英文药名：Exjade(Deferasirox dispersible Tablets)

中文药名：地拉罗斯片（去铁斯若）

生产厂家：德国诺华公司
药品介绍
2012年12月24日，地拉罗司Exjade（deferasirox，商品名：恩瑞格）获欧盟委员会批准，用于因甲磺酸去铁胺疗法（deferoxamine therapy）禁忌或不足而需螯合疗法（chelation therapy）的10岁及以上非输血依赖性地中海贫血（non-transfusion-dependent thalassemia，NTDT）综合征患者慢性铁过载（chronic iron overload）的治疗。Exjade是欧盟首个专门用于治疗这类型地中海贫血患者慢性铁过载的口服药物。
临床应用
用于治疗年龄大于6岁的B-地中海贫血患者因频繁输血（每月浓缩红细胞的给予量≥7mL/kg）所致慢性铁过载；对于6岁以下儿童以及其它输血依赖性疾病所致的铁过载，患者的安全有效性数据有限，建议根据患者的具体情况慎用。
用法用量：
起始剂量：
推荐起始日剂量为20mg/kg。对于每月接受超过14mL/kg浓缩红细胞（即成人超过4单位/月）输注，并需要减少过量铁暴露的患者可以考虑起始剂量为30mg/kg/天。对于每月接受低于7mL/kg浓缩红细胞（即成人小于2单位/月）输注和需要维持体内铁平衡的患者可以考虑起始剂量为10mg/kg/天。已经对去铁胺治疗有良好反应的患者，可以考虑初始的恩瑞格剂量相当于去铁胺剂量的一半。（例如，1位接受去铁胺40mg/kg/天，每周5天或相当剂量治疗的患者，如改换用恩瑞格可以从20mg/kg开始。）
药理作用：
地拉罗司是口服的活性螯合剂，与铁（Fe3+）具有高度选择性。它是具有3个突起的配基，以2:1的比例与铁高亲和性结合。尽管地拉罗司与锌和铜的亲合力非常低，但是给药后血清中这些痕量金属的浓度仍有不同程度的下降。尚不明确这些金属浓度的降低的临床意义
包装规格：（盒）
125mgx84片
250mgx84片
500mgx84片

EXJADE 125mg, 250mg, 500mg dispersible tablets
1. Name of the medicinal product
EXJADE® 125mg dispersible tablets
EXJADE® 250mg dispersible tablets
EXJADE® 500mg dispersible tablets
2. Qualitative and quantitative composition
Each dispersible tablet contains 125 mg deferasirox.
Each dispersible tablet contains 250 mg deferasirox.
Each dispersible tablet contains 500 mg deferasirox.
Excipient:
Each dispersible tablet contains 136 mg lactose.
For the full list of excipients, see section 6.1.
3. Pharmaceutical form
Dispersible tablet
Off-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).
4. Clinical particulars
4.1 Therapeutic 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 deferoxamine therapy is contraindicated or inadequate in the following patient groups:
- in patients with beta thalassaemia major with iron overload due to frequent blood transfusions (≥7 ml/kg/month of packed red blood cells) 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) aged 2 years and older,
- in patients with other anaemias aged 2 years and older.
EXJADE is also indicated for the treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or inadequate in patients with non-transfusion-dependent thalassaemia syndromes aged 10 years and older.
4.2 Posology and method of administration
Treatment with EXJADE should be initiated and maintained by physicians experienced in the treatment of chronic iron overload.
Posology- transfusional iron overload
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 dose
The 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 (see section 5.1).
For patients already well managed on treatment with deferoxamine, a starting dose of EXJADE that is numerically half that of the deferoxamine dose could be considered (e.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 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 (see section 5.1).
Dose adjustment
It 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 (see section 4.4).
Posology - 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. Caution should be taken during chelation therapy to minimise the risk of over-chelation in all patients.
Starting dose
The recommended initial daily dose of EXJADE in patients with non-transfusion-dependent thalassaemia syndromes is 10 mg/kg body weight.
Dose adjustment
It is recommended that serum ferritin be monitored every month. After every 3 to 6 months of treatment, a dose increase in increments of 5 to 10 mg/kg should be considered if the patient's LIC is ≥7 mg Fe/g dw, or if serum ferritin is consistently >2,000 µg/l and not showing a downward trend, and the patient is tolerating the medicinal product well. Doses above 20mg/kg are not recommended because there is no experience with doses above this level in patients with non-transfusion-dependent thalassaemia syndromes.
In patients in whom LIC was not assessed and serum ferritin is ≤2,000 µg/l, dosing should not exceed 10mg/kg.
For patients in whom the dose was increased to >10 mg/kg, dose reduction to 10 mg/kg or less is recommended when LIC is <7 mg Fe/g dw or serum ferritin is ≤2,000 µg/l.
Treatment cessation
Once a satisfactory body iron level has been achieved (LIC <3 mg Fe/g dw or serum ferritin <300 µg/l), treatment should be stopped. There are no data available on the retreatment of patients who reaccumulate iron after having achieved a satisfactory body iron level and therefore retreatment cannot be recommended.
Special populations
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 reactions that may require a dose adjustment.
Paediatric population
The dosing recommendations for paediatric patients aged 2 to 17 years with transfusional iron overload 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 with transfusional iron overload aged between 2 and 5 years, exposure is lower than in adults (see section 5.2). 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.
In paediatric patients with non-transfusion-dependent thalassaemia syndromes, dosing should not exceed 10 mg/kg. In these patients, closer monitoring of LIC and serum ferritin is essential to avoid overchelation: in addition to monthly serum ferritin assessments, LIC should be monitored every three months when serum ferritin is ≤800 µg/l.
The safety and efficacy of EXJADE in children from birth to 23 months of age have not been established. No data are available.
Patients with renal impairment
EXJADE has not been studied in patients with renal impairment and is contraindicated in patients with estimated creatinine clearance <60 ml/min (see sections 4.3 and 4.4).
Patients with hepatic impairment
EXJADE is not recommended in patients with severe hepatic impairment (Child-Pugh Class C). In patients with moderate hepatic impairment (Child-Pugh Class B), the dose should be considerably reduced followed by progressive increase up to a limit of 50% (see sections 4.4 and 5.2), and EXJADE must be used with caution in such patients. Hepatic function in all patients should be monitored before treatment, every 2 weeks during the first month and then every month (see section 4.4).
Method of administration
For oral use.
EXJADE must be taken once daily on an empty stomach at least 30 minutes before food, preferably at the same time each day (see sections 4.5 and 5.2).
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 (see also section 6.2).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Combination with other iron chelator therapies as the safety of such combinations has not been established (see section 4.5).
Patients with estimated creatinine clearance <60 ml/min.
4.4 Special warnings and precautions for use
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 (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 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.
There have been post-marketing reports of metabolic acidosis occurring during treatment with EXJADE. The majority of these patients had renal impairment, renal tubulopathy (Fanconi's 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.
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.
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. Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE.
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. Post-marketing 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 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 (Child-Pugh Class C) (see section 5.2).
Summary of safety monitoring recommendations:

Test	Frequency
Serum creatinine, creatinine clearance and/or plasma cystatin C	In duplicate prior to therapy. Weekly during first month of therapy and during first month after dose modification. Monthly thereafter.
Proteinuria	Monthly.
Other markers of renal tubular function (such as glycosuria in non-diabetics and low levels of serum potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria)	As needed.
Serum transaminases, bilirubin, alkaline phosphatase	Prior to therapy. Every 2 weeks during first month of therapy. Monthly thereafter.
Auditory and ophthalmic testing	Prior to therapy. Annually thereafter.
Body weight, height and sexual development	Annually in paediatric patients

In 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).
Data in children with non-transfusion-dependent thalassaemia are very limited (see section 5.1). As a consequence, EXJADE therapy should be closely monitored to detect side effects and to follow iron burden in the paediatric population. In addition, before treating heavily iron-overloaded children with non-transfusion-dependent thalassaemia with EXJADE, the physician should be aware that the consequences of long-term exposure in such patients are currently not known.
Gastrointestinal
Upper gastrointestinal ulceration and haemorrhage have been reported in patients, including children and adolescents, receiving EXJADE. Multiple ulcers have been observed in some patients (see section 4.8). There have been reports of ulcers complicated with digestive perforation. Also, 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 evaluation and treatment if a serious gastrointestinal adverse reaction 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) (see section 4.5).
Skin disorders
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 Stevens-Johnson syndrome (SJS) have been reported post marketing. The risk of other more severe skin reactions (TEN [toxic epidermal necrolysis], DRESS [drug reaction with eosinophilia and systemic symptoms]) cannot be excluded. If SJS or any other severe skin reaction is suspected, EXJADE should be discontinued immediately and should not be reintroduced.
Hypersensitivity reactions
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 (see section 4.8). If such reactions occur, EXJADE should be discontinued and appropriate medical intervention instituted.
Vision and hearing
Auditory (decreased hearing) and ocular (lens opacities) disturbances have been reported (see section 4.8). 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.
Blood disorders
There have been post-marketing reports of leukopenia, thrombocytopenia or pancytopenia (or aggravation of these cytopenias) and of aggravated anaemia 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.
Other considerations
Monthly monitoring of serum ferritin is recommended in order to assess the patient's response to therapy (see section 4.2). If serum ferritin falls consistently below 500 µg/l (in transfusional iron overload) or below 300 µg/l (in non-transfusion-dependent thalassaemia syndromes), 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.
Each tablet contains 136 mg lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or severe lactase deficiency should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
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 (see section 4.3).
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 (see section 4.4). 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.
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 (see sections 4.2 and 5.2).
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.
Cholestyramine significantly reduced the deferasirox exposure in a mechanistic study to determine the degree of enterohepatic recycling (see section 5.2).
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).
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 (see section 4.4). An interaction between deferasirox and other CYP2C8 substrates like paclitaxel cannot be excluded.
In a healthy volunteer study, the concomitant administration of EXJADE as a CYP1A2 inhibitor (repeated dose of 30 mg/kg/day) and the CYP1A2 substrate theophylline (single dose of 120 mg) resulted in an increase of theophylline AUC by 84% (90% CI: 73% to 95%). The single dose Cmax was not affected, but an increase of theophylline Cmax is expected to occur with chronic dosing. Therefore, the concomitant use of EXJADE with theophylline is not recommended. If EXJADE and theophylline are used concomitantly, monitoring of theophylline concentration and theophylline dose reduction should be considered. An interaction between EXJADE and other CYP1A2 substrates cannot be excluded. For substances that are predominantly metabolised by CYP1A2 and that have a narrow therapeutic index (e.g. clozapine, tizanidine), the same recommendations apply as for theophylline.
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 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.
No interaction was observed between EXJADE and digoxin in healthy adult volunteers.
4.6 Fertility, pregnancy and lactation
Pregnancy
No clinical data on exposed pregnancies are available for deferasirox. Studies in animals have shown some reproductive toxicity at maternally toxic doses (see section 5.3). The potential risk for humans is unknown.
As a precaution, it is recommended that EXJADE is not used during pregnancy unless clearly necessary.
EXJADE may decrease the efficacy of hormonal contraceptives (see section 4.5).
Breast-feeding
In animal studies, deferasirox was found to be rapidly and extensively secreted into maternal milk. No effect on the offspring was noted. It is not known if deferasirox is secreted into human milk. Breast-feeding while taking EXJADE is not recommended.
Fertility
No fertility data is available for humans. In animals, no adverse effects on male or female fertility were found (see section 5.3).
4.7 Effects on ability to drive and use machines
No studies on the effects of EXJADE on the ability to drive and use machines have been performed. Patients experiencing the uncommon adverse reaction of dizziness should exercise caution when driving or operating machinery (see section 4.8).
4.8 Undesirable effects
Summary of the safety profile
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 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 trials, increases in serum creatinine of >33% on two or more 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 (see section 4.4).
In a retrospective meta-analysis of 2,102 adult and paediatric beta-thalassaemia patients with transfusional iron overload (including patients with different characteristics such as transfusion intensity, posology and treatment duration) treated in two randomised clinical trials and four open label studies of up to five years' duration, a mean creatinine clearance decrease of 13.2% in adult patients (95% CI: -14.4% to -12.1%; n=935) and 9.9% (95% CI: -11.1% to -8.6%; n=1,142) in paediatric patients was observed during the first year of treatment. In a subset of patients followed for more than one year (n=250 up to five years), no further decrease in mean creatinine clearance levels was observed in subsequent years.
In a 1-year, randomised, double-blind, placebo-controlled study in patients with non-transfusion-dependent thalassaemia syndromes and iron overload, diarrhoea (9.1%), rash (9.1%), and nausea (7.3%) were the most frequent study drug-related adverse events reported by patients receiving 10 mg/kg/day of EXJADE. Abnormal serum creatinine and creatinine clearance values were reported in 5.5% and 1.8%, respectively, of patients receiving 10 mg/kg/day of EXJADE. Elevations of liver transaminases greater than 2 times the baseline and 5 times the upper limit of normal were reported in 1.8% of patients treated with 10 mg/kg/day of EXJADE.
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 1

Blood and lymphatic system disorders
Not known:	Pancytopenia1, thrombocytopenia1, anaemia aggravated1, neutropenia
Immune system disorders
Not known:	Hypersensitivity reactions (including anaphylaxis and angioedema)1
Metabolism and nutrition disorders
Not known:	Metabolic acidosis
Psychiatric disorders
Uncommon:	Anxiety, sleep disorder
Nervous system disorders
Common:	Headache
Uncommon:	Dizziness
Eye disorders
Uncommon:	Early cataract, maculopathy
Rare:	Optic neuritis
Ear and labyrinth disorders
Uncommon:	Hearing loss
Respiratory, thoracic and mediastinal disorders
Uncommon:	Pharyngolaryngeal 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 perforation
Hepatobiliary disorders
Common:	Transaminases increased
Uncommon:	Hepatitis, cholelithiasis
Not known:	Hepatic failure1
Skin and subcutaneous tissue disorders
Common:	Rash, pruritus
Uncommon:	Pigmentation disorder
Not known:	Stevens-Johnson syndrome1, leukocytoclastic vasculitis1, urticaria1, erythema multiforme1, alopecia1
Renal and urinary disorders
Very common:	Blood creatinine increased
Common:	Proteinuria
Uncommon:	Renal tubulopathy (acquired Fanconi's syndrome), glycosuria
Not known:	Acute renal failure1, tubulointerstitial nephritis1, nephrolithiasis, 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.
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. Elevations of transaminases greater than 10 times the upper limit of the normal range, suggestive of hepatitis, were uncommon (0.3%). During post-marketing experience, hepatic failure, sometimes fatal, has been reported with EXJADE, especially in patients with pre-existing liver cirrhosis (see section 4.4). There have been post-marketing reports of metabolic acidosis. The majority of these patients had renal impairment, renal tubulopathy (Fanconi's syndrome) or diarrhoea, or conditions where acid-base imbalance is a known complication (see section 4.4). Serious acute pancreatitis may potentially occur as a complication of gallstones (and related biliary disorders). As with other iron chelator treatment, high-frequency hearing loss and lenticular opacities (early cataracts) have been uncommonly observed in patients treated with EXJADE (see section 4.4).
Paediatric population
Diarrhoea is reported more commonly in paediatric patients aged 2 to 5 years than in older patients.
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassaemia treated with EXJADE.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 Overdose
Cases of overdose (2-3 times the prescribed dose for several weeks) have been reported. In one case, this resulted in subclinical hepatitis which resolved after a dose interruption. Single doses of 80 mg/kg in iron-overloaded thalassaemic patients caused mild nausea and diarrhoea.
Acute signs of overdose may include nausea, vomiting, headache and diarrhoea. Overdose may be treated by induction of emesis or by gastric lavage, and by symptomatic treatment.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Iron chelating agent, ATC code: V03AC03
Mechanism of action
Deferasirox is an orally active chelator that is highly selective for iron (III). It is a tridentate ligand that binds iron with high affinity in a 2:1 ratio. Deferasirox promotes excretion of iron, primarily in the faeces. Deferasirox has low affinity for zinc and copper, and does not cause constant low serum levels of these metals.
Pharmacodynamic effects
In an iron-balance metabolic study in iron-overloaded adult thalassaemic patients, EXJADE at daily doses of 10, 20 and 40 mg/kg induced the mean net excretion of 0.119, 0.329 and 0.445 mg Fe/kg body weight/day, respectively.
Clinical efficacy and safety
EXJADE has been investigated in 411 adult (age ≥16 years) and 292 paediatric patients (aged 2 to <16 years) with chronic iron overload due to blood transfusions. Of the paediatric patients 52 were aged 2 to 5 years. The underlying conditions requiring transfusion included beta-thalassaemia, sickle cell disease and other congenital and acquired anaemias (myelodysplastic syndromes, Diamond-Blackfan syndrome, aplastic anaemia and other very rare anaemias).
Daily treatment at doses of 20 and 30 mg/kg for one year in frequently transfused adult and paediatric patients with beta-thalassaemia led to reductions in indicators of total body iron; liver iron concentration was reduced by about -0.4 and -8.9 mg Fe/g liver (biopsy dry weight (dw)) on average, respectively, and serum ferritin was reduced by about -36 and -926 µg/l on average, respectively. At these same doses the ratios of iron excretion : iron intake were 1.02 (indicating net iron balance) and 1.67 (indicating net iron removal), respectively. EXJADE induced similar responses in iron-overloaded patients with other anaemias. Daily doses of 10 mg/kg for one year could maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Serum ferritin assessed by monthly monitoring reflected changes in liver iron concentration indicating that trends in serum ferritin can be used to monitor response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI indicate that treatment with EXJADE 10-30 mg/kg/day for 1 year may also reduce levels of iron in the heart (on average, MRI T2* increased from 18.3 to 23.0 milliseconds).
The principal analysis of the pivotal comparative study in 586 patients suffering from beta-thalassaemia and transfusional iron overload did not demonstrate non-inferiority of EXJADE to deferoxamine in the analysis of the total patient population. It appeared from a post-hoc analysis of this study that, in the subgroup of patients with liver iron concentration ≥7 mg Fe/g dw treated with EXJADE (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), the non-inferiority criteria were achieved. However, in patients with liver iron concentration <7 mg Fe/g dw treated with EXJADE (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), non-inferiority was not established due to imbalance in the dosing of the two chelators. This imbalance occurred because patients on deferoxamine were allowed to remain on their pre-study dose even if it was higher than the protocol specified dose. Fifty-six patients under the age of 6 years participated in this pivotal study, 28 of them receiving EXJADE.
It appeared from preclinical and clinical studies that EXJADE could be as active as deferoxamine when used in a dose ratio of 2:1 (i.e. a dose of EXJADE that is numerically half of the deferoxamine dose). However, this dosing recommendation was not prospectively assessed in the clinical trials.
In addition, in patients with liver iron concentration ≥7 mg Fe/g dw with various rare anaemias or sickle cell disease, EXJADE up to 20 and 30 mg/kg produced a decrease in liver iron concentration and serum ferritin comparable to that obtained in patients with beta-thalassaemia.
In patients with non-transfusion-dependent thalassaemia syndromes and iron overload, treatment with EXJADE was assessed in a 1-year, randomised, double-blind, placebo-controlled study. The study compared the efficacy of two different deferasirox regimens (starting doses of 5 and 10 mg/kg/day, 55 patients in each arm) and of matching placebo (56 patients). The study enrolled 145 adult and 21 paediatric patients. The primary efficacy parameter was the change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was the change in serum ferritin between baseline and fourth quarter. At a starting dose of 10 mg/kg/day, EXJADE led to reductions in indicators of total body iron. On average, liver iron concentration decreased by 3.80 mg Fe/g dw in patients treated with EXJADE (starting dose 10 mg/kg/day) and increased by 0.38 mg Fe/g dw in patients treated with placebo (p<0.001). On average, serum ferritin decreased by 222.0 µg/l in patients treated with EXJADE (starting dose 10 mg/kg/day) and increased by 115 µg/l in patients treated with placebo (p<0.001).
The European Medicines Agency has deferred the obligation to submit the results of studies with EXJADE in one or more subsets of the paediatric population in the treatment of chronic iron overload requiring chelation therapy (see section 4.2 for information on paediatric use).
5.2 Pharmacokinetic properties
Absorption
Deferasirox is absorbed following oral administration with a median time to maximum plasma concentration (tmax) of about 1.5 to 4 hours. The absolute bioavailability (AUC) of deferasirox from EXJADE tablets is about 70% compared to an intravenous dose. Total exposure (AUC) was approximately doubled when taken along with a high-fat breakfast (fat content >50% of calories) and by about 50% when taken along with a standard breakfast. The bioavailability (AUC) of deferasirox was moderately (approx. 13–25%) elevated when taken 30 minutes before meals with normal or high fat content.
Distribution
Deferasirox is highly (99%) protein bound to plasma proteins, almost exclusively serum albumin, and has a small volume of distribution of approximately 14 litres in adults.
Biotransformation
Glucuronidation is the main metabolic pathway for deferasirox, with subsequent biliary excretion. Deconjugation of glucuronidates in the intestine and subsequent reabsorption (enterohepatic recycling) is likely to occur: in a healthy volunteer study, the administration of cholestyramine after a single dose of deferasirox resulted in a 45% decrease in deferasirox exposure (AUC).
Deferasirox is mainly glucuronidated by UGT1A1 and to a lesser extent UGT1A3. CYP450-catalysed (oxidative) metabolism of deferasirox appears to be minor in humans (about 8%). No inhibition of deferasirox metabolism by hydroxyurea was observed in vitro.
Elimination
Deferasirox and its metabolites are primarily excreted in the faeces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean elimination half-life (t1/2) ranged from 8 to 16 hours. The transporters MRP2 and MXR (BCRP) are involved in the biliary excretion of deferasirox.
Linearity/non-linearity
The Cmax and AUC0-24h of deferasirox increase approximately linearly with dose under steady-state conditions. Upon multiple dosing exposure increased by an accumulation factor of 1.3 to 2.3.
Characteristics in patients
Paediatric patients
The overall exposure of adolescents (12 to ≤17 years) and children (2 to <12 years) to deferasirox after single and multiple doses was lower than that in adult patients. In children younger than 6 years old exposure was about 50% lower than in adults. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Gender
Females have a moderately lower apparent clearance (by 17.5%) for deferasirox compared to males. Since dosing is individually adjusted according to response this is not expected to have clinical consequences.
Elderly patients
The pharmacokinetics of deferasirox have not been studied in elderly patients (aged 65 or older).
Renal or hepatic impairment
The pharmacokinetics of deferasirox have not been studied in patients with renal impairment. The pharmacokinetics of deferasirox were not influenced by liver transaminase levels up to 5 times the upper limit of the normal range.
In a clinical study using single doses of 20 mg/kg deferasirox, the average exposure was increased by 16% in subjects with mild hepatic impairment (Child-Pugh Class A) and by 76% in subjects with moderate hepatic impairment (Child-Pugh Class B) compared to subjects with normal hepatic function. The average Cmax of deferasirox in subjects with mild or moderate hepatic impairment was increased by 22%. Exposure was increased 2.8-fold in one subject with severe hepatic impairment (Child-Pugh Class C) (see sections 4.2 and 4.4).
5.3 Preclinical safety data
Preclinical data reveal no special hazard for patients with iron overload, based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity or carcinogenic potential. The main findings were kidney toxicity and lens opacity (cataracts). Similar findings were observed in neonatal and juvenile animals. The kidney toxicity is considered mainly due to iron deprivation in animals that were not previously overloaded with iron.
Tests of genotoxicity in vitro were either negative (Ames test, chromosomal aberration test) or positive (V79 screen). Deferasirox caused formation of micronuclei in vivo in the bone marrow, but not liver, of non-iron-loaded rats at lethal doses. No such effects were observed in iron-preloaded rats. Deferasirox was not carcinogenic when administered to rats in a 2-year study and transgenic p53+/- heterozygous mice in a 6-month study.
The potential for toxicity to reproduction was assessed in rats and rabbits. Deferasirox was not teratogenic, but caused increased frequency of skeletal variations and stillborn pups in rats at high doses that were severely toxic to the non-iron-overloaded mother. Deferasirox did not cause other effects on fertility or reproduction.
6. Pharmaceutical particulars
6.1 List of excipients
Lactose monohydrate
Crospovidone type A
Cellulose, microcrystalline
Povidone
Sodium laurilsulfate
Silica, colloidal anhydrous
Magnesium stearate
6.2 Incompatibilities
Dispersion in carbonated drinks or milk is not recommended due to foaming and slow dispersion, respectively.
6.3 Shelf life
3 years
6.4 Special precautions for storage
Store in the original package in order to protect from moisture.
6.5 Nature and contents of container
PVC/PE/PVDC/Aluminium blisters.
Packs containing 28, 84 or 252 dispersible tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal and other handling
No special requirements.
7. Marketing authorisation holder
Novartis Europharm Limited
Frimley Business Park
Camberley GU16 7SR
United Kingdom
8. Marketing authorisation number(s)
Exjade 125mg dispersible tablets:
EU/1/06/356/001
EU/1/06/356/002
EU/1/06/356/007
Exjade 250mg dispersible tablets:
EU/1/06/356/003
EU/1/06/356/004
EU/1/06/356/008
Exjade 500mg dispersible tablets:
EU/1/06/356/005
EU/1/06/356/006
EU/1/06/356/009
9. Date of first authorisation/renewal of the authorisation
Date of first authorisation: 28.08.2006
Date of latest renewal: 28.08.2011
10. Date of revision of the text
06.11.2014
Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu