pediatric patients who are receiving deferasirox in the 14 to 28 mg/kg/day range and when iron burden is approaching normal.

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

Avoid the use of deferasirox in patients with severe (Child-Pugh C) hepatic impairment. 7) ] . Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity. 3 Gastrointestinal (GI) Ulceration, Hemorrhage, and Perforation GI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts.

1) ] . Monitor for signs and symptoms of GI ulceration and hemorrhage during deferasirox therapy, and promptly initiate additional evaluation and treatment if a serious GI adverse reaction is suspected. The risk of GI hemorrhage may be increased when administering deferasirox in combination with drugs that have ulcerogenic or hemorrhagic potential, such as nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, oral bisphosphonates, or anticoagulants.

2) ] . 4 Bone Marrow Suppression Neutropenia, agranulocytosis, worsening anemia, and thrombocytopenia, including fatal events, have been reported in patients treated with deferasirox. Preexisting hematologic disorders may increase this risk.

Monitor blood counts in all patients. Interrupt treatment with deferasirox in patients who develop cytopenias until the cause of the cytopenia has been determined. Deferasirox is contraindicated in patients with platelet counts below 50 x 10 9 /L.

5 Age-Related Risk of Toxicity Elderly Patients Deferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting among adults, predominantly in elderly patients. 5) ] . Pediatric Patients Deferasirox has been associated with serious and fatal adverse reactions in pediatric patients in the postmarketing setting.

These events were frequently associated with volume depletion or with continued deferasirox tablets for oral suspension doses in the 20 to 40 mg/kg/day range equivalent to 14 to 28 mg/kg/day deferasirox when body iron burden was approaching or in the normal range.

Interrupt deferasirox in patients with volume depletion, and resume deferasirox when renal function and fluid volume have normalized. Monitor liver and renal function more frequently during volume depletion and in patients receiving deferasirox in the 14 to 28 mg/kg/day range when iron burden is approaching the normal range.

4) ] . 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. 5 mg/kg/day deferasirox while their serum ferritin values were less than 1,000 mcg/L.

Consider dose reduction or closer monitoring of renal and hepatic function, and serum ferritin levels during these periods. 4) ] . 1) ] . If the serum ferritin falls below 500 mcg/L, interrupt therapy with deferasirox and continue monthly monitoring.

Evaluate the need for ongoing chelation for patients whose conditions do not require regular blood transfusions. Use the minimum effective dose to maintain iron burden in the target range. 1) ] . For patients with NTDT, measure LIC by liver biopsy or by using an FDA-cleared or approved method for monitoring patients receiving deferasirox therapy every 6 months on treatment.

Interrupt deferasirox administration when the LIC is less than 3 mg Fe/g dw. Measure serum ferritin monthly, and if the serum ferritin falls below 300 mcg/L, interrupt deferasirox and obtain a confirmatory LIC [see Clinical Studies (14) ] .

2) ] . If reactions are severe, discontinue deferasirox and institute appropriate medical intervention. Deferasirox is contraindicated in patients with known hypersensitivity to deferasirox products and should not be reintroduced in patients who have experienced previous hypersensitivity reactions on deferasirox products due to the risk of anaphylactic shock.

2 )] . Cases of erythema multiforme have been observed. Advise patients of the signs and symptoms of severe skin reactions, and closely monitor. If any severe skin reactions are suspected, discontinue deferasirox immediately and do not reintroduce deferasirox therapy.

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

10 Auditory and Ocular Abnormalities Auditory disturbances (high frequency hearing loss, decreased hearing), and ocular disturbances (lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders) were reported at a frequency of less than 1% with deferasirox therapy in the clinical studies.

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

Consider dose reduction or interruption.