Iron chelating agent.
Pharmacology: Pharmacodynamics: Mechanism of Action:
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the feces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals.
In an iron balance metabolic study in iron overloaded adult thalassemic patients, deferasirox at daily doses of 10, 20 and 40 mg/kg (dispersible tablet formulation) induced the mean net excretion of 0.119, 0.329, and 0.445 mg Fe/kg body weight/day, respectively.
Deferasirox has been investigated in adult and pediatric patients (aged 2 years and older) with chronic iron overload due to blood transfusions. The underlying conditions requiring transfusion included beta-thalassemia, sickle cell disease, and other congenital and acquired anemias (myelodysplastic syndromes, Diamond-Blackfan syndrome, aplastic anemia and other very rare anemias).
Daily treatment with the deferasirox dispersible tablet formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and pediatric patients with beta-thalassemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight) on average, respectively, and serum ferritin was reduced by about -36 and -926 microgram /L on average, respectively. At these same doses the ratios of iron excretion: iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. Deferasirox induced similar responses in iron overloaded patients with other anemias. Daily doses of 10 mg/kg (dispersible tablet formulation) for one year could maintain liver iron and serum ferritin levels, and induce net iron balance in patients receiving infrequent tr ansfusions or exchange transfusions (see Dosage & Administration). Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy.
In patients with deferasirox cardiac iron deposition (MRI T2* <20 ms), treatment with deferasirox was shown to remove cardiac iron as demonstrated by progressive improvements in T2* values over 3 years of observation. In patients without cardiac deposition, deferasirox was shown to prevent clinically relevant cardiac iron deposition (maintenance of T2* at >20 ms) over 1 year of observation, despite significant ongoing transfusion exposure.
In patients with non-transfusion-dependent thalassemia syndromes and iron overload, treatment with deferasirox at a dose of 10 mg/kg/day (dispersible tablet formulation) for one year led to a reduction in mean liver iron concentration from baseline by -3.80 mg Fe/g dw, while an increase of 0.38 mg Fe/g dw was observed in patients treated with placebo. In addition, treatment with deferasirox at a dose of 10 mg/kg/day for one year led to a reduction in mean serum ferritin from baseline by -222.0 microgram/L, while an increase of 114.5 microgram/L was observed in patients treated with placebo.
Clinical efficacy studies were conducted with deferasirox dispersible tablets. An open-label, randomized, Phase III, active comparator control study to compare deferasirox dispersible tablets and Desferal (deferoxamine) was conducted in patients with beta-thalassemia and transfusional hemosiderosis. Patients ≥2 years of age were randomized in a 1:1 ratio to receive either oral deferasirox at starting doses of 5, 10, 20 or 30 mg/kg once daily or subcutaneous (deferoxamine) at starting doses of 20 to 60 mg/kg for at least 5 days per week based on liver iron concentration (LIC) at baseline (2 to 3, >3 to 7, >7 to 14 and >14 mg Fe/g dry weight (dw)). Patients randomized to deferoxamine who had LIC values <7 mg Fe/g dw were permitted to continue on their prior deferoxamine dose, even though the dose may have been higher than specified in the protocol.
LIC was assessed at baseline and after 12 months of therapy by liver biopsy or non-invasively by biomagnetic susceptometry. Success rate, the primary efficacy endpoint, was defined as a reduction in LIC of ≥3 mg Fe/g dw for baseline values ≥10 mg Fe/g dw, reduction of baseline values between 7 and <10 to <7 mg Fe/g dw, or maintenance or reduction for baseline values <7 mg Fe/g dw. Deferasirox was to be declared non-inferior to deferoxamine if the lower limit of the 95% confidence interval (two-sided) of the difference in success rates was above -15%.
In total, 586 patients were randomized. Demographics were well balanced. Fifty-one percent of the patients were <16 years of age. The overall success rates were 52.9% for deferasirox and 66.4% for deferoxamine with a difference of -13.5 in success rates and a 95% CI of [-21.6, -5.4]. Non-inferiority to deferoxamine was not achieved because the lower limit of the CI was below -15%. This is attributed to the imbalance of the protocol-specified dose to the actual dose in the two lowest dose cohorts of the deferoxamine arm (Table 1). However, non-inferiority was demonstrated in a group of patients with baseline LIC levels ≥7 mg Fe/g dw who were allocated to the higher dose groups (deferasirox doses of 20 or 30 mg/kg and deferoxamine doses of ≥35 mg/kg). The success rates with deferasirox and deferoxamine were 58.6% and 58.9%, respectively, and the lower limit of the 95% CI (-10.2%) was above the non-inferiority threshold of -15%.
In patients with LIC ≥7 mg Fe/g dw who were treated with deferasirox 20 to 30 mg/kg per day, a statistically significant reduction in LIC from baseline was observed (-5.3 ± 8.0 mg Fe/g dw, p <0.001, t-test) which was not statistically significantly different from deferoxamine (-4.3 ± 5.8 mg Fe/g dw, p=0.367). Dose dependent effects in serum ferritin and in the ratio of iron excretion/iron intake from deferasirox doses of 5 to 30 mg/kg were also observed (see Table 1).
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A second trial, an open-label, non-comparative, Phase II trial of efficacy and safety of deferasirox dispersible tablets given for 1 year to patients with chronic anemias and transfusional hemosiderosis unable to be treated with deferoxamine, was also conducted. Patients received 5, 10, 20, or 30 mg/kg per day of deferasirox based on baseline LIC. The primary endpoint was to demonstrate a success rate significantly greater than 50% with deferasirox.
A total of 184 patients were treated in this study: 85 patients with beta-thalassemia and 99 patients with other congenital or acquired anemias (myelodysplastic syndromes, n=47; Diamond-Blackfan syndrome, n=30; other, n=22). Nineteen percent of patients were <16 years of age and 16% were ≥65. Thirty-seven patients had not received prior chelation therapy. In the total population, the success rate (50.5%) was not statistically significantly higher than 50%. This was attributed to the fact that the doses of 5 and 10 mg/kg were insufficient for the ongoing rate of iron intake from blood transfusions. However, in patients with LIC ≥7 mg Fe/g dw for whom both baseline and end of study LIC was available and who received deferasirox 20 to 30 mg/kg per day, the success rate was 58.5% [p=0.022 (50.3, 66.6)] and there was a statistically significant reduction in the absolute LIC from baseline to end of study (-5.5 ± 7.4 mg Fe/g dw, p <0.001, t-test). There was also a dose dependent effect on serum ferritin and the ratio of iron excretion to iron intake from doses of 5 to 30 mg/kg per day.
A third study was conducted in patients with sickle cell disease and transfusional hemosiderosis. This study was an open-label, randomized, Phase II study of the safety and efficacy of deferasirox dispersible tablets relative to deferoxamine given for 1 year. Patients were randomized to deferasirox at doses of 5, 10, 20, or 30 mg/kg per day or subcutaneous deferoxamine at doses of 20 to 60 mg/kg per day for 5 days per week according to baseline LIC.
A total of 195 patients were treated in this study: 132 with deferasirox and 63 with deferoxamine. Forty-four percent of patients were <16 years of age and 91% were Black. At the end of the study, the mean change in LIC in the per protocol-1 (PP-1) population, which consisted of patients who had at least one post-baseline LIC assessment, was -1.3 mg Fe/g dry weight for patients receiving deferasirox (n=113) and -0.7 mg Fe/g dry weight for patients receiving deferoxamine (n=54).
A cardiac sub-study was conducted as part of a Phase IV study with deferasirox dispersible tablets. The cardiac sub-study was a one year, prospective, open-label, single-arm study which included two cohorts of severely iron overloaded beta-thalassemia patients with LVEF values ≥56%: 114 patients with baseline T2* values >5 to <20 ms indicating myocardial siderosis (treatment cohort) and 78 patients with myocardial T2* ≥20 ms indicating no clinically significant cardiac iron deposition (prevention cohort). In the treatment cohort, the deferasirox starting dose was 30 mg/kg/day, with escalation to a maximum of 40 mg/kg/day. In the prevention cohort, the deferasirox starting dose was 20-30 mg/kg/day, with escalation to a maximum of 40 mg/kg/day. The primary endpoint of the cardiac sub-study was the change in T2* at one year. In the treatment cohort, T2* (geometric mean ± coefficient of variation) significantly increased from a baseline value of 11.2 ms ± 40.5% to 12.9 ms ± 49.5%, representing a significant improvement of 16% (p<0.0001). In the treatment cohort, improvement in T2* was observed in 69.5% of patients and stabilization of T2* in 14.3% of patients. LVEF remained stable and within the normal range: 67.4 ± 5.7% to 67.1 ± 6.0%. In the prevention cohort, myocardial T2* remained within the normal range and was unchanged from a baseline value of 32.0 ms ± 25.6% to 32.5 ms ± 25.1% (+2%; p=0.565) indicating that daily treatment with deferasirox can prevent cardiac iron loading in beta-thalassemia patients with a history of high transfusion exposure, and regular, ongoing transfusions.
Patients in the treatment cohort of the 1-year core study had the option to participate in two 1-year extensions. Over a three-year treatment duration period, there was a statistically significant (p<0.0001), progressive and clinically relevant increase in the geometric mean of cardiac T2* from baseline overall, in the severe cardiac iron overload sub-group, which is associated with a high risk of cardiac failure (T2* >5 to <10 ms), and in the mild to moderate cardiac iron overload sub-group (T2* 10 to <20 ms) (Table 2). Using the geometric mean ratio, the T2* increase was 43% above baseline in all patients, 37% increase from baseline in the T2* >5 to <10 ms sub-group, and 46% increase from baseline in the T2* 10 to <20 ms sub-group. Continuous treatment with deferasirox dispersible tablets for up to 3 years at doses >30 mg/kg/day effectively reduced cardiac iron in thalassemia major patients with myocardial siderosis as shown by the number of patients who normalized their T2* or improved to a category associated with a lower risk of cardiac failure (Table 3). (See Tables 2 and 3).
Click on icon to see table/diagram/image
Click on icon to see table/diagram/image
A randomized, double-blind, placebo-controlled study to compare deferasirox dispersible tablets and placebo was conducted in patients with non-transfusion-dependent thalassemia syndromes and iron overload. Patient's ≥10 years of age were enrolled in the study in a 2:1:2:1 randomization to receive deferasirox dispersible tablets 5 mg/kg/day, or 10 mg/kg/day, or matching placebo.
Transfusion independency of the patients was confirmed by the fact that blood transfusions 6 months prior to study start were not allowed and patients were excluded if a regular transfusion program was anticipated during the study. Iron overload was diagnosed by a serum ferritin >300 microgram/L at screening (two consecutive values at least 14 days apart from each other) and LIC ≥5 mg Fe/g dw measured by R2 MRI at screening. All patients with non-transfusion-dependent thalassemia syndromes were allowed with the exception of patients with HbS-variants or those whose clinical condition allowed phlebotomy.
In total, 166 patients were randomized. Demographics were well balanced. The main underlying disease was beta-thalassemia intermedia in 95 (57.2%) patients and HbE beta-thalassemia in 49 (29.5%) patients. The primary efficacy endpoint of change in liver iron concentration (LIC) from baseline to Week 52 was statistically significant in favor of both deferasirox treatment groups compared with placebo (Table 4). Furthermore, a statistically significant dose effect of d eferasirox was observed in favor of the 10 mg/kg/day dispersible tablet dose. (See Table 4).
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The primary efficacy result was supported by additional analyses which showed a clear dose-response effect; this was reflected by a greater percentage of patients with an LIC decrease of ≥3 mg Fe/g dw in the 10 mg/kg/day deferasirox dispersible tablet group compared to the 5 mg/kg/day group (56.4% versus 32.7%, respectively). In addition, a reduction of ≥30% in LIC between baseline and Week 52 was reported in approximately twice as many patients in the 10 mg/kg/day deferasirox dispersible tablet group (49.15%) compared to the 5 mg/kg/day group (25.5%).
Jadenu film-coated tablets are a strength-adjusted formulation of deferasirox with higher bioavailability compared to the Exjade dispersible tablet formulation. After strength-adjustment, the film-coated tablet formulation (360 mg strength) was equivalent to Exjade dispersible tablets (500 mg strength) with respect to the mean area under the plasma concentration time curve (AUC) underfasting conditions. The Cmax
was increased by 30% (90% CI: 20.3%-40.0%); however a clinical exposure/response analysis has revealed no evidence of clinically relevant effects of such an increase.
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) was about 70% compared to an intravenous dose. The absolute bioavailability of the film-coated tablet formulation has not been determined. Bioavailability of deferasirox with Jadenu film-coated tablets was 36% greater than that with Exjade 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 Jadenu should be taken either on an empty stomach or with a light meal.
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 L in adults.
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur. Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro
. Deferasirox undergoes enterohepatic recycling. 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 and its metabolites are primarily excreted in the feces (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.
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.
Pediatric 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 has not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment: The pharmacokinetics of deferasirox has not been studied in patients with renal impairment.
The average AUC of deferasirox in 6 subjects with mild hepatic impairment (Child-Pugh A) increased 16% over that found in 6 subjects with normal hepatic function, while the average AUC of deferasirox in 6 subjects with moderate hepatic impairment (Child-Pugh B) increased 76% over that found in 6 subjects with normal hepatic function. The average Cmax
of deferasirox in subjects with mild or moderate hepatic impairment increased 22% over that found in subjects with normal hepatic function. The impact of severe hepatic impairment (Child-Pugh C) was assessed in only one subject (see Dosage & Administration and Precautions). The pharmacokinetics of deferasirox was not influenced by liver transaminase levels up to 5 times the upper limit of the normal range.
Toxicology: Non-Clinical Safety Data:
Preclinical data reveal no special hazard for patients with iron overload, 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.
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.