Drug Class Description
Iron Chelating Agent

Generic Name
Deferasirox

Drug Description
Each dispersible tablet contains 125 mg deferasirox.Each dispersible tablet contains 250 mg deferasirox.Each dispersible tablet contains 500 mg deferasirox.

Presentation
Dispersible tabletOff-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 125 on the other).Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 250 on the other).Off-white, round, flat tablets with bevelled edges and imprints (NVR on one face and J 500 on the other).

Indications
EXJADE 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.EXJADE is also indicated for the treatment of chronic iron overload due to blood transfusions when desferrioxamine therapy is contraindicated or inadequate in the following patient groups:- in patients with other anaemias,- in patients aged 2 to 5 years,- in patients with beta thalassaemia major with iron overload due to infrequent blood transfusions (<7 ml/kg/month of packed red blood cells).

Adult Dosage
Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload due to blood transfusions. It is recommended that treatment be started after the transfusion of approximately 20 units (about 100 ml/kg) of packed red blood cells or when there is evidence from clinical monitoring that chronic iron overload is present (e.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.Starting doseThe recommended initial daily dose of EXJADE is 20 mg/kg body weight.An initial daily dose of 30 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 10 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). The patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained.For patients already well managed on treatment with desferrioxamine, a starting dose of EXJADE that is numerically half that of the desferrioxamine dose could be considered (e.g. a patient receiving 40 mg/kg/day of desferrioxamine for 5 days per week (or equivalent) could be transferred to a starting daily dose of 20 mg/kg/day of EXJADE). When this results in a daily dose less than 20 mg/kg body weight, the patient's response must be monitored and a dose increase should be considered if sufficient efficacy is not obtained.Maintenance doseIt is recommended that serum ferritin be monitored every month and that the dose of EXJADE be adjusted, if necessary, every 3 to 6 months based on the trends in serum ferritin. Dose adjustments may be made in steps of 5 to 10 mg/kg and are to be tailored to the individual patient's response and therapeutic goals (maintenance or reduction of iron burden). In patients not adequately controlled with doses of 30 mg/kg (e.g. serum ferritin levels persistently above 2,500 µg/l and not showing a decreasing trend over time), doses of up to 40 mg/kg may be considered. The availability of long-term efficacy and safety data with EXJADE 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 30 mg/kg, a further increase (to a maximum of 40 mg/kg) may not achieve satisfactory control, and alternative treatment options may be considered. If no satisfactory control is achieved at doses above 30 mg/kg, treatment at such doses should not be maintained and alternative treatment options should be considered whenever possible. Doses above 40 mg/kg are not recommended because there is only limited experience with doses above this level.In patients treated with doses greater than 30 mg/kg, dose reductions in steps of 5 to 10 mg/kg should be considered when control has been achieved (e.g. serum ferritin levels persistently below 2,500 µg/l and showing a decreasing trend over time). In patients whose serum ferritin level has reached the target (usually between 500 and 1,000 µg/l), dose reductions in steps of 5 to 10 mg/kg should be considered to maintain serum ferritin levels within the target range. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered.PreparationEXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day. The tablets are dispersed by stirring in a glass of water or orange or apple juice (100 to 200 ml) until a fine suspension is obtained. After the suspension has been swallowed, any residue must be resuspended in a small volume of water or juice and swallowed. The tablets must not be chewed or swallowed whole.Elderly patients (65 years of age)The dosing recommendations for elderly patients are the same as described above. In clinical trials, elderly patients experienced a higher frequency of adverse reactions than younger patients (in particular, diarrhoea) and should be monitored closely for adverse events that may require a dose adjustment.Paediatric patients (2 to 17 years of age)The dosing recommendations for paediatric patients are the same as for adult patients. Changes in weight of paediatric patients over time must be taken into account when calculating the dose. In children aged between 2 and 5 years, exposure is lower than in adults. This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration.Patients with renal impairmentEXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min.Patients with hepatic impairmentEXJADE has not been studied in patients with hepatic impairment and must be used with caution in such patients. The initial dosing recommendations for patients with hepatic impairment are the same as described above. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month.

Child Dosage
Paediatric patients (2 to 17 years of age)The dosing recommendations for paediatric patients are the same as for adult patients. Changes in weight of paediatric patients over time must be taken into account when calculating the dose. In children aged between 2 and 5 years, exposure is lower than in adults. This age group may therefore require higher doses than are necessary in adults. However, the initial dose should be the same as in adults, followed by individual titration.

Elderly Dosage
The dosing recommendations for elderly patients are the same as Adult Dosage.

Contra Indications
Hypersensitivity to the active substance or to any of the excipients.Combination with other iron chelator therapies as the safety of such combinations has not been established.Patients with estimated creatinine clearance <60 ml/min.

Special Precautions
Renal function:EXJADE has been studied only in patients with baseline serum creatinine within the age-appropriate normal range.During clinical trials, 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. Cases of acute renal failure have been reported following post-marketing use of EXJADE. 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 EXJADE 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 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. 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.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 cannot be attributed to other causes, EXJADE should be interrupted. Once the cause of the liver function test abnormalities has been clarified or after return to normal levels, cautious re-initiation of treatment at a lower dose followed by gradual dose escalation may be considered.EXJADE is not recommended in patients with severe hepatic impairment as it has not been studied in such patients. Treatment has been initiated only in patients with baseline liver transaminase levels up to 5 times the upper limit of the normal rangeIn patients with a short life expectancy (e.g. high-risk myelodysplastic syndromes), especially when co-morbidities could increase the risk of adverse events, the benefit of EXJADE might be limited and may be inferior to risks. As a consequence, treatment with EXJADE is not recommended in these patients.Caution should be used in elderly patients due to a higher frequency of adverse reactions (in particular, diarrhoea).Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving EXJADE. Multiple ulcers have been observed in some patients. There have been reports of fatal gastrointestinal haemorrhages, especially in elderly patients who had haematological malignancies and/or low platelet counts. Physicians and patients should remain alert for signs and symptoms of gastrointestinal ulceration and haemorrhage during EXJADE therapy and promptly initiate additional eva luation and treatment if a serious gastrointestinal adverse event is suspected.Caution should be exercised in patients who are taking EXJADE, in combination with substances that have known ulcerogenic potential, such as NSAIDs, corticosteroids, or oral bisphosphonates, in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm3 (50 x 109/l).Skin rashes may appear during EXJADE treatment. The rashes resolve spontaneously in most cases. When interruption of treatment may be necessary, treatment may be reintroduced after resolution of the rash, at a lower dose followed by gradual dose escalation. In severe cases this reintroduction could be conducted in combination with a short period of oral steroid administration.Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXJADE, with the onset of the reaction occurring in the majority of cases within the first month of treatment. If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted.Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported. Auditory and ophthalmic testing (including fundoscopy) is recommended before the start of treatment and at regular intervals thereafter (every 12 months). If disturbances are noted during the treatment, dose reduction or interruption may be considered.There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia, or aggravation of these cytopenias in patients treated with EXJADE. Most of these patients had pre-existing haematological disorders that are frequently associated with bone marrow failure. However, a contributory or aggravating role cannot be excluded. Interruption of treatment should be considered in patients who develop unexplained cytopenia.Monthly monitoring of serum ferritin is recommended in order to assess the patient's response to therapy. If serum ferritin falls consistently below 500 µg/l, an interruption of treatment should be considered.The results of the tests for serum creatinine, serum ferritin and serum transaminases should be recorded and regularly assessed for trends. The results should also be noted in the provided patient's booklet.In one clinical study, growth and sexual development of paediatric patients treated with EXJADE for up to 5 years were not affected. However, as a general precautionary measure in the management of paediatric patients with transfusional iron overload, body weight, height and sexual development should be monitored at regular intervals (every 12 months).Cardiac dysfunction is a known complication of severe iron overload. Cardiac function should be monitored in patients with severe iron overload during long-term treatment with EXJADE.The tablets contain lactose (1.1 mg lactose for each mg of deferasirox). Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or severe lactase deficiency should not take this medicineThe concomitant use of deferasirox with aluminium-containing antacid preparations is not recommended. Caution should be exercised when deferasirox is combined with strong UDP-glucuronosyl transferase (UGT) inducers, or CYP2C8 substrates.

Interactions
The concomitant administration of EXJADE and aluminium-containing antacid preparations has not been formally studied. Although deferasirox has a lower affinity for aluminium than for iron, it is not recommended to take EXJADE tablets with aluminium-containing antacid preparations.The bioavailability of deferasirox was increased to a variable extent when taken along with food. EXJADE must therefore be taken on an empty stomach at least 30 minutes before food, preferably at the same time each day.Deferasirox metabolism depends on UGT enzymes. In a healthy volunteer study, the concomitant administration of EXJADE (single dose of 30 mg/kg) and the potent UGT inducer, rifampicin, (repeated dose of 600 mg/day) resulted in a decrease of deferasirox exposure by 44% (90% CI: 37%-51%). Therefore, the concomitant use of EXJADE with potent UGT inducers (e.g. rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may result in a decrease in EXJADE efficacy. The patient's serum ferritin should be monitored during and after the combination, and the dose of EXJADE adjusted if necessary.In a healthy volunteer study, the concomitant administration of EXJADE and midazolam (a CYP3A4 probe substrate) resulted in a decrease of midazolam exposure by 17% (90% CI: 8% - 26%). In the clinical setting, this effect may be more pronounced. Therefore, due to a possible decrease in efficacy, caution should be exercised when deferasirox is combined with substances metabolised through CYP3A4 (e.g. ciclosporin, simvastatin, hormonal contraceptive agents, bepridil, ergotamine).The safety of EXJADE in combination with other iron chelators has not been established. Therefore, it must not be combined with other iron chelator therapies.No interaction was observed between EXJADE and digoxin in healthy adult volunteers.In a healthy volunteer study, the concomitant administration of deferasirox as a moderate CYP2C8 inhibitor (30 mg/kg daily), with repaglinide, a CYP2C8 substrate, given as a single dose of 0.5 mg, increased repaglinide AUC and Cmax about 2.3-fold (90% CI[2.03-2.63]) and 1.6-fold (90% CI[1.42-1.84]), respectively. Since the interaction has not been established with dosages higher than 0.5 mg for repaglinide, the concomitant use of deferasirox with repaglinide should be avoided. If the combination appears necessary, careful clinical and blood glucose monitoring should be performed. An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.The concomitant administration of EXJADE and vitamin C has not been formally studied. Doses of vitamin C up to 200 mg per day have not been associated with adverse consequences.The concomitant administration of EXJADE with substances that have known ulcerogenic potential, such as NSAIDs (including acetylsalicylic acid at high dosage), corticosteroids, or oral bisphosphonates, may increase the risk of gastrointestinal toxicity. The concomitant administration of EXJADE with anticoagulants may also increase the risk of gastrointestinal haemorrhage. Close clinical monitoring is required when deferasirox is combined with these substances.

Adverse Reactions
The most frequent reactions reported during chronic treatment with EXJADE in adult and paediatric patients include gastrointestinal disturbances in about 26% of patients (mainly nausea, vomiting, diarrhoea or abdominal pain) and skin rash in about 7% of patients. Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients. These reactions are dose-dependent, mostly mild to moderate, generally transient and mostly resolve even if treatment is continued.During clinical trials, 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. Indeed, in some cases, only a stabilisation of the serum creatinine values has been observed after dose reduction.Gallstones and related biliary disorders were reported in about 2% of patients. Elevations of liver transaminases were reported as an adverse drug reaction in 2% of patients. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During postmarketing experience, hepatic failure, sometimes fatal, has been reported with EXJADE, especially in patients with pre-existing liver cirrhosis. As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with EXJADE.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 1Blood and lymphatic system disordersNot known:Pancytopenia1 , thrombocytopenia1Immune system disordersNot known:Hypersensitivity reactions (including anaphylaxis and angioedema)1Psychiatric disorders Uncommon:Anxiety, sleep disorderNervous system disorders Common:HeadacheUncommon:DizzinessEye disorders Uncommon:Early cataract, maculopathyEar and labyrinth disorders Uncommon:Hearing lossRespiratory, thoracic and mediastinal disorders Uncommon:Pharyngolaryngeal painGastrointestinal disorders Common:Diarrhoea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsiaUncommon:Gastrointestinal haemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritisRare:OesophagitisHepatobiliary disorders Common:Transaminases increasedUncommon:Hepatitis, cholelithiasisNot known:Hepatic failure1Skin and subcutaneous tissue disorders Common:Rash, pruritusUncommon:Pigmentation disorderNot knownLeukocytoclastic vasculitis1 , urticaria1 , erythema multiforme1 , alopecia1Renal and urinary disorders Very common:Blood creatinine increasedCommon:ProteinuriaUncommon:Renal tubulopathy (acquired Fanconi's syndrome), glycosuriaNot known:Acute renal failure1General disorders and administration site conditions Uncommon:Pyrexia, oedema, fatigue1 Adverse reactions reported during postmarketing 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.

Manufacturer
Novartis Pharmaceuticals

Drug Availability
(POM)

Updated
04 March 2010