Exjade

Treatment with EXJADE 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 EXJADE 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 body weight) must be calculated and rounded to the nearest whole tablet size.

4). In the EU, medicines containing deferasirox are available as film-coated tablets and dispersible tablets marketed under different tradenames as generic alternatives to EXJADE. 1). g. serum ferritin >1 000 μg/l) (see Table 1). Table 1 Recommended starting doses for transfusional iron overload Recommended starting dose Serum ferritin Patient population Recommended starting dose >1 000 μg/l or Patients who have already received approximately 20 units (about 100 ml/kg) of PRBC.

14 mg/kg/day Alternative starting doses Patient population Alternative starting dose Patients who do not require reduction of body iron levels and who are also receiving <7 ml/kg/month of PRBC (approx. <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.

7 mg/kg/day Patients who require reduction of elevated body iron levels and who are also receiving >14 ml/kg/month of PRBC (approx. >4 units/month for an adult). 21 mg/kg/day Patients who are well managed on deferoxamine. 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 EXJADE film-coated tablets).

1). 4 Dose adjustment It is recommended that serum ferritin be monitored every month and that the dose of EXJADE film- coated tablets be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin (see Table 2).

5 to 7 mg/kg/day and are to be tailored to the individual patient’s response and therapeutic goals (maintenance or reduction of iron burden). 5 to 7 mg/kg/day. The maximum allowed dose is 28 mg/kg/day. If only very poor haemosiderosis control is achieved at doses up to 21 mg/kg/day, a further increase (to a maximum of 28 mg/kg/day) may not achieve satisfactory control, and alternative treatment options may be considered.

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- 13 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 6 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 14 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.

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.

7 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 EXJADE 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 EXJADE (including switch of formulation), and monthly thereafter.

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