Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg of the deferasirox dispersible tablet formulation (corresponding to a dose of 56 mg/kg film-coated tablets) in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.
Acute signs of overdose may include nausea, vomiting, headache and diarrhoea. Overdose may be treated by induction of emesis or by gastric lavage, and by symptomatic treatment.
Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported. In 1 case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. 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. There is no specific antidote for Dzhadenu. In case of overdose, induce vomiting and employ gastric lavage.
Cases of overdose (2 to 3 times the prescribed dose for several weeks) have been reported. In 1 case, this resulted in hepatitis which resolved without long-term consequences after a dose interruption. 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. There is no specific antidote for JADENU. In case of overdose, induce vomiting and employ gastric lavage.
Combination with other iron chelator therapies as the safety of such combinations has not been established.
Patients with estimated creatinine clearance <60 ml/min.
Dzhadenu is contraindicated in patients with:
JADENU is contraindicated in patients with:
Not applicable.
Summary of the safety profile
The most frequent reactions reported during chronic treatment in clinical studies conducted with deferasirox dispersible tablets in adult and paediatric patients include gastrointestinal disturbances (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years and in the elderly. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued.
During clinical studies dose-dependent increases in serum creatinine occurred in about 36% of patients, though most remained within the normal range. Decreases in mean creatinine clearance have been observed in both paediatric and adult patients with beta-thalassemia and iron overload during the first year of treatment, but there is evidence that this does not decrease further in subsequent years of treatment. Elevations of liver transaminases have been reported. Safety monitoring schedules for renal and liver parameters are recommended. Auditory (decreased hearing) and ocular (lens opacities) disturbances are uncommon, and yearly examinations are also recommended.
Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with the use of Dzhadenu.
Tabulated list of adverse reactions
Adverse reactions are ranked below using the following convention: very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 5
| Blood and lymphatic system disorders | |
| Not known: | Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia1 |
| Immune system disorders | |
| Not known: | Hypersensitivity reactions (including anaphylactic reactions and angioedema)1 |
| Metabolism and nutrition disorders | |
| Not known: | Metabolic acidosis1 |
| Psychiatric disorders | |
| Uncommon: | Anxiety, sleep disorder |
| Nervous system disorders | |
| Common: | Headache |
| Uncommon: | Dizziness |
| Eye disorders | |
| Uncommon: | Cataract, maculopathy |
| Rare: | Optic neuritis |
| Ear and labyrinth disorders | |
| Uncommon: | Deafness |
| Respiratory, thoracic and mediastinal disorders | |
| Uncommon: | Laryngeal pain |
| Gastrointestinal disorders | |
| Common: | Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia |
| Uncommon: | Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis |
| Rare: | Oesophagitis |
| Not known: | Gastrointestinal perforation1, acute pancreatitis1 |
| Hepatobiliary disorders | |
| Common: | Transaminases increased |
| Uncommon: | Hepatitis, cholelithiasis |
| Not known: | Hepatic failure1 |
| Skin and subcutaneous tissue disorders | |
| Common: | Rash, pruritus |
| Uncommon: | Pigmentation disorder |
| Rare: | Drug reaction with eosinophilia and systemic symptoms (DRESS) |
| Not known: | Stevens-Johnson syndrome1, hypersensitivity vasculitis1, urticaria1, erythema multiforme1, alopecia1, toxic epidermal necrolysis (TEN)1 |
| Renal and urinary disorders | |
| Very common: | Blood creatinine increased |
| Common: | Proteinuria |
| Uncommon: | Renal tubular disorder (acquired Fanconi syndrome), glycosuria |
| Not known: | Acute renal failure1, tubulointerstitial nephritis1, nephrolithiasis1, renal tubular necrosis1 |
| General disorders and administration site conditions | |
| Uncommon: | Pyrexia, oedema, fatigue |
1 Adverse reactions reported during post-marketing experience. These are derived from spontaneous reports for which it is not always possible to reliably establish frequency or a causal relationship to exposure to the medicinal product.
Description of selected adverse reactions
Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with the deferasirox dispersible tablet formulation, especially in patients with pre-existing liver cirrhosis. There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with deferasirox.
Creatinine clearance in transfusional iron overload
In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload treated with deferasirox dispersible tablets in two randomised and four open label studies of up to five years' duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In 250 patients who were followed for up to five years, no further decrease in mean creatinine clearance levels was observed.
Clinical study in patients with non-transfusion-dependent thalassaemia syndromes
In a 1-year study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload (dispersible tablets at a dose of 10 mg/kg/day), diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8% of patients, respectively. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients.
Paediatric population
In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected.
Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with deferasirox. In post-marketing reports, a high proportion of cases of metabolic acidosis occurred in children in the context of Fanconi syndrome.
Acute pancreatitis has been reported, particularly in children and adolescents.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
The following adverse reactions are also discussed in other sections of the labeling:
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. Dzhadenu was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with Dzhadenu tablets and Dzhadenu Sprinkle granules. Dzhadenu contains the same active ingredient as Exjade (deferasirox) tablets for oral suspension. The following adverse reactions have been reported with Exjade tablets for oral suspension.
Transfusional Iron OverloadA total of 700 adult and pediatric patients were treated with deferasirox for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were less than 16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88 to 205 weeks.
Six hundred twenty-seven patients with 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% (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* 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 | |||
| Preferred Term | Deferasirox N=296 n (%) | Deferoxamine N=290 n (%) | Deferasirox N=132 n (%) | Deferoxamine N=63 n (%) | Deferasirox N=627 n (%) |
| Abdominal Pain** | 63 (21) | 41 (14) | 37 (28) | 9 (14) | 145 (23) |
| Diarrhea | 35 (12) | 21 (7) | 26 (20) | 3 (5) | 297 (47) |
| Creatinine Increased*** | 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) |
| *Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug. **Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’ which were reported as adverse events. ***Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’ which were reported as adverse events. Also see Table 2. |
In Study 1, a total of 113 (38%) patients treated with 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 SGPT/ALT levels greater than 5 times the 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.
Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool
| Laboratory Parameter | Study 1 (Beta-thalassemia) | Study 3 (Sickle Cell Disease) | MDS Pool | ||
| 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 postbaseline visits | 113 (38) | 41 (14) | 48 (36) | 14 (22) | 229 (37) |
| Creatinine increase >33% and >ULN at 2 consecutive postbaseline visits | 7 (2) | 1 (0) | 3 (2) | 2 (3) | 126 (20) |
| SGPT/ALT | |||||
| SGPT/ALT >5 x ULN at 2 postbaseline visits | 25 (8) | 7 (2) | 2 (2) | 0 | 9 (1) |
| SGPT/ALT >5 x ULN at 2 consecutive postbaseline visits | 17 (6) | 5 (2) | 5 (4) | 0 | 5 (1) |
In Study 4, 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 5, 130 of the patients who completed Study 4 were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year. Table 3 displays adverse reactions occurring in greater than 5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea.
Table 3. Adverse Reactions Occurring in >5% in NTDT Patients
| Study 4 | Study 5 | ||
| Deferasirox | Placebo | Deferasirox | |
| N=110 | N=56 | N=130 | |
| n (%) | n (%) | n (%) | |
| Any adverse reaction | 31 (28) | 9 (16) | 27 (21) |
| Nausea | 7 (6) | 4 (7) | 2 (2) |
| Rash | 7 (6) | 1 (2) | 2 (2) |
| Diarrhea | 5 (5) | 1 (2) | 7 (5) |
In Study 4, 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 4.
Table 4. Number (%) of NTDT Patients with Increases in Serum Creatinine or SGPT/ALT
| Laboratory Parameter | Study 4 | Study 5 | |
| Deferasirox | Placebo | Deferasirox | |
| N=110 | N=56 | N=130 | |
| n (%) | n (%) | n (%) | |
| Serum creatinine (>33% increase from baseline and >ULN at ≥2 consecutive postbaseline values) | 3 (3) | 0 | 2 (2) |
| SGPT/ALT (>5 x ULN and >2 x baseline) | 1 (1) | 1 (2) | 2 (2) |
Proteinuria
In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) occurred in 18.6% of deferasirox-treated patients compared to 7.2% of deferoxaminetreated patients in Study 1.
Other Adverse Reactions
In the population of more than 5,000 patients with transfusional iron overload who have been treated with deferasirox during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, laryngeal pain, cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi’s 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, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.
Postmarketing ExperienceThe 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
Gastrointestinal disorders: gastrointestinal perforation
Blood and lymphatic system disorders: worsening anemia
The following adverse reactions are also discussed in other sections of the labeling:
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. JADENU was evaluated in healthy volunteer trials. Currently, there are no clinical data in patients with JADENU tablets and JADENU Sprinkle granules. JADENU contains the same active ingredient as Exjade (deferasirox) tablets for oral suspension. The following adverse reactions have been reported with Exjade tablets for oral suspension.
Transfusional Iron OverloadA total of 700 adult and pediatric patients were treated with deferasirox for 48 weeks in premarketing studies. These included 469 patients with beta-thalassemia, 99 with rare anemias, and 132 with sickle cell disease. Of these patients, 45% were male, 70% were Caucasian and 292 patients were less than 16 years of age. In the sickle cell disease population, 89% of patients were black. Median treatment duration among the sickle cell patients was 51 weeks. Of the 700 patients treated, 469 (403 beta-thalassemia and 66 rare anemias) were entered into extensions of the original clinical protocols. In ongoing extension studies, median durations of treatment were 88 to 205 weeks.
Six hundred twenty-seven patients with 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% (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* 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 | |||
| Preferred Term | Deferasirox N=296 n (%) | Deferoxamine N=290 n (%) | Deferasirox N=132 n (%) | Deferoxamine N=63 n (%) | Deferasirox N=627 n (%) |
| Abdominal Pain** | 63 (21) | 41 (14) | 37 (28) | 9 (14) | 145 (23) |
| Diarrhea | 35 (12) | 21 (7) | 26 (20) | 3 (5) | 297 (47) |
| Creatinine Increased*** | 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) |
| *Adverse reaction frequencies are based on adverse events reported regardless of relationship to study drug. **Includes ‘abdominal pain’, ‘abdominal pain lower’, and ‘abdominal pain upper’ which were reported as adverse events. ***Includes ‘blood creatinine increased’ and ‘blood creatinine abnormal’ which were reported as adverse events. Also see Table 2. |
In Study 1, a total of 113 (38%) patients treated with 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 SGPT/ALT levels greater than 5 times the 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.
Table 2. Number (%) of Patients with Increases in Serum Creatinine or SGPT/ALT in Study 1, Study 3, and MDS Pool
| Laboratory Parameter | Study 1 (Beta-thalassemia) | Study 3 (Sickle Cell Disease) | MDS Pool | ||
| 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 postbaseline visits | 113 (38) | 41 (14) | 48 (36) | 14 (22) | 229 (37) |
| Creatinine increase >33% and >ULN at 2 consecutive postbaseline visits | 7 (2) | 1 (0) | 3 (2) | 2 (3) | 126 (20) |
| SGPT/ALT | |||||
| SGPT/ALT >5 x ULN at 2 postbaseline visits | 25 (8) | 7 (2) | 2 (2) | 0 | 9 (1) |
| SGPT/ALT >5 x ULN at 2 consecutive postbaseline visits | 17 (6) | 5 (2) | 5 (4) | 0 | 5 (1) |
In Study 4, 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 5, 130 of the patients who completed Study 4 were treated with open-label deferasirox at 5, 10, or 20 mg/kg/day (depending on the baseline LIC) for 1 year. Table 3 displays adverse reactions occurring in greater than 5% in any group. The most frequent adverse reactions with a suspected relationship to study drug were nausea, rash, and diarrhea.
Table 3. Adverse Reactions Occurring in >5% in NTDT Patients
| Study 4 | Study 5 | ||
| Deferasirox | Placebo | Deferasirox | |
| N=110 | N=56 | N=130 | |
| n (%) | n (%) | n (%) | |
| Any adverse reaction | 31 (28) | 9 (16) | 27 (21) |
| Nausea | 7 (6) | 4 (7) | 2 (2) |
| Rash | 7 (6) | 1 (2) | 2 (2) |
| Diarrhea | 5 (5) | 1 (2) | 7 (5) |
In Study 4, 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 4.
Table 4. Number (%) of NTDT Patients with Increases in Serum Creatinine or SGPT/ALT
| Laboratory Parameter | Study 4 | Study 5 | |
| Deferasirox | Placebo | Deferasirox | |
| N=110 | N=56 | N=130 | |
| n (%) | n (%) | n (%) | |
| Serum creatinine (>33% increase from baseline and >ULN at ≥2 consecutive postbaseline values) | 3 (3) | 0 | 2 (2) |
| SGPT/ALT (>5 x ULN and >2 x baseline) | 1 (1) | 1 (2) | 2 (2) |
Proteinuria
In clinical studies, urine protein was measured monthly. Intermittent proteinuria (urine protein/creatinine ratio greater than 0.6 mg/mg) occurred in 18.6% of deferasirox-treated patients compared to 7.2% of deferoxaminetreated patients in Study 1.
Other Adverse Reactions
In the population of more than 5,000 patients with transfusional iron overload who have been treated with deferasirox during clinical trials, adverse reactions occurring in 0.1% to 1% of patients included gastritis, edema, sleep disorder, pigmentation disorder, dizziness, anxiety, maculopathy, cholelithiasis, pyrexia, fatigue, laryngeal pain, cataract, hearing loss, gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, renal tubular disorder (Fanconi’s 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, and erythema multiforme. Adverse reactions which most frequently led to dose interruption or dose adjustment during clinical trials were rash, gastrointestinal disorders, infections, increased serum creatinine, and increased serum transaminases.
Postmarketing ExperienceThe 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
Gastrointestinal disorders: gastrointestinal perforation
Blood and lymphatic system disorders: worsening anemia
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron.
Tests of genotoxicity in vitro were negative (Ames test, chromosomal aberration test) while deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction.
Dzhadenu is indicated for the treatment of chronic iron overload due to frequent blood transfusions (>7 ml/kg/month of packed red blood cells) in patients with beta thalassaemia major aged 6 years and older.
Dzhadenu is also indicated for the treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or inadequate in the following patient groups:
- in paediatric patients with beta thalassaemia major with iron overload due to frequent blood transfusions (>7 ml/kg/month of packed red blood cells) aged 2 to 5 years,
- in adult and paediatric patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells) aged 2 years and older,
- in adult and paediatric patients with other anaemias aged 2 years and older.
Dzhadenu is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older.
Treatment Of Chronic Iron Overload Due To Blood Transfusions (Transfusional Iron Overload)Dzhadenu is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. This indication is approved under accelerated approval based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Treatment Of Chronic Iron Overload In Non-Transfusion-Dependent Thalassemia SyndromesDzhadenu 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Limitations Of UseControlled clinical trials of Dzhadenu with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed.
The safety and efficacy of Dzhadenu when administered with other iron chelation therapy have not been established.
Treatment Of Chronic Iron Overload Due To Blood Transfusions (Transfusional Iron Overload)JADENU is indicated for the treatment of chronic iron overload due to blood transfusions (transfusional hemosiderosis) in patients 2 years of age and older. This indication is approved under accelerated approval based on a reduction of liver iron concentrations and serum ferritin levels. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Treatment Of Chronic Iron Overload In Non-Transfusion-Dependent Thalassemia SyndromesJADENU 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. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Limitations Of UseControlled clinical trials of JADENU with myelodysplastic syndromes (MDS) and chronic iron overload due to blood transfusions have not been performed.
The safety and efficacy of JADENU when administered with other iron chelation therapy have not been established.
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.
Cardiac ElectrophysiologyThe effect of 20 and 40 mg per kg per day of deferasirox (tablets for oral suspension) on the QT interval was evaluated in a single-dose, double-blind, randomized, placebo-and active-controlled (moxifloxacin 400 mg), parallel group study in 182 healthy male and female subjects age 18 to 65 years. No evidence of prolongation of the QTc interval was observed in this study.
Dzhadenu film-coated tablets demonstrate higher bioavailability compared to the Dzhadenu dispersible tablet formulation. After adjustment of the strength, the film-coated tablet formulation (360 mg strength) was equivalent to Dzhadenu dispersible tablets (500 mg strength) with respect to the mean area under the plasma concentration time curve (AUC) under fasting conditions. The Cmax was increased by 30% (90% CI: 20.3% - 40.0%); however a clinical exposure/response analysis revealed no evidence of clinically relevant effects of such an increase.
Absorption
Deferasirox (dispersible tablet formulation) is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox (dispersible tablet formulation) is about 70% compared to an intravenous dose. The absolute bioavailability of the film-coated tablet formulation has not been determined. Bioavailability of deferasirox film-coated tablets was 36% greater than that with dispersible tablets.
A food-effect study involving administration of the film-coated tablets to healthy volunteers under fasting conditions and with a low-fat (fat content <10% of calories) or high-fat (fat content >50% of calories) meal indicated that the AUC and Cmax were slightly decreased after a low-fat meal (by 11% and 16%, respectively). After a high-fat meal, AUC and Cmax were increased (by 18% and 29%, respectively). The increases in Cmax due to the change in formulation and due to the effect of a high-fat meal may be additive and therefore, it is recommended that the film-coated tablets should be taken either on an empty stomach or with a light meal.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
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: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).
Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro.
Elimination
Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox.
Linearity / non-linearity
The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients
Paediatric patients
The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Gender
Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment
The pharmacokinetics of deferasirox have not been studied in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range.
In a clinical study using single doses of 20 mg/kg deferasirox dispersible tablets, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C).
AbsorptionBased on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5 to 4 hours. In healthy subjects, Dzhadenu showed comparable tmax. The maximal concentrations (Cmax) and area under the curve (AUC0-24h, AUCτ) of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation.
Tablets
The absolute bioavailability [as measured by area under the curve over time to infinity (AUCinf)] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUCinf) of Dzhadenu tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf of Dzhadenu 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 Cmax was increased by 30%. The 30% increase in Cmax observed with Dzhadenu tablets is not clinically meaningful.
The administration of Dzhadenu tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUCinf and Cmax were similar to that under fasting conditions. The administration of Dzhadenu tablets with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories), increased AUCinf by 18% and Cmax by 29% compared to that under fasting conditions.
Granules
The bioavailability (as measured by AUCinf) of Dzhadenu Sprinkle granules was 52% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf of the Dzhadenu Sprinkle granules (i.e., 4 x 90 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however, the mean Cmax was increased by 34%. The 34% increase in Cmax observed with Dzhadenu Sprinkle granules is not clinically meaningful.
The administration of Dzhadenu Sprinkle granules with a soft meal (e.g., yogurt and apple sauce) or with a low-fat (approximately 450 calories with fat content approximately 30% of total calories) indicated that the AUCinf and Cmax after a low-fat meal or soft foods were similar to that under fasting conditions. The administration of Dzhadenu Sprinkle granules with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories) increased AUCinf by 18% with no changes in Cmax compared to that under fasting conditions.
DistributionDeferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults.
MetabolismGlucuronidation 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 (AUCinf) by interfering with the enterohepatic recycling of deferasirox.
ExcretionDeferasirox 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 (t1/2) ranged from 8 to 16 hours following oral administration.
AbsorptionBased on studies in patients with the tablet for oral suspension, deferasirox is absorbed following oral administration with median times to maximum plasma concentration (tmax) of about 1.5 to 4 hours. In healthy subjects, JADENU showed comparable tmax. The maximal concentrations (Cmax) and area under the curve (AUC0-24h, AUCτ) of deferasirox increase approximately linearly with dose after both single administration and under steady-state conditions. Exposure to deferasirox increased by an accumulation factor of 1.3 to 2.3 after multiple doses with the tablet for oral suspension formulation.
Tablets
The absolute bioavailability [as measured by area under the curve over time to infinity (AUCinf)] of deferasirox tablets for oral suspension is 70% compared to an intravenous dose. The bioavailability (as measured by AUCinf) of JADENU tablets was 36% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf of JADENU 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 Cmax was increased by 30%. The 30% increase in Cmax observed with JADENU tablets is not clinically meaningful.
The administration of JADENU tablets with a light meal (approximately 250 calories with fat content less than 7% of total calories) indicated that the AUCinf and Cmax were similar to that under fasting conditions. The administration of JADENU tablets with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories), increased AUCinf by 18% and Cmax by 29% compared to that under fasting conditions.
Granules
The bioavailability (as measured by AUCinf) of JADENU Sprinkle granules was 52% greater than with deferasirox tablets for oral suspension. After strength-adjustment, the mean AUCinf of the JADENU Sprinkle granules (i.e., 4 x 90 mg strength) was similar to that of deferasirox tablets for oral suspension (i.e., 500 mg strength) under fasting conditions; however, the mean Cmax was increased by 34%. The 34% increase in Cmax observed with JADENU Sprinkle granules is not clinically meaningful.
The administration of JADENU Sprinkle granules with a soft meal (e.g., yogurt and apple sauce) or with a low-fat (approximately 450 calories with fat content approximately 30% of total calories) indicated that the AUCinf and Cmax after a low-fat meal or soft foods were similar to that under fasting conditions. The administration of JADENU Sprinkle granules with a high-fat meal (approximately 1000 calories with fat content greater than 50% of total calories) increased AUCinf by 18% with no changes in Cmax compared to that under fasting conditions.
DistributionDeferasirox is highly (~99%) protein bound almost exclusively to serum albumin. The percentage of deferasirox confined to the blood cells was 5% in humans. The volume of distribution at steady state (Vss) of deferasirox is 14.37 ± 2.69 L in adults.
MetabolismGlucuronidation 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 (AUCinf) by interfering with the enterohepatic recycling of deferasirox.
ExcretionDeferasirox 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 (t1/2) ranged from 8 to 16 hours following oral administration.
| Renal function Deferasirox has been studied only in patients with baseline serum creatinine within the age-appropriate normal range. During clinical studies, increases in serum creatinine of >33% on >2 consecutive occasions, sometimes above the upper limit of the normal range, occurred in about 36% of patients. These were dose-dependent. About two-thirds of the patients showing serum creatinine increase returned below the 33% level without dose adjustment. In the remaining third the serum creatinine increase did not always respond to a dose reduction or a dose interruption. In some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction. Cases of acute renal failure have been reported following post-marketing use of deferasirox. In some post-marketing cases, renal function deterioration has led to renal failure requiring temporary or permanent dialysis. The causes of the rises in serum creatinine have not been elucidated. Particular attention should therefore be paid to monitoring of serum creatinine in patients who are concomitantly receiving medicinal products that depress renal function, and in patients who are receiving high doses of deferasirox and/or low rates of transfusion (<7 ml/kg/month of packed red blood cells or <2 units/month for an adult). While no increase in renal adverse events was observed after dose escalation of Dzhadenu dispersible tablets to doses above 30 mg/kg in clinical studies, an increased risk of renal adverse events with film-coated tablet doses above 21 mg/kg cannot be excluded. It is recommended that serum creatinine be assessed in duplicate before initiating therapy. Serum creatinine, creatinine clearance (estimated with the Cockcroft-Gault or MDRD formula in adults and with the Schwartz formula in children) and/or plasma cystatin C levels should be monitored prior to therapy, weekly in the first month after initiation or modification of therapy with Dzhadenu (including switch of formulation), and monthly thereafter. Patients with pre-existing renal conditions and patients who are receiving medicinal products that depress renal function may be more at risk of complications. Care should be taken to maintain adequate hydration in patients who develop diarrhoea or vomiting. There have been post-marketing reports of metabolic acidosis occurring during treatment with deferasirox. The majority of these patients had renal impairment, renal tubulopathy (Fanconi syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication. Acid-base balance should be monitored as clinically indicated in these populations. Interruption of Dzhadenu therapy should be considered in patients who develop metabolic acidosis. Table 3 Dose adjustment and interruption of treatment for renal monitoring | |||
| Serum creatinine | Creatinine clearance | ||
| Before initiation of therapy | Twice (2x) | and | Once (1x) |
| Contraindicated | <60 ml/min | ||
| Monitoring | |||
| - First month after start of therapy or dose modification (including switch of formulation) | Weekly | and | Weekly |
| - Thereafter | Monthly | and | Monthly |
| Reduction of daily dose by 7 mg/kg/day (film-coated tablet formulation), if following renal parameters are observed at two consecutive visits and cannot be attributed to other causes | |||
| Adult patients | >33% above pre-treatment average | and | Decreases <LLN* (<90 ml/min) |
| Paediatric patients | > age appropriate ULN** | and/or | Decreases <LLN* (<90 ml/min) |
| After dose reduction, interrupt treatment, if | |||
| Adult and paediatric | Remains >33% above pre-treatment average | and/or | Decreases <LLN* (<90 ml/min) |
| *LLN: lower limit of the normal range **ULN: upper limit of the normal range | |||
| Treatment may be reinitiated depending on the individual clinical circumstances. Dose reduction or interruption may be also considered if abnormalities occur in levels of markers of renal tubular function and/or as clinically indicated: - Proteinuria (test should be performed prior to therapy and monthly thereafter) - Glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria (monitor as needed). Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with Dzhadenu. Patients should be referred to a renal specialist, and further specialised investigations (such as renal biopsy) may be considered if the following occur despite dose reduction and interruption: - Serum creatinine remains significantly elevated and - Persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi Syndrome). Hepatic function Liver function test elevations have been observed in patients treated with deferasirox. Post-marketing cases of hepatic failure, sometimes fatal, have been reported in patients treated with deferasirox. Most reports of hepatic failure involved patients with significant morbidities including pre-existing liver cirrhosis. However, the role of deferasirox as a contributing or aggravating factor cannot be excluded. It is recommended that serum transaminases, bilirubin and alkaline phosphatase be checked before the initiation of treatment, every 2 weeks during the first month and monthly thereafter. If there is a persistent and progressive increase in serum transaminase levels that cannot be attributed to other causes, Dzhadenu should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered. Dzhadenu is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). Table 4 Summary of safety monitoring recommendations | |||
| Test | Frequency | ||
| Serum creatinine | In duplicate prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. | ||
| Creatinine clearance and/or plasma cystatin C | Prior to therapy. Weekly during first month of therapy or after dose modification (including switch of formulation). Monthly thereafter. | ||
| Proteinuria | Prior to therapy. Monthly thereafter. | ||
| Other markers of renal tubular function (such as glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria) | As needed. | ||
| Serum transaminases, bilirubin, alkaline phosphatase | Prior to therapy. Every 2 weeks during first month of therapy. Monthly thereafter. | ||
| Auditory and ophthalmic testing | Prior to therapy. Annually thereafter. | ||
| Body weight, height and sexual development | Prior to therapy. Annually in paediatric patients. | ||
In patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of Dzhadenu might be limited and may be inferior to risks. As a consequence, treatment with Dzhadenu is not recommended in these patients.
Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea).
Data in children with non-transfusion-dependent thalassaemia are very limited. As a consequence, Dzhadenu therapy should be closely monitored to detect adverse reactions and to follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded children with non-transfusion-dependent thalassaemia with Dzhadenu, the physician should be aware that the consequences of long-term exposure in such patients are currently not known.
Gastrointestinal disorders
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients. There have been reports of ulcers complicated with digestive perforation. Also, there have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during Dzhadenu therapy and promptly initiate additional evaluation and treatment if a serious gastrointestinal adverse reaction is suspected. Caution should be exercised in patients who are taking Dzhadenu in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm3 (50 x 109/l).
Skin disorders
Skin rashes may appear during Dzhadenu treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration. 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. If any SCAR is suspected, Dzhadenu should be discontinued immediately and should not be reintroduced. At the time of prescription, patients should be advised of the signs and symptoms of severe skin reactions, and be closely monitored.
Hypersensitivity reactions
Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, with the onset of the reaction occurring in the majority of cases within the first month of treatment. If such reactions occur, Dzhadenu should be discontinued and appropriate medical intervention instituted. Deferasirox should not be reintroduced in patients who have experienced a hypersensitivity reaction due to the risk of anaphylactic shock.
Vision and hearing
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported. Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered.
Blood disorders
There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia in patients treated with deferasirox. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia.
Other considerations
Monthly monitoring of serum ferritin is recommended in order to assess the patient's response to therapy. If serum ferritin falls consistently below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent thalassaemia syndromes), an interruption of treatment should be considered.
The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends.
In two clinical studies, growth and sexual development of paediatric patients treated with deferasirox for up to 5 years were not affected. However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored prior to therapy and at regular intervals (every 12 months).
Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with Dzhadenu.
WARNINGSIncluded as part of the "PRECAUTIONS" Section
PRECAUTIONS Renal Toxicity, Renal Failure, And ProteinuriaDzhadenu can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, deferasirox-treated patients experienced dose-dependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3).
Measure serum creatinine in duplicate (due to variations in measurements) and determine the CLcr (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or CLcr more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary.
Dzhadenu is contraindicated in patients with CLcr less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate ULN.
Renal tubular damage, including Fanconi’s Syndrome, has been reported in patients treated with deferasirox, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels less than 1500 mcg/L.
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 clinical trials in patients with transfusional iron overload, deferasirox was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain.
Hepatic Toxicity And FailureDeferasirox can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure.
Measure transaminases (AST and 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 Dzhadenu in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.
Gastrointestinal (GI) Ulceration, Hemorrhage, And PerforationGI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Monitor for signs and symptoms of GI ulceration and hemorrhage during Dzhadenu therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering Dzhadenu 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 gastrointestinal perforation (including fatal outcome).
Bone Marrow SuppressionNeutropenia, 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 Dzhadenu in patients who develop cytopenias until the cause of the cytopenia has been determined. Dzhadenu is contraindicated in patients with platelet counts below 50 x 109/L.
Increased Risk Of Toxicity In The ElderlyDeferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting, predominantly in elderly patients. Monitor elderly patients treated with Dzhadenu more frequently for toxicity.
HypersensitivityDzhadenu may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue Dzhadenu and institute appropriate medical intervention. Dzhadenu 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.
Severe Skin ReactionsSevere skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme, have been reported during deferasirox therapy. The risk of other skin reactions including DRESS (drug reaction with eosinophilia and systemic symptoms) cannot be excluded. If severe skin reactions are suspected, discontinue Dzhadenu immediately and do not reintroduce Dzhadenu therapy.
Skin RashRashes may occur during Dzhadenu treatment. For rashes of mild to moderate severity, Dzhadenu may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with Dzhadenu. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.
Auditory And Ocular AbnormalitiesAuditory 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. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting Dzhadenu treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.
OverchelationFor patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with Dzhadenu, since overchelation may increase Dzhadenu toxicity.
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 Dzhadenu 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 Dzhadenu and obtain a confirmatory LIC.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityA 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg/day (0.7 times the MRHD on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg/day (1.2 times the MRHD on a mg/m2 basis) in males and 300 mg/kg/day (1.7 times the MRHD on a mg/m2 basis) in females.
Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests.
Deferasirox at oral doses up to 75 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
Use In Specific Populations Pregnancy Risk SummaryThere are no studies with the use of Dzhadenu 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/m2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on a mg/m2 basis. Dzhadenu 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. 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.
DataAnimal Data
In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on a mg/m2 basis). These doses resulted in maternal toxicity but no fetal harm was observed.
In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m2 basis).
Lactation Risk SummaryNo data are available regarding the presence of Dzhadenu or its metabolites in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseOf the 700 patients with transfusional iron overload who received deferasirox during clinical studies, 292 were pediatric patients 2 to less than 16 years of age with various congenital and acquired anemias, including 52 patients age 2 to less than 6 years, 121 patients age 6 to less than 12 years and 119 patients age 12 to less than 16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2 to less than 6 years have a systemic exposure to deferasirox approximately 50% of that of adults. However, the safety and efficacy of deferasirox in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults.
Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials.
Sixteen pediatric patients (10 to less than 16 years of age) with chronic iron overload and NTDT were treated with deferasirox in clinical studies. The safety and efficacy of deferasirox in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT.
Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age.
Geriatric UseFour 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 65 and 75 years of age while 206 were greater than or equal to 75 years of age. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.
Renal ImpairmentFor patients with creatinine clearance (CLcr) 40 to 60 mL/min, reduce the starting dose by 50%. Dzhadenu is contraindicated in patients with a CLcr less than 40 mL/min or serum creatinine greater than two times the age-appropriate upper limit of normal (ULN).
Dzhadenu can cause renal failure. Monitor serum creatinine and calculate creatinine clearance during treatment in all patients. Reduce, interrupt or discontinue Dzhadenu dosing based on increases in serum creatinine.
Hepatic ImpairmentAvoid use in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, reduce the starting dose by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration.
WARNINGSIncluded as part of the "PRECAUTIONS" Section
PRECAUTIONS Renal Toxicity, Renal Failure, And ProteinuriaJADENU can cause acute renal failure, fatal in some patients and requiring dialysis in others. Postmarketing experience showed that most fatalities occurred in patients with multiple comorbidities and who were in advanced stages of their hematological disorders. In the clinical trials, deferasirox-treated patients experienced dose-dependent increases in serum creatinine. In patients with transfusional iron overload, these increases in creatinine occurred at a greater frequency compared to deferoxamine-treated patients (38% versus 14%, respectively, in Study 1 and 36% versus 22%, respectively, in Study 3).
Measure serum creatinine in duplicate (due to variations in measurements) and determine the CLcr (estimated by the Cockcroft-Gault method) before initiating therapy in all patients in order to establish a reliable pretreatment baseline. Monitor serum creatinine weekly during the first month after initiation or modification of therapy and at least monthly thereafter. Monitor serum creatinine and/or CLcr more frequently if creatinine levels are increasing. Dose reduction, interruption, or discontinuation based on increases in serum creatinine may be necessary.
JADENU is contraindicated in patients with CLcr less than 40 mL/minute or serum creatinine greater than 2 times the age appropriate ULN.
Renal tubular damage, including Fanconi’s Syndrome, has been reported in patients treated with deferasirox, most commonly in children and adolescents with beta-thalassemia and serum ferritin levels less than 1500 mcg/L.
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 clinical trials in patients with transfusional iron overload, deferasirox was temporarily withheld until the urine protein/creatinine ratio fell below 0.6 mg/mg. Monthly monitoring for proteinuria is recommended. The mechanism and clinical significance of the proteinuria are uncertain.
Hepatic Toxicity And FailureDeferasirox can cause hepatic injury, fatal in some patients. In Study 1, 4 patients (1.3%) discontinued deferasirox because of hepatic toxicity (drug-induced hepatitis in 2 patients and increased serum transaminases in 2 additional patients). Hepatic toxicity appears to be more common in patients greater than 55 years of age. Hepatic failure was more common in patients with significant comorbidities, including liver cirrhosis and multiorgan failure.
Measure transaminases (AST and 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 JADENU in patients with severe (Child-Pugh C) hepatic impairment. Reduce the starting dose in patients with moderate (Child-Pugh B) hepatic impairment. Patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment may be at higher risk for hepatic toxicity.
Gastrointestinal (GI) Ulceration, Hemorrhage, And PerforationGI hemorrhage, including deaths, has been reported, especially in elderly patients who had advanced hematologic malignancies and/or low platelet counts. Nonfatal upper GI irritation, ulceration and hemorrhage have been reported in patients, including children and adolescents, receiving deferasirox. Monitor for signs and symptoms of GI ulceration and hemorrhage during JADENU therapy and promptly initiate additional evaluation and treatment if a serious GI adverse event is suspected. The risk of gastrointestinal hemorrhage may be increased when administering JADENU 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 gastrointestinal perforation (including fatal outcome).
Bone Marrow SuppressionNeutropenia, 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 JADENU in patients who develop cytopenias until the cause of the cytopenia has been determined. JADENU is contraindicated in patients with platelet counts below 50 x 109/L.
Increased Risk Of Toxicity In The ElderlyDeferasirox has been associated with serious and fatal adverse reactions in the postmarketing setting, predominantly in elderly patients. Monitor elderly patients treated with JADENU more frequently for toxicity.
HypersensitivityJADENU may cause serious hypersensitivity reactions (such as anaphylaxis and angioedema), with the onset of the reaction usually occurring within the first month of treatment. If reactions are severe, discontinue JADENU and institute appropriate medical intervention. JADENU 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.
Severe Skin ReactionsSevere skin reactions, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and erythema multiforme, have been reported during deferasirox therapy. The risk of other skin reactions including DRESS (drug reaction with eosinophilia and systemic symptoms) cannot be excluded. If severe skin reactions are suspected, discontinue JADENU immediately and do not reintroduce JADENU therapy.
Skin RashRashes may occur during JADENU treatment. For rashes of mild to moderate severity, JADENU may be continued without dose adjustment, since the rash often resolves spontaneously. In severe cases, interrupt treatment with JADENU. Reintroduction at a lower dose with escalation may be considered after resolution of the rash.
Auditory And Ocular AbnormalitiesAuditory 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. Perform auditory and ophthalmic testing (including slit lamp examinations and dilated fundoscopy) before starting JADENU treatment and thereafter at regular intervals (every 12 months). If disturbances are noted, monitor more frequently. Consider dose reduction or interruption.
OverchelationFor patients with transfusional iron overload, measure serum ferritin monthly to assess for possible overchelation of iron. If the serum ferritin falls below 500 mcg/L, consider interrupting therapy with JADENU, since overchelation may increase JADENU toxicity.
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 JADENU 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 JADENU and obtain a confirmatory LIC.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityA 104-week oral carcinogenicity study in Wistar rats showed no evidence of carcinogenicity from deferasirox at doses up to 60 mg/kg/day (0.7 times the MRHD on a mg/m2 basis). A 26-week oral carcinogenicity study in p53 (+/-) transgenic mice has shown no evidence of carcinogenicity from deferasirox at doses up to 200 mg/kg/day (1.2 times the MRHD on a mg/m2 basis) in males and 300 mg/kg/day (1.7 times the MRHD on a mg/m2 basis) in females.
Deferasirox was negative in the Ames test and chromosome aberration test with human peripheral blood lymphocytes. It was positive in 1 of 3 in vivo oral rat micronucleus tests.
Deferasirox at oral doses up to 75 mg/kg/day (0.9 times the MRHD on a mg/m2 basis) was found to have no adverse effect on fertility and reproductive performance of male and female rats.
Use In Specific Populations Pregnancy Risk SummaryThere are no studies with the use of JADENU 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/m2 basis. No fetal effects were noted in pregnant rabbits at doses equivalent to the human recommended dose on a mg/m2 basis. JADENU 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. 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.
DataAnimal Data
In embryo-fetal developmental studies, pregnant rats and rabbits received oral deferasirox during the period of organogenesis at doses up to 100 mg/kg/day in rats and 50 mg/kg/day in rabbits (1.2 times the maximum recommended human dose (MRHD) on a mg/m2 basis). These doses resulted in maternal toxicity but no fetal harm was observed.
In a prenatal and postnatal developmental study, pregnant rats received oral deferasirox daily from organogenesis through lactation day 20 at doses of 10, 30, and 90 mg/kg/day (0.1, 0.3, and 1.0 times the MRHD on a mg/m2 basis). Maternal toxicity, loss of litters, and decreased offspring viability occurred at 90 mg/kg/day (1.0 times the MRHD on a mg/m2 basis), and increases in renal anomalies in male offspring occurred at 30 mg/kg/day (0.3 times the MRHD on a mg/m2 basis).
Lactation Risk SummaryNo data are available regarding the presence of JADENU or its metabolites in human milk, the effects of the drug on the breastfed infant, or the effects of the drug on milk production. Deferasirox and its metabolites were excreted in rat milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from deferasirox and its metabolites, a decision should be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the drug to the mother.
Pediatric UseOf the 700 patients with transfusional iron overload who received deferasirox during clinical studies, 292 were pediatric patients 2 to less than 16 years of age with various congenital and acquired anemias, including 52 patients age 2 to less than 6 years, 121 patients age 6 to less than 12 years and 119 patients age 12 to less than 16 years. Seventy percent of these patients had beta-thalassemia. Children between the ages of 2 to less than 6 years have a systemic exposure to deferasirox approximately 50% of that of adults. However, the safety and efficacy of deferasirox in pediatric patients was similar to that of adult patients, and younger pediatric patients responded similarly to older pediatric patients. The recommended starting dose and dosing modification are the same for children and adults.
Growth and development in patients with chronic iron overload due to blood transfusions were within normal limits in children followed for up to 5 years in clinical trials.
Sixteen pediatric patients (10 to less than 16 years of age) with chronic iron overload and NTDT were treated with deferasirox in clinical studies. The safety and efficacy of deferasirox in these children was similar to that seen in the adults. The recommended starting dose and dosing modification are the same for children and adults with chronic iron overload in NTDT.
Safety and effectiveness have not been established in pediatric patients with chronic iron overload due to blood transfusions who are less than 2 years of age or pediatric patients with chronic iron overload and NTDT who are less than 10 years of age.
Geriatric UseFour 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 65 and 75 years of age while 206 were greater than or equal to 75 years of age. The majority of these patients had myelodysplastic syndrome (MDS) (n=393). In these trials, elderly patients experienced a higher frequency of adverse reactions than younger patients. Monitor elderly patients for early signs or symptoms of adverse reactions that may require a dose adjustment. Elderly patients are at increased risk for toxicity due to the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.
Renal ImpairmentFor patients with creatinine clearance (CLcr) 40 to 60 mL/min, reduce the starting dose by 50%. JADENU is contraindicated in patients with a CLcr less than 40 mL/min or serum creatinine greater than two times the age-appropriate upper limit of normal (ULN).
JADENU can cause renal failure. Monitor serum creatinine and calculate creatinine clearance during treatment in all patients. Reduce, interrupt or discontinue JADENU dosing based on increases in serum creatinine.
Hepatic ImpairmentAvoid use in patients with severe (Child-Pugh C) hepatic impairment. For patients with moderate (Child-Pugh B) hepatic impairment, reduce the starting dose by 50%. Closely monitor patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment for efficacy and adverse reactions that may require dose titration.
Dzhadenu has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines.
Treatment with Dzhadenu should be initiated and maintained by physicians experienced in the treatment of chronic iron overload.
Posology
Transfusional iron overload
It is recommended that treatment be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells (PRBC) or when there is evidence from clinical monitoring that chronic iron overload is present (e.g. serum ferritin >1,000 µg/l). Doses (in mg/kg) must be calculated and rounded to the nearest whole tablet size.
The goals of iron chelation therapy are to remove the amount of iron administered in transfusions and, as required, to reduce the existing iron burden.
Dzhadenu film-coated tablets demonstrate higher bioavailability compared to the Dzhadenu dispersible tablet formulation. In case of switching from dispersible tablets to film-coated tablets, the dose of the film-coated tablets should be 30% lower than the dose of the dispersible tablets, rounded to the nearest whole tablet.
The corresponding doses for the different formulations are shown in the table below.
Table 1 Recommended doses for transfusional iron overload
| Film-coated tablets/granules | Dispersible tablets | Transfusions | Serum ferritin | ||
| Starting dose | 14 mg/kg/day | 20 mg/kg/day | After 20 units (about 100 ml/kg) of PRBC | or | >1,000 µg/l |
| Alternative starting doses | 21 mg/kg/day | 30 mg/kg/day | >14 ml/kg/month of PRBC (approx. >4 units/month for an adult) | ||
| 7 mg/kg/day | 10 mg/kg/day | <7 ml/kg/month of PRBC (approx. <2 units/month for an adult) | |||
| For patients well managed on deferoxamine | One third of deferoxamine dose | Half of deferoxamine dose | |||
| Monitoring | Monthly | ||||
| Target range | 500-1,000 µg/l | ||||
| Adjustment steps (every 3-6 months) | Increase | >2,500 µg/l | |||
| 3.5 - 7 mg/kg/day Up to 28 mg/kg/day | 5-10 mg/kg/day Up to 40 mg/kg/day | ||||
| Decrease | |||||
| 3.5 - 7 mg/kg/day | 5-10 mg/kg/day | <2,500 µg/l | |||
| In patients treated with doses >21 mg/kg/day | In patients treated with doses >30 mg/kg/day | ||||
| - When target is reached | 500-1,000 µg/l | ||||
| Maximum dose | 28 mg/kg/day | 40 mg/kg/day | |||
| Consider interruption | <500 µg/l | ||||
Starting dose
The recommended initial daily dose of Dzhadenu film-coated tablets is 14 mg/kg body weight.
An initial daily dose of 21 mg/kg may be considered for patients who require reduction of elevated body iron levels and who are also receiving more than 14 ml/kg/month of packed red blood cells (approximately >4 units/month for an adult).
An initial daily dose of 7 mg/kg may be considered for patients who do not require reduction of body iron levels and who are also receiving less than 7 ml/kg/month of packed red blood cells (approximately <2 units/month for an adult). The patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained.
For patients already well managed on treatment with deferoxamine, a starting dose of Dzhadenu film-coated tablets that is numerically one third that of the deferoxamine dose could be considered (e.g. a patient receiving 40 mg/kg/day of deferoxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 14 mg/kg/day of Dzhadenu film-coated tablets). When this results in a daily dose less than 14 mg/kg body weight, the patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained.
Dose adjustment
It is recommended that serum ferritin be monitored every month and that the dose of Dzhadenu be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 3.5 to 7 mg/kg and are to be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 21 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 28 mg/kg may be considered. The availability of long-term efficacy and safety data from clinical studies conducted with Dzhadenu dispersible tablets used at doses above 30 mg/kg is currently limited (264 patients followed for an average of 1 year after dose escalation). If only very poor haemosiderosis control is achieved at doses up to 21 mg/kg, a further increase (to a maximum of 28 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 21 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 28 mg/kg are not recommended because there is only limited experience with doses above this level.
In patients treated with doses greater than 21 mg/kg, dose reductions in steps of 3.5 to 7 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/l), dose reductions in steps of 3.5 to 7 mg/kg should be considered to maintain serum ferritin levels within the target range. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered.
Non-transfusion-dependent thalassaemia syndromes
Chelation therapy should only be initiated when there is evidence of iron overload (liver iron concentration [LIC] >5 mg Fe/g dry weight [dw] or serum ferritin consistently >800 µg/l). LIC is the preferred method of iron overload determination and should be used wherever available. Caution should be taken during chelation therapy to minimise the risk of over-chelation in all patients.
Dzhadenu film-coated tablets demonstrate higher bioavailability compared to the Dzhadenu dispersible tablet formulation. In case of switching from dispersible tablets to film-coated tablets, the dose of the film-coated tablets should be 30% lower than the dose of the dispersible tablets, rounded to the nearest whole tablet.
The corresponding doses for the different formulations are shown in the table below.
Table 2 Recommended doses for non-transfusion-dependent thalassaemia syndromes
| Film-coated tablets/granules | Dispersible tablets | Liver iron concentration (LIC)* | Serum ferritin | ||
| Starting dose | 7 mg/kg/day | 10 mg/kg/day | >5 mg Fe/g dw | or | >800 µg/l |
| Monitoring | Monthly | ||||
| Adjustment steps (every 3-6 months) | Increase | >7 mg Fe/g dw | or | >2,000 µg/l | |
| 3.5 - 7 mg/kg/day | 5-10 mg/kg/day | ||||
| Decrease | <7 mg Fe/g dw | or | ≤2,000 µg/l | ||
| 3.5 - 7 mg/kg/day | 5-10 mg/kg/day | ||||
| Maximum dose | 14 mg/kg/day | 20 mg/kg/day | |||
| 7 mg/kg/day | 10 mg/kg/day | ||||
| For adults | not assessed | and | ≤2,000 µg/l | ||
| For paediatric patients | |||||
| Interruption | <3 mg Fe/g dw | or | <300 µg/l | ||
| Retreatment |
|
| Not recommended | ||
*LIC is the preferred method of iron overload determination.
Starting dose
The recommended initial daily dose of Dzhadenu film-coated tablets in patients with non-transfusion-dependent thalassaemia syndromes is 7 mg/kg body weight.
Dose adjustment
It is recommended that serum ferritin be monitored every month. After every 3 to 6 months of treatment, a dose increase in increments of 3.5 to 7 mg/kg should be considered if the patient's LIC is >7 mg Fe/g dw, or if serum ferritin is consistently >2,000 µg/l and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 14 mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassaemia syndromes.
In patients in whom LIC was not assessed and serum ferritin is ≤2,000 µg/l, dosing should not exceed 7 mg/kg.
For patients in whom the dose was increased to >7 mg/kg, dose reduction to 7 mg/kg or less is recommended when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 µg/l.
Treatment cessation
Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 µg/l), treatment should be stopped. There are no data available on the retreatment of patients who reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment cannot be recommended.
Special populations
Elderly patients (>65 years of age)
The dosing recommendations for elderly patients are the same as described above. In clinical studies, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse reactions that may require a dose adjustment.
Paediatric population
Transfusional iron overload:
The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron overload are the same as for adult patients. Changes in weight of paediatric patients over time must be taken into account when calculating the dose.
In children with transfusional iron overload aged between 2 and 5 years, exposure is lower than in adults. This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration.
Non-transfusion-dependent thalassaemia syndromes:
In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 7 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid overchelation: in addition to monthly serum ferritin assessments, LIC should be monitored every three months when serum ferritin is ≤800 µg/l.
Children from birth to 23 months:
The safety and efficacy of Dzhadenu in children from birth to 23 months of age have not been established. No data are available.
Patients with renal impairment
Dzhadenu has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min.
Patients with hepatic impairment
Dzhadenu is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably reduced followed by progressive increase up to a limit of 50% , and Dzhadenu must be used with caution in such patients. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month.
Method of administration
For oral use.
The film-coated tablets should be swallowed whole with some water. For patients who are unable to swallow whole tablets, the film-coated tablets may be crushed and administered by sprinkling the full dose onto soft food, e.g. yogurt or apple sauce (pureed apple). The dose should be immediately and completely consumed, and not stored for future use.
The film-coated tablets should be taken once a day, preferably at the same time each day, and may be taken on an empty stomach or with a light meal.
Transfusional Iron OverloadDzhadenu 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 1000 mcg/L.
Prior to starting therapy, obtain:
The recommended initial dose of Dzhadenu for patients 2 years of age and older 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.
After commencing therapy, monitor serum ferritin monthly and adjust the dose of Dzhadenu, if necessary, every 3 to 6 months based on serum ferritin trends. 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 2500 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.
If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with Dzhadenu.
Iron Overload In Non-Transfusion-Dependent Thalassemia SyndromesDzhadenu 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:
Initiating therapy:
During therapy:
Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.
AdministrationSwallow Dzhadenu tablets once daily with water or other liquids, preferably at the same time each day. Take Dzhadenu 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 Dzhadenu tablets with aluminum-containing antacid products. For patients who have difficulty swallowing whole tablets, Dzhadenu tablets may be crushed and mixed with soft foods (e.g., yogurt or apple sauce) 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 Dzhadenu Sprinkle granules on an empty stomach or with a light meal. Administer Dzhadenu Sprinkle granules by sprinkling the full dose on soft food (e.g. yogurt or apple sauce) immediately prior to use and administered orally. Dzhadenu Sprinkle granules should be taken once a day, preferably at the same time each day. Do not take Dzhadenu Sprinkle granules with aluminum-containing antacid products.
For patients who are currently on chelation therapy with Exjade tablets for oral suspension and converting to Dzhadenu, 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 Dzhadenu.
| EXJADE Tablets for oral suspension (white round tablet) | Dzhadenu Tablets (film coated blue oval tablet) Dzhadenu 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 |
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 Dzhadenu tablets or Dzhadenu Sprinkle granules.
Patients With Baseline Renal ImpairmentFor patients with CLcr 40 to 60 mL/min, reduce the starting dose by 50%. Do not use Dzhadenu in patients with serum creatinine greater than two times the age-appropriate upper limit of normal (ULN) or CLcr less than 40 mL/min.
Dose Modifications For Increases In Serum CreatinineFor serum creatinine increases while receiving Dzhadenu modify the dose as follows:
Transfusional Iron OverloadAdults and Adolescents (ages 16 years and older):
Pediatric Patients (ages 2 to 15 years):
All Patients (regardless of age):
Adults and Adolescents (ages 16 years and older):
Pediatric Patients (ages 10 to 15 years):
All Patients (regardless of age):
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 Dzhadenu tablets or Dzhadenu 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.
Bile Acid SequestrantsConcomitant 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 Dzhadenu tablets or Dzhadenu 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.
Transfusional Iron OverloadJADENU 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 1000 mcg/L.
Prior to starting therapy, obtain:
The recommended initial dose of JADENU for patients 2 years of age and older 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.
After commencing therapy, monitor serum ferritin monthly and adjust the dose of JADENU, if necessary, every 3 to 6 months based on serum ferritin trends. 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 2500 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.
If the serum ferritin falls consistently below 500 mcg/L, consider temporarily interrupting therapy with JADENU.
Iron Overload In Non-Transfusion-Dependent Thalassemia SyndromesJADENU 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:
Initiating therapy:
During therapy:
Restart treatment when the LIC rises again to more than 5 mg Fe/g dw.
AdministrationSwallow 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. For patients who have difficulty swallowing whole tablets, JADENU tablets may be crushed and mixed with soft foods (e.g., yogurt or apple sauce) 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. Administer JADENU Sprinkle granules by sprinkling the full dose on soft food (e.g. yogurt or apple sauce) 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.
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 |
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.
Patients With Baseline Renal ImpairmentFor patients with CLcr 40 to 60 mL/min, reduce the starting dose by 50%. Do not use JADENU in patients with serum creatinine greater than two times the age-appropriate upper limit of normal (ULN) or CLcr less than 40 mL/min.
Dose Modifications For Increases In Serum CreatinineFor serum creatinine increases while receiving JADENU modify the dose as follows:
Transfusional Iron OverloadAdults and Adolescents (ages 16 years and older):
Pediatric Patients (ages 2 to 15 years):
All Patients (regardless of age):
Adults and Adolescents (ages 16 years and older):
Pediatric Patients (ages 10 to 15 years):
All Patients (regardless of age):
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.
Bile Acid SequestrantsConcomitant 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.
No special requirements.
