Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

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. Cases of acute renal failure have been reported following post-marketing use of deferasirox (see section 4.8). 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 EXJADE to doses above 30 mg/kg in clinical studies, 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 
EXJ API AUG21 V13                                                                    EU SmPC Aug 2021 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, 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 EXJADE 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 Exjade therapy.


Table 3      Dose adjustment and interruption of treatment for renal monitoring 
Serum creatinine                            Creatinine clearance
Before initiation of        Twice (2x)                  and             Once (1x) therapy
Contraindicated                                                       <60 ml/min Monitoring
- First month after        Weekly                       and           Weekly start of therapy or dose modification
- Thereafter               Monthly                      and           Monthly Reduction of daily dose by 10 mg/kg/day,
if following renal parameters are observed at two consecutive visits and cannot be attributed to other causes
Adult patients             >33% above pre-treatment and               Decreases  age appropriate ULN**      and/or        Decreases 33% above pre- and/or             Decreases 
                                
Effects on Driving
                                
4.7   Effects on ability to drive and use machines

EXJADE has minor influence on the ability to drive and use machines. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machines (see section 4.8).