Exjade

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT EXJADE® (EXJADE®)

Composition:

Active substance: deferasirox;

1 tablet contains 250 mg or 500 mg of deferasirox;

Excipients: lactose monohydrate, crospovidone, microcrystalline cellulose, povidone (K30), sodium lauryl sulfate, colloidal anhydrous silicon dioxide, magnesium stearate.

Pharmaceutical form. Dispersible tablets.

Main physicochemical properties:

250 mg tablets: almost white, round, flat tablets with bevelled edges and engraved (imprint) J 250 on one side and NVR on the other side.

500 mg tablets: almost white, round, flat tablets with bevelled edges and engraved (imprint) J 500 on one side and NVR on the other side.

Pharmacotherapeutic group. Agents forming chelate complexes with iron.

ATC code V03A C03.

Pharmacological properties.

Pharmacodynamics.

Deferasirox is an orally active chelator with high selective activity towards iron (III). It is a tridentate ligand with high affinity for iron, binding it in a 2:1 ratio. Deferasirox promotes iron elimination predominantly via feces. Deferasirox has low affinity for zinc and copper and does not cause persistent low serum levels of these metals.

In an iron-balance metabolic study in adult patients with iron overload due to transfusion, Exjade administered at daily doses of 10, 20, and 40 mg/kg induced mean net iron excretion of 0.119, 0.329, and 0.445 mg iron/kg body weight/day, respectively.

Clinical efficacy and safety.

Exjade was studied in 411 adults (aged 16 years and older) and 292 children (aged 2 to 16 years) with chronic iron overload due to blood transfusions. Among children, 52 were aged 2 to 5 years. Main conditions requiring transfusion include beta-thalassemia, sickle cell anemia, and other congenital and acquired anemias (myelodysplastic syndrome (MDS), Diamond-Blackfan syndrome, aplastic anemia, and other very rare anemias).

Treatment at doses of 20 and 30 mg/kg body weight per day for one year in adults and children with beta-thalassemia receiving frequent blood transfusions led to reduction in total body iron levels; liver iron concentration decreased on average to approximately –0.4 and –8.9 mg iron/g dry weight (liver biopsy), respectively, and serum ferritin levels decreased on average to approximately –36 and –926 µg/L, respectively. At these same doses, the ratio of iron excretion to iron absorption was 1.02 (net iron balance index) and 1.67 (net iron excretion index), respectively. Exjade produced similar responses in patients with other forms of anemia. A daily dose of 10 mg/kg body weight over one year may maintain liver iron and serum ferritin levels and induce net iron balance in patients receiving infrequent or exchange transfusions. Monthly serum ferritin levels reflected changes in liver iron concentration. Changes in serum ferritin levels can be used to monitor the appropriate response to Exjade therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI show that treatment with Exjade at 10–30 mg/kg/day for 1 year may also reduce cardiac iron levels (mean MRI T2 increased from 18.3 to 23 milliseconds).

The primary analysis of a pivotal comparative study involving 586 patients with beta-thalassemia and transfusional iron overload did not demonstrate superiority of Exjade over deferoxamine in the overall patient population. As indicated by the analysis of results from this study, in the subgroup of patients with liver iron concentration ≥7 mg iron/g dry weight liver, no efficacy advantage was demonstrated between Exjade (20 and 30 mg/kg) and deferoxamine (35 to ≥50 mg/kg). In patients with liver iron concentration <7 mg/g receiving Exjade (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), no efficacy advantage was established due to imbalance in dosing between the two chelators. This imbalance occurred because patients receiving deferoxamine did not have their dose adjusted from the pre-study level, even if it exceeded the protocol-specified dose. Fifty-six patients under age 6 participated in this pivotal study, 28 of whom received Exjade.

Based on preclinical and clinical studies, Exjade may be as effective as deferoxamine when administered at a 2:1 dose ratio (i.e., Exjade dose numerically equal to half the deferoxamine dose). However, this dosing recommendation has not been prospectively evaluated in clinical trials.

Furthermore, in patients with liver iron concentration ≥7 mg iron/g dry weight liver with various rare anemias or sickle cell anemia, Exjade at doses up to 20 and 30 mg/kg led to reductions in liver iron concentration and serum ferritin compared to patients with beta-thalassemia.

A placebo-controlled, randomized study was conducted in 225 patients with MDS (Low/Int-1 risk) and transfusional iron overload. Results of this study suggest a positive effect of deferasirox on event-free survival (EFS, a composite endpoint including non-fatal cardiovascular and hepatic events) and on serum ferritin levels. The safety profile was consistent with previous studies in adult patients with MDS.

In a 5-year non-interventional study, 267 children aged 2 to <6 years (at study entry) with transfusional hemochromatosis received deferasirox. No clinically significant differences in the safety and tolerability profile of Exjade were observed in children aged 2 to <6 years compared to the overall population of adult and older pediatric patients, including serum creatinine increases >33% above the upper limit of normal in ≥2 consecutive assessments (3.1%) and alanine aminotransferase (ALT) levels >5 times the upper limit of normal (4.3%). Isolated elevations in ALT and aspartate aminotransferase were observed in 20.0% and 8.3% of 145 patients who completed the study, respectively.

During a safety study of deferasirox film-coated tablets, 173 adult and pediatric patients with transfusion-dependent thalassemia syndromes or myelodysplastic syndrome received treatment for 24 weeks. The safety profile of film-coated tablets was comparable to that of dispersible tablets.

In patients with non-transfusion-dependent thalassemia syndromes and iron overload, treatment with Exjade was evaluated in a one-year, randomized, double-blind, placebo-controlled study. The study compared the efficacy of two different deferasirox regimens (initial doses of 5 and 10 mg/kg/day, 55 patients in each group) versus placebo (56 patients). A total of 145 adult patients and 21 children were included. The primary efficacy endpoint was change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy endpoints was change in serum ferritin concentration from baseline after twelve months of treatment. With an initial dose of 10 mg/kg/day, Exjade led to a reduction in total body iron levels. On average, liver iron concentration decreased by 3.80 mg iron/g dry weight in patients receiving Exjade (initial dose 10 mg/kg/day) and increased by 0.38 mg iron/g dry weight in patients receiving placebo (p < 0.001). On average, serum ferritin levels decreased by 222.0 µg/L in patients receiving Exjade (initial dose 10 mg/kg/day) and increased by 115 µg/L in patients receiving placebo (p < 0.001).

Pharmacokinetics.

Absorption.

After oral administration, deferasirox reaches peak plasma concentration (Tmax) within 1.5–4 hours. Absolute bioavailability (AUC) of deferasirox is approximately 70%. Total exposure (AUC) was about twice higher when taken with a high-fat breakfast (fat content >50% of calories) and about 50% higher when taken with a standard breakfast. Bioavailability (AUC) of deferasirox was moderately (approximately 13–25%) increased when taken 30 minutes before a meal with normal or high fat content.

Distribution.

Deferasirox is highly bound (99%) to plasma proteins, almost entirely to serum albumin; volume of distribution in adults is approximately 14 L.

Biotransformation.

Glucuronidation is the main metabolic pathway for deferasirox, followed by biliary excretion. Enterohepatic recirculation (deconjugation of glucuronides in the intestine and subsequent reabsorption) is likely: in a study involving healthy volunteers, administration of cholestyramine after a single dose of deferasirox resulted in a 45% reduction in exposure (AUC).

Deferasirox is primarily glucuronidated by UGT1A1 and to a lesser extent by UGT1A3. CYP450 (oxidative) metabolism of deferasirox in humans is minimal (approximately 8%). In vitro inhibition of deferasirox metabolism by hydroxyurea was not observed.

Elimination.

Deferasirox and its metabolites are primarily excreted in feces (84% of dose). Renal excretion of deferasirox and its metabolites is minimal (8% of dose). Mean elimination half-life (t1/2) ranges from 8 to 16 hours. Transporters MRP2 and MXR (BCRP) are involved in biliary excretion of deferasirox.

Linearity/Non-linearity.

Cmax and AUC0-24h of deferasirox increase almost linearly with dose up to steady state. After multiple dosing, exposure increases by a accumulation factor of 1.3 to 2.3.

Special patient groups.

Children. Total exposure to deferasirox in adolescents (aged 12 to 17 years) and children (aged 2 to 12 years) after single and multiple doses was lower than in adult patients. In children under 6 years of age, exposure was 50% lower than in adults; however, this has no clinical consequences, as dosing is individualized based on treatment response.

Gender. Apparent clearance of deferasirox in women is moderately lower (by 17.5%) than in men, which has no clinical significance, as dosing is individualized based on treatment response.

Elderly patients. Pharmacokinetics of deferasirox in elderly patients (aged 65 years and older) has not been studied.

Renal or hepatic impairment. Pharmacokinetics of deferasirox in patients with renal or hepatic impairment has not been studied. No effect on deferasirox pharmacokinetics was observed with liver transaminase levels elevated up to 5 times the upper limit of normal.

In a clinical study using single doses of deferasirox 20 mg/kg, exposure increased on average by 16% in patients with mild hepatic impairment (Child-Pugh class A) and by 76% in patients with moderate hepatic impairment (Child-Pugh class B), compared to patients with normal liver function. Mean Cmax of deferasirox increased by 22% in patients with mild or moderate hepatic impairment. Exposure increased by 2.8-fold in one patient with severe hepatic impairment (Child-Pugh class C).

Clinical characteristics.

Indications.

Treatment of chronic iron overload due to repeated blood transfusions (≥ 7 mL/kg/month of packed red blood cells) in patients with beta-thalassemia major aged 6 years and older.

Treatment of chronic iron overload due to blood transfusions when deferoxamine therapy is contraindicated or ineffective in the following patients:

• children aged 2 to 5 years with beta-thalassemia major and iron overload due to frequent blood transfusions (≥ 7 mL/kg/month of packed red blood cells);
• patients aged 2 years and older with beta-thalassemia major and iron overload due to infrequent blood transfusions (< 7 mL/kg/month of packed red blood cells);
• patients aged 2 years and older with other anemias.

Treatment of chronic iron overload requiring chelation therapy when deferoxamine therapy is contraindicated or ineffective in patients aged 10 years and older with non-transfusion-dependent thalassemia syndromes.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients.

Combination with another iron-chelating therapy, as the safety of such combinations has not been established.

Creatinine clearance < 60 mL/min or serum creatinine more than twice the upper age-appropriate normal limit.

High risk of myelodysplastic syndrome and other hematological and non-hematological malignancies where benefit from chelation therapy is not expected due to rapid disease progression.

Interaction with other medicinal products and other types of interactions.

The safety of using Exjade in combination with other iron chelators has not been established. Therefore, it should not be combined with other iron-chelating therapies.

Deferasirox bioavailability was increased to varying degrees when administered with food. Therefore, Exjade should be taken on an empty stomach, at least 30 minutes before food, preferably at the same time each day.

Deferasirox metabolism is dependent on UDP-glucuronosyltransferase enzymes. In a study involving healthy volunteers, concomitant administration of Exjade (single dose 30 mg/kg) and the potent UDP-glucuronosyltransferase inducer rifampicin (repeated dose 600 mg/day) resulted in a 44% reduction in deferasirox exposure (90% CI: 37–51%). Thus, concomitant use of Exjade with potent UDP-glucuronosyltransferase inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may lead to reduced efficacy of Exjade. Serum ferritin levels should be monitored during and after combination therapy, and the Exjade dose adjusted as necessary.

Cholestyramine significantly reduced deferasirox exposure in a mechanistic study assessing hepatic extraction ratio.

In a study involving healthy volunteers, concomitant administration of Exjade and midazolam (a CYP3A4 substrate marker) resulted in a 17% reduction in midazolam exposure (90% CI: 8–26%). In clinical settings, this effect may be more pronounced. Therefore, caution should be exercised when combining deferasirox with substances metabolized via CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptives, bepridil, ergotamine) due to potential reduction in efficacy.

In a study involving healthy volunteers, concomitant administration of deferasirox, a moderate inhibitor of CYP2C8 (30 mg/kg/day), with a single 0.5 mg dose of repaglinide, a CYP2C8 substrate, increased the AUC and Cmax of repaglinide by approximately 2.3-fold (90% CI [2.03–2.63]) and 1.6-fold (90% CI [1.42–1.84]), respectively. Since interactions with repaglinide doses higher than 0.5 mg have not been established, concomitant use of deferasirox with repaglinide should be avoided. If combination is necessary, careful clinical and blood glucose monitoring is required. Interactions between deferasirox and other CYP2C8 substrates, such as paclitaxel, cannot be excluded.

In a study involving healthy volunteers, concomitant administration of Exjade, an inhibitor of CYP1A2 (repeated dose 30 mg/kg/day), and the CYP1A2 substrate theophylline (single dose 120 mg) resulted in an 84% increase in theophylline AUC (90% CI: 73% to 95%). Cmax after a single dose was not affected, but an increase in Cmax of theophylline is expected with long-term administration. Therefore, concomitant use of Exjade with theophylline is not recommended. If Exjade and theophylline are used together, theophylline concentrations should be monitored and dose reduction considered. Interactions between Exjade and other CYP1A2 substrates cannot be excluded. For substances primarily metabolized by CYP1A2 with a narrow therapeutic index (e.g., clozapine, tizanidine), the same recommendations as for theophylline should be followed.

Concomitant use of Exjade with antacids containing aluminum has not been formally studied. Although deferasirox has lower affinity for aluminum than for iron, Exjade tablets should not be taken simultaneously with antacids containing aluminum.

Concomitant use of Exjade with substances known to have ulcerogenic potential, such as NSAIDs (including high-dose acetylsalicylic acid), corticosteroids, or oral bisphosphonates, may increase the risk of gastrointestinal toxicity. Concomitant use of Exjade with anticoagulants may also increase the risk of gastrointestinal bleeding. Careful clinical monitoring is required when combining deferasirox with these substances.

Concomitant use of deferasirox and busulfan leads to increased busulfan exposure (AUC), but the mechanism of interaction remains undefined. If possible, pharmacokinetic parameters (AUC, clearance) of a test dose of busulfan should be assessed to guide dose adjustment.

Special precautions for use.

Renal function.

Exjade has been studied only in patients with baseline serum creatinine levels within the normal range for age.

During clinical trials, approximately 36% of patients developed a dose-dependent increase in serum creatinine by > 33% in ≥ 2 consecutive measurements, sometimes exceeding the upper limit of normal. About two-thirds of patients who experienced elevated serum creatinine returned to levels below 33% without dose adjustment. In the remaining third, increased serum creatinine did not always respond to dose reduction or discontinuation of the drug. Cases of acute renal failure have been reported in post-marketing experience with Exjade. In some cases, worsening renal function led to renal failure requiring temporary or permanent dialysis.

The cause of increased serum creatinine levels has not been fully elucidated. Particular attention should be paid to monitoring serum creatinine in patients who are concurrently receiving medications that impair renal function, and in patients receiving high doses of Exjade and/or with low transfusion frequency (< 7 ml/kg/month of packed red blood cells or < 2 units/month in adults). Although an increase in renal adverse events was not observed after dose escalation up to 30 mg/kg in clinical trials, the possibility of an increased risk of renal adverse events cannot be excluded.

Serum creatinine should be assessed before initiating therapy and re-evaluated after starting treatment. Serum creatinine, creatinine clearance (calculated using Cockcroft-Gault or MDRD formulas in adults and the Schwartz formula in children), and/or plasma cystatin C levels should be monitored weekly during the first month of treatment or after any change in Exjade therapy, and monthly thereafter. Patients with a history of kidney disease and those receiving medications that impair renal function are more susceptible to complications. Adequate hydration should be maintained in patients who develop diarrhea or vomiting.

In post-marketing surveillance, cases of metabolic acidosis have been reported during treatment with Exjade. Most of these patients had impaired renal function, renal tubulopathy (Fanconi syndrome), diarrhea, or conditions affecting acid-base balance. Acid-base parameters should be monitored according to clinical indications in these patients. Discontinuation of Exjade therapy should be considered in patients who develop metabolic acidosis.

Post-marketing reports have also included cases of severe renal tubulopathy (Fanconi syndrome) and renal failure associated with altered mental status in the context of hyperammonemic encephalopathy in patients taking deferasirox, predominantly in children. The risk of hyperammonemic encephalopathy should be considered, and ammonia levels should be measured in patients who experience unexplained changes in mental status during Exjade therapy.

Table 1

	Serum creatinine		Creatinine clearance
Before starting therapy	Twice	and	Once
Contraindicated			<60 mL/min
Monitoring
First month after initiation of therapy or dose change	Weekly	and	Weekly
Thereafter	Monthly	and	Monthly
Reduce daily dose by 10 mg/kg/day (dispersible tablets) If the parameters below are observed during two consecutive visits and cannot be attributed to other causes
Adults	>33% above the pre-treatment average value	and	Decrease < ULN* (<90 mL/min)
Children	> age-appropriate upper limit **	and/or	Decrease < ULN* (<90 mL/min)
After dose reduction, discontinue treatment if
Adults and children	Remains >33% above pre-treatment average value	and/or	Decrease < ULN* (<90 mL/min)

Dose adjustment and treatment interruption for monitoring renal function

*LLN: lower limit of normal

**ULN: upper limit of normal

Treatment may be resumed depending on individual parameters. Dose reduction or treatment interruption may be considered in the event of abnormalities in markers of renal tubular function and/or based on clinical indications:

• proteinuria (testing should be performed prior to initiation of therapy and subsequently on a monthly basis);
• glucosuria in patients without diabetes mellitus, and low serum levels of potassium, phosphate, magnesium, or urate, phosphaturia, aminoaciduria (monitoring as needed).

Renal tubulopathy has been primarily reported in children and adolescents with beta-thalassemia treated with Exjade.

Patients should be referred to a renal specialist, and further specialized investigations (such as kidney biopsy) may be considered if, despite dose reduction and treatment interruption:

• serum creatinine remains significantly elevated, and
• persistent abnormalities in other renal functions are observed (e.g. proteinuria, Fanconi syndrome).

Liver function.

Elevations in liver function tests have been observed in patients treated with Exjade. Post-marketing cases of liver failure, some of which were fatal, have been reported in patients receiving Exjade. Severe forms associated with altered consciousness in the context of hyperammonemic encephalopathy may occur in patients receiving deferasirox, particularly in children. The risk of hyperammonemic encephalopathy should be considered, and ammonia levels should be measured in patients who develop unexplained changes in mental status during treatment with Exjade. Careful attention should be paid to adequate hydration in patients with reduced circulating blood volume (e.g. due to diarrhea or vomiting), particularly in children with acute illness. Most reports of liver failure involved patients with significant comorbidities, including pre-existing chronic liver disease (including cirrhosis and hepatitis C) and multi-organ failure. The role of deferasirox cannot be excluded as a contributing or aggravating factor.

It is recommended to monitor serum transaminases, bilirubin, and alkaline phosphatase prior to starting treatment, every 2 weeks during the first month, and then monthly thereafter. If there is a persistent and progressive increase in serum transaminases that cannot be attributed to other causes, Exjade should be discontinued. After identifying the cause of liver function abnormalities or after normalization of liver tests, re-initiation of Exjade treatment at a lower dose with subsequent gradual dose escalation may be considered.

Exjade is not recommended for patients with severe hepatic impairment (Child-Pugh class C).

Table 2

Recommendations for safety monitoring.

Parameter	Frequency
Serum creatinine	Double before starting therapy. Weekly during the first month of therapy and during the first month after dose change. Then monthly.
Creatinine clearance and/or plasma cystatin C levels	Before starting therapy. Weekly during the first month of therapy and during the first month after dose change. Then monthly.
Proteinuria	Before starting therapy. Then monthly.
Other markers of renal tubular function (e.g. glucosuria not related to diabetes and low serum levels of potassium, phosphate, magnesium or urate, phosphaturia, aminoaciduria)	As needed.
Serum transaminases, bilirubin and alkaline phosphatase levels	Before starting therapy. Every 2 weeks during the first month of therapy. Then monthly.
Hearing and vision examination	Before starting therapy. Then annually.
Body weight, height and sexual development	Before starting therapy. Annually in children.

In patients with a predicted short life expectancy (e.g., with a high risk of myelodysplastic syndrome), especially when comorbidities may increase the risk of adverse events, the benefit of treatment with EXJADE may be limited and may be outweighed by the risks. Therefore, treatment of such patients with EXJADE is not recommended.

EXJADE should be used with caution in elderly patients due to the higher frequency of adverse reactions (particularly diarrhea).

Limited data are available in children with non-transfusion-dependent thalassemia. Therefore, treatment with EXJADE should be accompanied by monitoring for adverse reactions and assessment of iron levels. Furthermore, before initiating EXJADE treatment in children with non-transfusion-dependent thalassemia and severe iron overload, physicians should be aware that the long-term consequences of treatment in such patients are currently unknown.

Gastrointestinal tract.

Ulcers and bleeding from the upper gastrointestinal tract have been reported in patients, including children and adolescents, treated with EXJADE. Multiple ulcers have been observed in some patients. Ulcers complicated by gastrointestinal tract perforation have been reported. Fatal gastrointestinal hemorrhages have also been reported, particularly in elderly patients with hematological malignancies and/or low platelet counts. Physicians should inform patients about the signs and symptoms of gastrointestinal ulcers and bleeding during EXJADE therapy. If gastrointestinal ulceration or upper gastrointestinal bleeding occurs, EXJADE should be discontinued and appropriate diagnostic evaluation and treatment initiated immediately. Caution should be exercised in patients taking EXJADE concomitantly with drugs known to have ulcerogenic potential (such as NSAIDs, corticosteroids, or oral bisphosphonates), as well as in patients receiving anticoagulants and in patients with platelet counts below 50,000/mm³ (50 x 10⁹/L).

Skin disorders.

Skin rashes may occur during treatment with EXJADE. In most cases, rashes resolve spontaneously. If treatment is interrupted due to rash, therapy may be resumed at a lower dose with gradual dose escalation after rash resolution. In severe cases, reinitiation may be considered in combination with short-term oral steroid therapy. Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported and may be life-threatening or fatal. If severe cutaneous adverse reactions are suspected, EXJADE therapy should be discontinued immediately and not restarted. Patients should be informed about the symptoms of severe skin reactions, which should be closely monitored.

Hypersensitivity reactions.

Cases of serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving EXJADE, predominantly during the first month of treatment. If such reactions occur, EXJADE should be discontinued and appropriate medical treatment initiated. Reinitiation of deferasirox therapy is not recommended in patients who have experienced hypersensitivity reactions due to the risk of anaphylactic shock.

Vision and hearing.

Cases of hearing impairment (hearing loss) and visual disturbances (lens opacities, optic neuritis, retinal changes) have been reported. Hearing and vision examinations (including fundoscopy) are recommended before starting treatment and at regular intervals (every 12 months). If disturbances occur during treatment, dose reduction or discontinuation of therapy should be considered.

Hematological disorders.

Post-marketing reports have described leukopenia, thrombocytopenia, or pancytopenia (or exacerbation of these conditions), as well as worsening anemia in patients receiving EXJADE. Most of these patients already had pre-existing hematological disorders, often associated with bone marrow insufficiency. However, a contributory or aggravating role of the drug cannot be excluded. Treatment interruption should be considered in patients who develop cytopenia of unknown etiology.

Other factors.

Monthly monitoring of serum ferritin is recommended to assess patient response to therapy and to avoid over-chelation. Dose reduction or more frequent monitoring of renal and hepatic function, as well as serum ferritin levels, is recommended during periods of high-dose therapy and when serum ferritin levels approach the desired range. If serum ferritin levels consistently fall below 500 µg/L (in transfusion-dependent iron overload) or below 300 µg/L (in non-transfusion-dependent thalassemia syndromes), discontinuation of treatment should be considered.

Results of serum creatinine, serum ferritin, and serum transaminase tests should be recorded and regularly evaluated to detect trends. These results should also be documented in the patient's medical record.

In two clinical studies, growth and sexual development in children treated with EXJADE for 5 years were not impaired. However, as a general precaution, body weight, growth, and sexual development should be monitored at regular intervals (every 12 months) in children receiving EXJADE for transfusion-dependent iron overload.

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.

Excipients.

This medicinal product contains lactose. Therefore, it is not recommended for patients with rare hereditary problems of galactose intolerance, severe lactase deficiency, or glucose-galactose malabsorption.

This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, i.e., essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy.

Clinical data on the effects of deferasirox on pregnancy are lacking.

Animal studies have shown some reproductive toxicity at maternally toxic doses. The potential risk in humans is unknown.

As a precautionary measure, EXJADE is not recommended during pregnancy unless there are compelling medical reasons.

EXJADE may reduce the efficacy of hormonal contraceptives; therefore, women of childbearing potential are advised to use additional or alternative non-hormonal contraceptive methods during treatment with EXJADE.

Breastfeeding.

Animal studies have shown that deferasirox is rapidly and extensively excreted into milk. No effects on offspring were observed. It is unknown whether deferasirox is excreted in human milk. Breastfeeding during treatment with EXJADE is not recommended.

Fertility.

There are no data on fertility in humans. In animal studies, no adverse effects on fertility in males or females were observed.

Ability to influence the speed of reactions while driving or operating machinery.

No studies on the effects of EXJADE on the ability to drive or operate machinery have been conducted. Patients who experience adverse effects such as dizziness should refrain from driving or operating machinery.

Dosage and Administration

Transfusional iron overload.

Initial and ongoing treatment with EXJADE should be administered by physicians experienced in managing chronic iron overload. It is recommended to initiate treatment after approximately 20 units (≈100 mL/kg) of red blood cell transfusions have been administered, or when clinical monitoring data indicate chronic iron overload (e.g., serum ferritin concentration > 1000 mcg/L). Doses (in mg/kg) should be calculated and rounded to the nearest whole tablet strength.

The goal of iron chelation therapy is to remove transfusion-derived iron and, if necessary, reduce existing iron stores.

Care should be taken during chelation therapy to minimize the risk of chelator overload in all patients.

Dosage.

Initial dose.

The recommended initial daily dose of EXJADE is 20 mg/kg body weight.

For patients who require reduction of elevated iron levels and who receive more than 14 mL/kg/month of red blood cells (approximately >4 units/month for an adult patient), the initial daily dose may be 30 mg/kg. For patients who do not require reduction of elevated iron levels and who receive less than 7 mL/kg/month of red blood cells (approximately <2 units/month for an adult patient), the initial daily dose may be 10 mg/kg. The patient's response should be monitored, and dose escalation should be considered if an adequate response is not achieved.

For patients who have had a good clinical response to deferoxamine, an initial dose of EXJADE equivalent to half the deferoxamine dose may be prescribed (e.g., a patient receiving deferoxamine at 40 mg/kg/day for 5 days per week may be switched to an initial daily dose of EXJADE of 20 mg/kg/day).

If the daily dose is less than 20 mg/kg body weight, the clinical response should be monitored and dose escalation should be considered if an adequate effect is not achieved.

Dose adjustment.

Serum ferritin levels should be monitored monthly, and the dose of EXJADE should be adjusted every 3–6 months based on changes in serum ferritin levels, if necessary. Dose adjustments should be made incrementally by 5–10 mg/kg according to individual patient response and therapeutic goals (maintenance or reduction of iron levels). For patients in whom treatment with EXJADE at a dose of 30 mg/kg does not provide adequate control (e.g., serum ferritin levels consistently exceed 2,500 mcg/L and do not show a downward trend over time), a dose up to 40 mg/kg may be considered. Data on the long-term efficacy and safety of EXJADE at doses exceeding 30 mg/kg are currently limited (after dose escalation, 264 patients were observed for a median of 1 year). In cases of very poor control of hemosiderosis at doses up to 30 mg/kg, further dose increases (maximum dose 40 mg/kg) may not provide adequate control, and alternative treatment options should be considered. If adequate control is not achieved with doses exceeding 30 mg/kg, treatment at such doses should not be continued, and alternative treatment options should be considered. Doses exceeding 40 mg/kg are not recommended due to limited experience with such dosing.

Patients receiving EXJADE at doses above 30 mg/kg should have their dose gradually reduced by 5–10 mg/kg upon achieving control (e.g., serum ferritin levels consistently below 2,500 mcg/L and showing a downward trend over time). For patients who achieve the desired serum ferritin level (typically between 500 and 1,000 mcg/L), the dose should be gradually reduced by 5–10 mg/kg to maintain serum ferritin levels within the desired range and minimize the risk of chelator overload. If serum ferritin levels consistently decline to below 500 mcg/L, treatment should be discontinued.

Non-transfusion-dependent thalassemia syndromes.

Chelation therapy should only be initiated in the presence of iron overload (liver iron concentration [LIC] ≥ 5 mg Fe/g dry weight [dw] or persistently elevated serum ferritin levels > 800 mcg/L). LIC is the preferred parameter for diagnosing iron overload and should be used whenever possible. Caution should be exercised during chelation therapy in all patients to minimize the risk of chelator overload.

Table 3

Recommended doses for non-transfusion-dependent thalassemia syndromes.

	Dispersible tablets	Liver iron concentration (LIC)*		Serum ferritin levels
Initial dose	10 mg/kg/day	≥5 mg iron/g dry weight	or	>800 µg/L
Monitoring				Monthly
Dose adjustment stages (every 3–6 months)	Increase dose 5–10 mg/kg/day	≥7 mg iron/g dry weight	or	>2000 µg/L
	Decrease dose 5–10 mg/kg/day	<7 mg iron/g dry weight	or	≤2000 µg/L
Maximum dose	20 mg/kg/day
	10 mg/kg/day
	For adults For children	Not assessed	and	≤2000 µg/L
Discontinue treatment		<3 mg iron/g dry weight	or	<300 µg/L
Resume treatment		Not recommended

Liver iron concentration assessment is the preferred method for determining the level of iron overload.

Dosing.

The recommended initial daily dose of Exjade for non-transfusion-dependent thalassemia syndrome patients is 10 mg/kg body weight.

Dose adjustment.

Serum ferritin levels should be monitored monthly to assess patient response to therapy and to minimize the risk of chelator overexposure. After 3–6 months of treatment, a stepwise dose increase by 5–10 mg/kg should be considered if the patient's LIC value is ≥ 7 mg Fe/g dry weight or serum ferritin levels remain consistently > 2,000 µg/L without showing a declining trend over time, and the patient tolerates the medication well. Doses exceeding 20 mg/kg are not recommended, as there is no experience with higher doses in non-transfusion-dependent thalassemia patients.

For patients whose LIC has not been measured and whose serum ferritin levels are ≤ 2,000 µg/L, doses should not exceed 10 mg/kg.

For patients whose dose has been increased to > 10 mg/kg, dose reduction to 10 mg/kg or lower is recommended when LIC is < 7 mg Fe/g dry weight or serum ferritin levels are ≤ 2,000 µg/L.

Treatment discontinuation.

Treatment should be discontinued once satisfactory body iron levels are achieved (LIC < 3 mg Fe/g dry weight or serum ferritin levels < 300 µg/L). There are no data on re-treatment of patients who experience iron re-accumulation after achieving satisfactory iron levels; therefore, re-treatment cannot be recommended.

Special patient groups.

Elderly patients (over 65 years of age).

Dosing recommendations for elderly patients are the same as described above. During clinical trials, elderly patients experienced a higher incidence of adverse reactions compared to younger patients (particularly diarrhea); therefore, careful monitoring for adverse events, which may require dose adjustment, is advised.

Patients with renal impairment.

The use of Exjade in patients with renal dysfunction has not been studied and is contraindicated in patients with creatinine clearance < 60 mL/min.

Patients with hepatic impairment.

The use of Exjade is not recommended in patients with severe hepatic impairment (Child-Pugh class C). For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced by 50%. The drug should be used with caution in these patients. Liver function should be monitored in all patients every 2 weeks during the first month and then monthly thereafter.

Administration method.

Exjade should be taken once daily on an empty stomach, 30 minutes before a meal, preferably at the same time each day. Dispersible tablets should be mixed in a glass of water, orange juice, or apple juice (100–200 mL) until a uniform suspension is obtained. After swallowing the suspension, any residue should be rinsed with a small amount of water or juice and consumed as well. Tablets must not be chewed or swallowed whole.

Children.

Dosing recommendations for children aged 2 to 17 years are the same as for adult patients. Serum ferritin levels should be monitored monthly to assess patient response to therapy and to minimize the risk of chelator overexposure. Dose calculations should take into account changes in children's body weight over time.

In children aged 2 to 5 years, exposure is lower than in adults. Therefore, this age group may require higher doses than adults. However, the initial dose should be the same as for adults, with subsequent individual dose titration.

For children with non-transfusion-dependent thalassemia syndromes, the dose must not exceed 10 mg/kg. In these patients, careful monitoring of LIC and serum ferritin levels is essential to avoid chelator overexposure: in addition to monthly assessment of serum ferritin levels, LIC should be closely monitored every three months if serum ferritin levels are ≤ 800 µg/L.

The safety and efficacy of Exjade in children from birth to 23 months of age have not yet been established.

Overdose.

Early signs of acute overdose include gastrointestinal disturbances such as abdominal pain, diarrhea, nausea, and vomiting. Cases of hepatic and renal dysfunction have been reported, including elevations in liver enzymes and creatinine, with recovery after discontinuation of treatment. A single accidental dose of 90 mg/kg resulted in Fanconi syndrome, which resolved following treatment.

There is no specific antidote for deferasirox. Standard procedures for managing overdose should be implemented, along with symptomatic treatment as appropriate from a medical standpoint.

Adverse Reactions

During treatment with Exjade in adults and children, the most commonly reported adverse reactions were gastrointestinal (GI) in nature: primarily nausea, vomiting, diarrhea, abdominal pain, and skin rash. Diarrhea was reported more frequently in children aged 2 to 5 years than in older patients. These reactions are dose-dependent and generally mild to moderate in severity; in most cases, they resolve even with continued administration of the drug.

In clinical studies, approximately 36% of patients experienced dose-dependent increases in serum creatinine concentration, although these elevations remained within normal limits in most patients. A reduction in mean creatinine clearance was observed in both adults and children with beta-thalassemia and iron overload during the first year of treatment; however, evidence indicates that no further decline in mean creatinine clearance occurred in subsequent years. Elevations in liver transaminases have been reported. Regular monitoring of renal and liver function tests is recommended. Infrequent occurrences of hearing impairment (hearing loss) and visual disturbances (lens opacities) have been observed; annual examinations are therefore recommended.

Severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported during treatment with Exjade.

The frequency categories of adverse reactions are defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

Blood and lymphatic system disorders: not known – pancytopenia¹, thrombocytopenia¹, worsening of anemia¹, neutropenia¹.

Immune system disorders: not known – hypersensitivity reactions (including anaphylaxis and angioedema)¹.

Metabolism and nutrition disorders: not known – metabolic acidosis¹.

Psychiatric disorders: uncommon – anxiety, sleep disorders.

Nervous system disorders: common – headache; uncommon – dizziness.

Eye disorders: uncommon – cataract, maculopathy; rare – optic neuritis.

Ear and labyrinth disorders: uncommon – hearing loss.

Respiratory, thoracic and mediastinal disorders: uncommon – throat pain.

Gastrointestinal disorders: common – diarrhea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia; uncommon – gastrointestinal hemorrhage, gastric ulcer (including multiple ulcers), duodenal ulcer, gastritis; rare – esophagitis; not known – gastrointestinal perforation¹, acute pancreatitis¹.

Hepatobiliary disorders: common – increased transaminase levels; uncommon – hepatitis, cholelithiasis; not known – liver failure¹,².

Skin and subcutaneous tissue disorders: common – rash, pruritus; uncommon – pigmentary changes; 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 – increased blood creatinine levels; common – proteinuria; uncommon – tubular dysfunction² (acquired Fanconi syndrome), glucosuria; not known – acute renal failure¹,², tubulointerstitial nephritis¹, nephrolithiasis¹, acute tubular necrosis¹.

General disorders and administration site conditions: uncommon – pyrexia, edema, fatigue.

¹ Adverse reactions reported during post-marketing experience from spontaneous reports, for which the frequency or causal relationship to drug exposure cannot always be reliably established.

² Severe cases associated with altered consciousness in the context of hyperammonemic encephalopathy have been reported.

Gallstones and related biliary tract disorders were reported in 2% of cases. Elevated liver transaminase activity was also observed in 2% of cases. In some cases (0.3%), transaminase levels increased more than 10-fold above the upper limit of normal, indicating the development of hepatitis. Post-marketing reports have documented cases of liver failure, sometimes fatal, during deferasirox treatment. Cases of metabolic acidosis have also been reported in post-marketing experience. Most of these patients had renal impairment, renal tubulopathy (Fanconi syndrome), diarrhea, or conditions affecting acid-base balance. Cases of severe acute pancreatitis have been observed without documented concomitant biliary disease. As with other iron chelators, a high incidence of hearing loss and lens opacities (early cataract) has been reported.

A retrospective meta-analysis of data from 2,102 adults and children with beta-thalassemia and transfusional iron overload (including various factors such as transfusion intensity, route of administration, and treatment duration) treated in two randomized clinical trials and four open-label studies with up to five years of follow-up showed that mean creatinine clearance decreased by 13.2% in adult patients (95% CI: –14.4% to 12.1%; n=935) and by 9.9% (95% CI: –11.1% to 8.6%; n=1,142) in children during the first year of treatment. In the subgroup of patients treated for more than one year (n=250 for over five years), no further decline in mean creatinine clearance was observed in subsequent years.

In a one-year, randomized, double-blind, placebo-controlled study in non-transfusion-dependent thalassemia patients with iron overload, diarrhea (9.1%), rash (9.1%), and nausea (7.3%) were the most common drug-related adverse events observed in patients receiving Exjade at a dose of 10 mg/kg/day. Abnormalities in serum creatinine and creatinine clearance were reported in 5.5% and 1.8% of patients, respectively, receiving Exjade at 10 mg/kg/day. Elevations in liver transaminases more than 2-fold above baseline and more than 5-fold above the upper limit of normal were recorded in 1.8% of patients receiving Exjade at 10 mg/kg/day.

Children.

In two clinical studies, growth and sexual development in children treated with deferasirox for up to 5 years were not impaired.

Diarrhea was reported more frequently in children aged 2 to 5 years compared to older patients.

Renal tubulopathy has been primarily reported in children and adolescents with beta-thalassemia treated with Exjade.

Post-marketing data indicate a higher frequency of reported cases of metabolic acidosis in children in the context of Fanconi syndrome. Cases of acute pancreatitis, particularly in children and adolescents, have been reported.

Incompatibilities.

Dissolving in carbonated beverages or milk is not recommended due to foaming and slow dispersion.

Shelf life. 3 years.

Storage conditions. Store in the original packaging to protect from moisture at temperatures not exceeding 30 °C. Keep out of reach of children.

Packaging. 28 tablets per pack.

Prescription category. Prescription only.

Manufacturer.

1. Novartis Pharma Stein AG / Novartis Pharma Stein AG
2. Sandoz S.R.L. / Sandoz S.R.L.

Manufacturer's address and location of operations.

1. Schaffhauserstrasse, 4332 Stein, Switzerland
2. Str. Livezeni nr. 7A, 540472, Targu Mures, Jud. Mures, Romania