lt;2 units/month for an adult). While no increase in renal adverse events was observed after dose escalation to doses above 30 mg/kg in clinical trials, an increased risk of renal adverse events with EXJADE doses above 30 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 weekly in the first month after initiation or modification of therapy with EXJADE, 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.
For adult patients, the daily dose may be reduced by 10 mg/kg if a rise in serum creatinine by >33% above the average of the pre-treatment measurements and estimated creatinine clearance decreases below the lower limit of the normal range (<90 ml/min) are seen at two consecutive visits, and cannot be attributed to other causes (see section 4.2). For paediatric patients, the dose may be reduced by 10 mg/kg if estimated creatinine clearance decreases below the lower limit of the normal range (<90 ml/min) and/or serum creatinine levels rise above the age-appropriate upper limit of normal at two consecutive visits.
After a dose reduction, for adult and paediatric patients, treatment should be interrupted if a rise in serum creatinine >33% above the average of the pre-treatment measurements is observed and/or the calculated creatinine clearance falls below the lower limit of the normal range. Treatment may be reinitiated depending on the individual clinical circumstances.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE. Tests for proteinuria should be performed monthly. As needed, additional markers of renal tubular function (e.g. glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria) may also be monitored. Dose reduction or interruption may be considered if there are abnormalities in levels of tubular markers and/or if clinically indicated.
If, despite dose reduction and interruption, the serum creatinine remains significantly elevated and there is also persistent abnormality in another marker of renal function (e.g. proteinuria, Fanconi's Syndrome), the patient should be referred to a renal specialist, and further specialised investigations (such as renal biopsy) may be considered.
Hepatic function:
Liver function test elevations have been observed in patients treated with EXJADE. Postmarketing cases of hepatic failure, sometimes fatal, have been reported in patients treated with EXJADE. Most reports of hepatic failure involved patients with significant morbidities including pre-existing liver cirrhosis. However, the role of EXJADE as a contributing or aggravating factor cannot be excluded (see section 4.8).
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 c
