- Approval Id
- 2f4383f1d3611ad5
- Drug Approval Emc Name
- Deferasirox 360 mg Film-coated Tablets
- Drug Name
- Deferasirox 360 mg Film-coated Tablets
- Company Name
- Aurobindo Pharma - Milpharm Ltd.
- Company Address
- Odyssey Business Park, Ares Block, West End Road, South Ruislip, Middlesex, HA4 6QD
- Company Website
- http://www.aurobindo.com
- Company Telephone
- + 44 (0)208 845 8811
- Company Fax
- +44 (0)208 845 8795
- Company Medical Info Email
- [email protected]
- Company Customer Care Direct Line
- +44 (0)208 845 8811
- Company Medical Info Fax
- +44 (0)208 845 8795
- Atc Code
- V03AC03
- Legal Category
- Prescription only medicine
- Authorisation Holder
- 7. Marketing authorisation holder Milpharm Limited Ares Block, Odyssey Business Park, West End Road, Ruislip, HA4 6QD United Kingdom
- Authorisation Number
- 8. Marketing authorisation number(s) PL 16363/0694
- Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 31/05/2022
- Instruction Authorisation Holder
- 7. Marketing authorisation holder Milpharm Limited Ares Block, Odyssey Business Park, West End Road, Ruislip, HA4 6QD United Kingdom
- Instruction Authorisation Number
- 8. Marketing authorisation number(s) PL 16363/0694
- Instruction Authorisation Date
- 9. Date of first authorisation/renewal of the authorisation 31/05/2022
- Instruction Composition
- 2. Qualitative and quantitative composition Each film-coated tablet contains 360 mg deferasirox. For the full list of excipients, see section 6.1.
- Instruction Dosage Form
- 3. Pharmaceutical form Film-coated tablet Dark blue, oval biconvex, film coated tablet with beveled edges, debossed with 'DF' on one side and '360' on other side. Size: about 15.6 mm × 6.6 mm
- Instruction Clinical Particulars
- 4. Clinical particulars 4.1 Therapeutic indications Deferasirox 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. Deferasirox 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. Deferasirox 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. 4.2 Posology and method of administration Treatment with Deferasirox should be initiated and maintained by physicians experienced in the treatment of chronic iron overload. Posology Transfusional iron overload and non-transfusion-dependent thalassaemia syndromes require different posologies. All physicians who intend to prescribe Deferasirox tablets must ensure they have received and are familiar with the physician educational material (Guide for healthcare professionals which also includes a prescriber checklist). Transfusional iron overload 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. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). Deferasirox is available as film-coated tablets and dispersible tablets marketed under different tradenames. Due to different pharmacokinetic profiles, a 30% lower dose of Deferasirox film-coated tablets is needed in comparison to the recommended dose for Deferasirox dispersible tablets (see section
- Instruction Pharmacology
- 5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Iron chelating agents, ATC code: V03AC03 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 faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals. Pharmacodynamic effects In an iron-balance metabolic study in iron-overloaded adult thalassaemic 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. Clinical efficacy and safety Clinical efficacy studies were conducted with deferasirox dispersible tablets(referred to below as'deferasirox'). Compared to the deferasirox dispersible tablet formulation, the dose of the deferasirox film-coated tablets is 30% lower than the dose of the deferasirox dispersible tablets, rounded to the nearest whole tablet (see section 5.2). Deferasirox has been investigated in 411 adult (age ≥16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes [MDS], Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias). Daily treatment with the deferasirox dispersible tablet formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia 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 (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/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 anaemias. 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 transfusions or exchange transfusions. 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. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with deferasirox 10-30 mg/kg/day (dispersible tablet formulation) for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds). The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of deferasirox dispersible tablets to deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with deferasirox dispersible tablets (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with deferasirox dispersible tablets (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving deferasirox dispersible tablets. It appeared from preclinical and clinical studies that deferasirox dispersible tablets could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox dispersible tablets that is numerically half of the deferoxamine dose). For deferasirox film-coated tablets, a dose ratio of 3:1 can be considered (i.e. a dose of deferasirox film-coated tablets that is numerically one third of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical studies. In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, deferasirox dispersible tablets up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia. A placebo-controlled randomised study was performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload. The results of this study suggest that there is a positive impact of deferasirox on event-free survival (EFS, a composite endpoint including non-fatal cardiac or liver events) and serum ferritin levels. The safety profile was consistent with previous studies in adult MDS patients. In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in the safety and tolerability profile of Deferasirox in paediatric patients aged 2 to <6 years compared to the overall adult and older paediatric population, including increases in serum creatinine of >33% and above the upper limit of normal on ≥2 consecutive occasions (3.1%), and elevation of alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145 patients who completed the study. In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatric patients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24 weeks. A comparable safety profile for film-coated and dispersible tablets was observed. An open-label 1:1 randomised study was performed in 224 paediatric patients aged 2 to <18 years old with transfusion-dependant anaemia and iron overload to evaluate treatment compliance, efficacy and safety of the deferasirox granule formulation compared to the dispersible tablet formulation. The majority of patients (142, 63.4%) in the study had beta-thalassemia major, 108 (48.2%) patients were naïve to iron chelation therapy (ICT) (median age 2 years, 92.6% aged 2 to <10 years) and 116 (51.8%) were ICT pre-treated (median age 7.5 years, 71.6% aged 2 to <10 years) of whom 68.1% had previously received deferasirox. In the primary analysis performed in ICT-naïve patients after 24 weeks of treatment, the compliance rate was 84.26% and 8
- Instruction Pharmaceutical Particulars
- 6. Pharmaceutical particulars 6.1 List of excipients Tablet Core Cellulose, Microcrystalline (Grade 101) Crospovidone (Type A) Poloxamer (Type 188) Povidone (K 30) Cellulose, Microcrystalline (Grade 102) Silica, colloidal anhydrous Magnesium stearate Coating Material Hypromellose 2910 Titanium Dioxide (E171) Macrogol 6000 Talc Indigo Carmine Aluminum Lake (E132) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Clear PVC/ PVdC - Aluminium foil blister and Clear PVC - Aluminium foil blister Pack sizes: 30 film-coated tablets. 6.6 Special precautions for disposal and other handling No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
- Instruction Content
- ## Composition
2. Qualitative and quantitative composition Each film-coated tablet contains 360 mg deferasirox. For the full list of excipients, see section 6.1.
## Pharmaceutical Form
3. Pharmaceutical form Film-coated tablet Dark blue, oval biconvex, film coated tablet with beveled edges, debossed with 'DF' on one side and '360' on other side. Size: about 15.6 mm × 6.6 mm
## Clinical Particulars
4. Clinical particulars 4.1 Therapeutic indications Deferasirox 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. Deferasirox 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. Deferasirox 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. 4.2 Posology and method of administration Treatment with Deferasirox should be initiated and maintained by physicians experienced in the treatment of chronic iron overload. Posology Transfusional iron overload and non-transfusion-dependent thalassaemia syndromes require different posologies. All physicians who intend to prescribe Deferasirox tablets must ensure they have received and are familiar with the physician educational material (Guide for healthcare professionals which also includes a prescriber checklist). Transfusional iron overload 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. Caution should be taken during chelation therapy to minimise the risk of overchelation in all patients (see section 4.4). Deferasirox is available as film-coated tablets and dispersible tablets marketed under different tradenames. Due to different pharmacokinetic profiles, a 30% lower dose of Deferasirox film-coated tablets is needed in comparison to the recommended dose for Deferasirox dispersible tablets (see section
## Pharmacological Properties
5. Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Iron chelating agents, ATC code: V03AC03 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 faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals. Pharmacodynamic effects In an iron-balance metabolic study in iron-overloaded adult thalassaemic 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. Clinical efficacy and safety Clinical efficacy studies were conducted with deferasirox dispersible tablets(referred to below as'deferasirox'). Compared to the deferasirox dispersible tablet formulation, the dose of the deferasirox film-coated tablets is 30% lower than the dose of the deferasirox dispersible tablets, rounded to the nearest whole tablet (see section 5.2). Deferasirox has been investigated in 411 adult (age ≥16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes [MDS], Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias). Daily treatment with the deferasirox dispersible tablet formulation at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia 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 (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/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 anaemias. 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 transfusions or exchange transfusions. 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. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with deferasirox 10-30 mg/kg/day (dispersible tablet formulation) for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds). The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of deferasirox dispersible tablets to deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with deferasirox dispersible tablets (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with deferasirox dispersible tablets (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving deferasirox dispersible tablets. It appeared from preclinical and clinical studies that deferasirox dispersible tablets could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of deferasirox dispersible tablets that is numerically half of the deferoxamine dose). For deferasirox film-coated tablets, a dose ratio of 3:1 can be considered (i.e. a dose of deferasirox film-coated tablets that is numerically one third of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical studies. In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, deferasirox dispersible tablets up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia. A placebo-controlled randomised study was performed in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload. The results of this study suggest that there is a positive impact of deferasirox on event-free survival (EFS, a composite endpoint including non-fatal cardiac or liver events) and serum ferritin levels. The safety profile was consistent with previous studies in adult MDS patients. In a 5-year observational study in which 267 children aged 2 to <6 years (at enrollment) with transfusional haemosiderosis received deferasirox, there were no clinically meaningful differences in the safety and tolerability profile of Deferasirox in paediatric patients aged 2 to <6 years compared to the overall adult and older paediatric population, including increases in serum creatinine of >33% and above the upper limit of normal on ≥2 consecutive occasions (3.1%), and elevation of alanine aminotransferase (ALT) greater than 5 times the upper limit of normal (4.3%). Single events of increase in ALT and aspartate aminotransferase were reported in 20.0% and 8.3%, respectively, of the 145 patients who completed the study. In a study to assess the safety of deferasirox film-coated and dispersible tablets, 173 adult and paediatric patients with transfusion dependent thalassaemia or myelodysplastic syndrome were treated for 24 weeks. A comparable safety profile for film-coated and dispersible tablets was observed. An open-label 1:1 randomised study was performed in 224 paediatric patients aged 2 to <18 years old with transfusion-dependant anaemia and iron overload to evaluate treatment compliance, efficacy and safety of the deferasirox granule formulation compared to the dispersible tablet formulation. The majority of patients (142, 63.4%) in the study had beta-thalassemia major, 108 (48.2%) patients were naïve to iron chelation therapy (ICT) (median age 2 years, 92.6% aged 2 to <10 years) and 116 (51.8%) were ICT pre-treated (median age 7.5 years, 71.6% aged 2 to <10 years) of whom 68.1% had previously received deferasirox. In the primary analysis performed in ICT-naïve patients after 24 weeks of treatment, the compliance rate was 84.26% and 8
## Pharmaceutical Particulars
6. Pharmaceutical particulars 6.1 List of excipients Tablet Core Cellulose, Microcrystalline (Grade 101) Crospovidone (Type A) Poloxamer (Type 188) Povidone (K 30) Cellulose, Microcrystalline (Grade 102) Silica, colloidal anhydrous Magnesium stearate Coating Material Hypromellose 2910 Titanium Dioxide (E171) Macrogol 6000 Talc Indigo Carmine Aluminum Lake (E132) 6.2 Incompatibilities Not applicable. 6.3 Shelf life 3 years 6.4 Special precautions for storage This medicinal product does not require any special storage conditions. 6.5 Nature and contents of container Clear PVC/ PVdC - Aluminium foil blister and Clear PVC - Aluminium foil blister Pack sizes: 30 film-coated tablets. 6.6 Special precautions for disposal and other handling No special requirements for disposal. Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
