DEFERASIROX

Treatment with Deferasirox / Pharmathen should be initiated and maintained by physicians experienced in the treatment of chronic iron overload. 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. 4). In the EU, medicines containing deferasirox are available as film-coated tablets and dispersible tablets marketed under different tradenames as generic alternatives to [Invented name].

1). The recommended doses are shown in the table below. Table 1 Recommended doses for transfusional iron overload Film-coated tablets Transfusions Serum ferritin Starting dose 14 mg/kg/day After 20 units (about 100 mL/kg) of PRBC or >1,000 μg/L 21 mg/kg/day > 14 mL/kg/month of PRBC (approx.

> 4 units/month for an adult) Alternative starting doses 7 mg/kg/day < 7 mL/kg/month of PRBC (approx. 5-7 mg/kg/day < 2,500 μg/L In patients treated with doses > 21 mg/kg/day Adjustment steps (every 3-6 months) - When target is reached 500-1,000 μg/L Maximum dose 28 mg/kg/day Consider interruption < 500 μg/L Starting dose The recommended initial daily dose of Deferasirox / Pharmathen 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).

1). 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 Deferasirox / Pharmathen film-coated tablets). 1). Dose adjustment It is recommended that serum ferritin be monitored every month and that the dose of Deferasirox / Pharmathen be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin.

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). 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 deferasirox 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 (film-coated tablet dose equivalent of 30 mg/kg of dispersible tablets) 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. 1). g. serum ferritin levels persistently ≤2,500 μg/L and showing a decreasing trend over time).

5 to 7 mg/kg should be considered to maintain serum ferritin levels within the target range and to minimise the risk of overchelation. 4). 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. 4). In the EU, medicines […]

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. 4). 4). 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, 2 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 disorder2 (acquired Fanconi syndrome), glycosuria Not known: Acute renal failure1, 2, 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. 2 Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported.

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. 3 %). 4). There have been post-marketing reports of metabolic acidosis.

4). Cases of serious acute pancreatitis were observed without documented underlying biliary conditions. 4). 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.

3 %) were the most frequent study medicinal product-related adverse events. Abnormal serum creatinine and creatinine […]

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. 8). 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 deferasirox 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 deferasirox (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 deferasirox therapy should be considered in patients who develop metabolic acidosis. Post-marketing cases of severe forms of renal tubulopathy (such as Fanconi syndrome) and renal failure associated with changes in consciousness in the context of hyperammonaemic encephalopathy have been reported in patients treated with deferasirox, mainly in children.

It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on deferasirox therapy. 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) - Thereafter Weekly Monthly and and Weekly 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 Paediatric patients > 33 % above pre- treatment average > age appropriate ULN** and and/or Decreases < LLN* (< 90 mL/min) 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 also be 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 deferasirox.

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.

g. proteinuria, Fanconi Syndrome). Hepatic function Liver function test elevations have been observed in patients treated with deferasirox. Post- marketing cases of hepatic failure, some of which were fatal, have been reported. Severe forms associated with changes in consciousness in the context of hyperammonaemic encephalopathy may occur in patients treated with deferasirox, particularly in children.

It is recommended that hyperammonaemic encephalopathy be considered and ammonia levels measured in patients who develop unexplained changes in mental status while on deferasirox therapy. Care should be taken to maintain adequate hydration in patients who experience volume-depleting events (such as diarrhoea or vomiting), particularly in children with acute illness.

Most reports of hepatic failure involved patients with significant comorbidities including pre-existing chronic liver conditions (including cirrhosis and hepatitis C) and multi- […]

1. 5). Patients with estimated creatinine clearance < 60 mL/min.