Deferasirox-vista
UkraineTable of Contents
INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT DEFERASIROX-VISTA (DEFERASIROX-VISTA)
Composition:
Active ingredient: deferasirox;
One film-coated tablet contains 90 mg, 180 mg, or 360 mg of deferasirox;
Excipients: microcrystalline cellulose (type 101), povidone K-30, crospovidone (type B), poloxamer 188;
extragranular layer: microcrystalline cellulose (type 102), crospovidone (type A), colloidal anhydrous silicon dioxide, magnesium stearate;
tablet coating: hypromellose (E 464); lactose monohydrate; titanium dioxide (E 171); triacetin; indigo carmine aluminum lake (E 132).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
90 mg tablets: oval, biconvex, film-coated tablets, pale blue in color, with "D7FX" embossed on one side and "90" on the other;
180 mg tablets: oval, biconvex, film-coated tablets, blue in color, with "D7FX" engraved on one side and "180" on the other;
360 mg tablets: oval, biconvex, film-coated tablets, blue in color, with "D7FX" engraved on one side and "360" on the other.
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 excretion predominantly via feces. Deferasirox has low affinity for zinc and copper and does not cause persistent low serum levels of these metals.
In a metabolic iron balance study in adult patients with thalassemia and iron overload, deferasirox 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.
The effect of deferasirox was evaluated in 411 adults (aged ≥16 years) and 292 children (aged 2 to 16 years) with chronic iron overload due to blood transfusions. Among the children, 52 were aged 2 to 5 years. The main conditions requiring transfusion include beta-thalassemia, sickle cell anemia, and other rare inherited and acquired anemias (myelodysplastic syndrome, Diamond-Blackfan syndrome, aplastic anemia, and other very rare anemias).
Treatment with doses of 20 and 30 mg/kg body weight daily for 1 year in adults and children with beta-thalassemia receiving frequent transfusions reduced total body iron levels; liver iron concentration decreased on average to approximately –0.4 and –8.9 mg iron/g liver (dry weight 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. Deferasirox 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 concentration and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions 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 drug therapy. Limited clinical data (29 patients with normal cardiac function at baseline), obtained by MRI, indicate that treatment with deferasirox at doses of 10–30 mg/kg daily 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 deferasirox over deferoxamine in the overall patient population. According to the analysis of this study, in the subgroup of patients with liver iron concentration ≥7 mg iron/g liver who received deferasirox (20 and 30 mg/kg) or deferoxamine (35 to ≥50 mg/kg), no superiority in efficacy was demonstrated. In patients with liver iron concentration <7 mg/g who received deferasirox (5 and 10 mg/kg) or deferoxamine (20 to 35 mg/kg), superiority in efficacy was not 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 dose they were receiving prior to the study, even if it exceeded the protocol-specified dose. A total of 56 patients aged up to 6 years participated in this pivotal study, 28 of whom received deferasirox.
According to preclinical and clinical studies, deferasirox may be as active as deferoxamine when administered at a 2:1 dose ratio (i.e., the deferasirox dose numerically equals half the deferoxamine dose). However, this dosing recommendation has not been prospectively evaluated in clinical trials.
Additionally, in patients with liver iron concentration ≥7 mg iron/g liver and various rare anemias or sickle cell anemia, deferasirox at doses up to 20 and 30 mg/kg reduced liver iron and serum ferritin concentrations compared to patients with beta-thalassemia.
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 deferasirox were observed in children aged 2 to <6 years compared to the overall population of adult and older pediatric patients, including increases in serum creatinine levels by >33% above the upper limit of normal in ≥2 consecutive assessments (3.1%) and increases in alanine aminotransferase (ALT) levels >5 times above the upper limit of normal (4.3%). Single episodes of elevated ALT and aspartate aminotransferase (AST) were observed in 20% 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. A similar safety profile was observed for film-coated tablets and dispersible tablets.
In patients with non-transfusion-dependent thalassemia syndromes and iron overload, treatment with deferasirox 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 daily, 55 patients in each group) versus placebo (56 patients). The study included 145 adult patients and 21 children. The primary efficacy parameter was change in liver iron concentration (LIC) from baseline after 12 months of treatment. One of the secondary efficacy parameters was change in serum ferritin concentration from baseline after 12 months of treatment. With an initial dose of 10 mg/kg daily, deferasirox reduced total body iron levels. On average, liver iron concentration decreased by 3.80 mg iron/g dry weight in patients receiving deferasirox (initial dose 10 mg/kg daily) 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 deferasirox (initial dose 10 mg/kg daily) and increased by 115 µg/L in patients receiving placebo (p < 0.001).
Pharmacokinetics.
After administration of deferasirox in film-coated tablets, higher bioavailability was observed compared to deferasirox in dispersible tablets. After dose adjustment of film-coated tablets (up to 360 mg), the mean area under the concentration-time curve (AUC) under fasting conditions was equivalent to that of dispersible tablets at a dose of 500 mg. The maximum concentration (Cmax) increased by 30% (90% CI [confidence interval]: 20.3–40.0%), but clinical analysis did not reveal a clinically significant effect of this increase.
Absorption.
After oral administration of deferasirox in dispersible tablets, maximum plasma concentration (Cmax) is reached approximately within 1.5–4 hours, and absolute bioavailability (AUC) is nearly 70% compared to intravenous administration. Absolute bioavailability (AUC) for film-coated tablets was not determined. The bioavailability of deferasirox in film-coated tablets was 36% higher than in dispersible tablets. In a food-effect study on bioavailability of film-coated tablets in healthy volunteers under fasting conditions, with low-fat food (fat content <10% of calories) or high-fat food (fat content >50% of calories), AUC and Cmax of deferasirox were moderately reduced after intake with low-fat food (by 11% and 16%, respectively). After intake with high-fat food, AUC and Cmax increased (by 18% and 29%, respectively). The increase in Cmax may be due to the combined effect of formulation and food with high fat content. Therefore, deferasirox in the form of film-coated tablets is recommended to be taken on an empty stomach or with light food.
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 of deferasirox, followed by biliary excretion. Intestinal deconjugation of glucuronides and subsequent reabsorption (enterohepatic recirculation) is likely: in a study involving healthy volunteers, administration of cholestyramine after a single dose of deferasirox resulted in a 45% reduction in AUC.
Deferasirox is primarily glucuronidated by UDP-glucuronosyltransferase 1A1 and to a lesser extent by UDP-glucuronosyltransferase 1A3. CYP450 (oxidative) metabolism of deferasirox in humans is minimal (approximately 8%). In vitro inhibition of deferasirox metabolism by hydroxyurea was not observed.
Excretion.
Deferasirox and its metabolites are excreted predominantly in feces (84% of dose). Renal excretion of deferasirox and its metabolites is minimal (8% of dose). The 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 increased 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, which has no clinical consequences since 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 consequences since dosing is individualized based on treatment response.
Elderly patients. Pharmacokinetics of deferasirox in elderly patients (aged ≥65 years) has not been studied.
Renal or hepatic impairment. Pharmacokinetics of deferasirox in patients with renal or hepatic impairment has not been studied. There is no effect on the pharmacokinetics of deferasirox at serum transaminase levels up to 5 times above 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 2.8-fold in one patient with severe hepatic impairment (Child-Pugh class C).
Clinical characteristics.
Indications.
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-thalassemia major aged 6 years and older.
For the treatment of chronic transfusional iron overload when deferoxamine therapy is contraindicated or ineffective in the following patients:
- patients 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.
For the 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 — the safety of such combinations has not been established. Creatinine clearance < 60 mL/min or serum creatinine more than twice the upper limit of normal for age.
High risk of myelodysplastic syndrome and other hematological and non-hematological malignancies when no benefit from chelation therapy is expected due to rapid disease progression.
Interaction with other medicinal products and other forms of interaction.
The safety of using deferasirox in combination with other iron chelators has not been established. Therefore, it should not be combined with other iron-chelating therapies. Interaction with food.
Cmax of deferasirox in film-coated tablets increased by 29% when taken with a high-fat meal. Film-coated tablets may be taken on an empty stomach or with a light meal, preferably at the same time each day (see sections "Pharmacokinetics" and "Dosage and administration").
Deferasirox metabolism is mediated by UDP-glucuronosyltransferase enzymes. In a study involving healthy volunteers, concomitant administration of deferasirox (single dose 30 mg/kg) and rifampicin, a strong inducer of UDP-glucuronosyltransferase (repeated dose 600 mg/day), reduced deferasirox exposure by 44% (90% CI: 37–51%). Thus, concomitant use of deferasirox with strong inducers of UDP-glucuronosyltransferase (such as rifampicin, carbamazepine, phenytoin, phenobarbital, ritonavir) may lead to reduced efficacy of deferasirox. Serum ferritin levels should be monitored during and after combination therapy, and the dose of deferasirox should be adjusted if necessary. Cholestyramine significantly reduced deferasirox exposure in a mechanistic study assessing hepatic extraction ratio.
In a study involving healthy volunteers, concomitant administration of deferasirox and midazolam (a CYP3A4 probe substrate) resulted in a 17% reduction in midazolam exposure (90% CI: 8–26%). In clinical settings, this effect may be more pronounced. Therefore, due to the potential for reduced efficacy, deferasirox should be used cautiously in combination with substances metabolized by CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptives, bepridil, ergotamine).
In a study involving healthy volunteers, concomitant administration of deferasirox (30 mg/kg/day), as a moderate inhibitor of CYP2C8, 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 monitoring and blood glucose monitoring should be performed. Interactions between deferasirox and other CYP2C8 substrates, such as paclitaxel, cannot be excluded.
In a study involving healthy volunteers, concomitant administration of deferasirox (repeated dose 30 mg/kg/day), as an inhibitor of CYP1A2, with a single 120 mg dose of theophylline, a CYP1A2 substrate, increased the AUC of theophylline by 84% (90% CI: 73–95%). Cmax after a single dose was not affected, but an increase in Cmax of theophylline is expected with long-term use. Therefore, concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used concomitantly, theophylline concentrations should be monitored and dose reduction considered. Interactions between deferasirox and other CYP1A2 substrates cannot be excluded. When using substances primarily metabolized by CYP1A2 and having a narrow therapeutic index (e.g., clozapine, tizanidine), the same recommendations as for theophylline should be followed.
Concomitant use of the medicinal product with antacids containing aluminum has not been formally studied. Although deferasirox has lower affinity for aluminum than for iron, the product is not recommended to be taken together with antacids containing aluminum.
Concomitant use of deferasirox with agents having ulcerogenic potential, such as non-steroidal anti-inflammatory drugs [NSAIDs] (including high-dose acetylsalicylic acid), corticosteroids, or oral bisphosphonates, increases the risk of gastrointestinal toxicity. Concomitant use of the medicinal product with anticoagulants also increases the risk of gastrointestinal bleeding. Careful clinical monitoring is required when combining deferasirox with these agents.
Concomitant administration of deferasirox and busulfan leads to increased busulfan AUC, but the mechanism of interaction remains unclear. If possible, the pharmacokinetics (AUC, clearance) of the investigational busulfan dose should be assessed to ensure appropriate dose adjustment.
Special precautions for use.
Renal function.
Deferasirox has been studied only in patients with baseline serum creatinine levels within the normal range for their age.
During clinical trials, approximately 36% of patients experienced a dose-dependent increase in serum creatinine levels by > 33% on ≥ 2 consecutive occasions, sometimes exceeding the upper limit of normal. In approximately two-thirds of patients who experienced an increase in serum creatinine, levels returned to below 33% above baseline without dose adjustment. In the remaining patients, elevated serum creatinine levels did not always respond to dose reduction or discontinuation of the medicinal product. Cases of acute renal failure have been reported during clinical studies of the medicinal product. In some cases, worsening renal function led to renal failure requiring temporary or permanent dialysis.
The causes of increased serum creatinine levels have not been fully elucidated. Particular attention should be paid to monitoring serum creatinine levels in patients receiving concomitant medications that impair renal function, and in patients receiving high doses of the medicinal product and/or having low transfusion rates (< 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 during clinical trials, an increased risk of renal adverse events cannot be excluded when using deferasirox film-coated tablets at doses exceeding 21 mg/kg.
It is recommended to assess serum creatinine levels prior to initiating therapy and to repeat measurements 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 once weekly during the first month of treatment or after any change in deferasirox therapy, and once monthly thereafter. Patients with a history of renal 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.
Cases of metabolic acidosis have been reported during clinical studies with deferasirox. Most of these patients had evidence of 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 deferasirox therapy should be considered in patients who develop metabolic acidosis. Cases of severe renal tubulopathy (such as Fanconi syndrome) and renal failure associated with altered consciousness due to hyperammonemic encephalopathy have been reported in patients receiving deferasirox, particularly in children. Hyperammonemic encephalopathy should be considered and ammonia levels should be measured in patients who develop unexplained changes in mental status during deferasirox therapy.
Table 1.
Dose adjustment and treatment interruption for monitoring of renal function.
| Serum creatinine |
Creatinine clearance |
||
| Before starting therapy |
2 times |
and |
1 time |
| Contraindicated |
< 60 mL/min |
||
| Monitoring |
|||
|
weekly |
and |
weekly |
|
monthly |
and |
monthly |
| Reduce daily dose by 10 mg/kg/day (film-coated 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 normal** |
and/or |
decrease < ULN* (< 90 mL/min) |
| After dose reduction, discontinue treatment if |
|||
| Adults and children |
Remains > 33% above the pre-treatment average value |
and/or |
decrease < ULN* (< 90 mL/min) |
*LLN: lower limit of normal.
**ULN: upper limit of normal.
Treatment may be resumed depending on individual parameters. Dose reduction or treatment interruption should be considered in the event of abnormalities in markers of renal tubular function and/or according to clinical indications:
- proteinuria (testing should be performed prior to initiation of therapy and monthly thereafter);
- glucosuria in patients without diabetes mellitus, and low serum levels of potassium, phosphate, magnesium, or urates, phosphaturia, aminoaciduria (monitoring as needed).
Renal tubulopathy has been reported primarily in children and adolescents with beta-thalassemia who received the medicinal product.
Patients should be referred to a specialist in renal medicine, and further specialized investigations (such as kidney biopsy) may be performed if, despite dose reduction and interruption of therapy, serum creatinine levels remain significantly elevated and persistent abnormalities in other kidney functions are observed (e.g., proteinuria, Fanconi syndrome).
Liver function.
Elevations in liver function tests have been observed in patients receiving deferasirox. Cases of liver failure, sometimes fatal, have been reported. Severe forms associated with altered consciousness due to hyperammonemic encephalopathy may occur in patients receiving deferasirox, particularly in children. Hyperammonemic encephalopathy should be considered, and ammonia levels should be measured in patients who develop unexplained changes in mental status during deferasirox therapy. Adequate hydration should be maintained in patients experiencing conditions that may lead to reduced circulating blood volume (such as diarrhea or vomiting), especially in children with acute illnesses. 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. However, a contributory or aggravating role of deferasirox cannot be excluded (see section "Adverse reactions"). It is recommended to monitor levels of transaminases, bilirubin, and alkaline phosphatase before starting treatment, every 2 weeks during the first month, and then once monthly. Deferasirox should be discontinued in the case of a persistent and progressive increase in serum transaminases that cannot be attributed to other causes. After identifying the cause of liver function test abnormalities or upon normalization of these parameters, re-initiation of deferasirox treatment may be considered at a lower dose, followed by gradual dose escalation.
Deferasirox is not recommended in patients with severe impairment of liver function (Child-Pugh class C).
Table 2.
Recommendations for safety monitoring.
| Parameter |
Frequency |
| Serum creatinine level |
Doubled before starting therapy. Weekly during the first month of therapy and during the first month after dose adjustment. Then monthly. |
| Creatinine clearance and/or plasma cystatin C level |
Before starting therapy. Weekly during the first month of therapy and during the first month after dose adjustment. 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, phosphates, magnesium or urates, phosphaturia, aminoaciduria) |
As needed. |
| Serum transaminase, 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), particularly when concomitant diseases increase the risk of adverse reactions, the benefit of deferasirox therapy may be limited and may be outweighed by the risks. Therefore, use of deferasirox in such patients is not recommended.
Deferasirox should be used with caution in elderly patients due to the higher frequency of adverse reactions (particularly diarrhea).
Data in children with non-transfusion-dependent thalassemia are limited. Therefore, treatment with this medicinal product should be accompanied by monitoring of the patient for adverse reactions and assessment of iron levels. Furthermore, prior to initiating deferasirox therapy 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 still unknown.
Gastrointestinal tract.
Ulcers and gastrointestinal bleeding from the upper gastrointestinal tract have been reported in patients, including children and adolescents, receiving deferasirox. Multiple ulcers have been observed in some patients. Ulcers complicated by gastrointestinal 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 treatment with this medicinal product. If upper gastrointestinal ulceration or bleeding occurs, deferasirox should be discontinued and appropriate diagnostic evaluation and treatment initiated immediately. Caution should be exercised in patients taking deferasirox concomitantly with medicinal products with ulcerogenic potential (such as NSAIDs, corticosteroids, or oral bisphosphonates), in patients taking anticoagulants, and in patients with platelet counts below 50,000/mm³ (50×10⁹/L).
Skin disorders.
Skin rashes may occur during treatment with deferasirox. In most cases, rashes resolve spontaneously. If treatment was interrupted due to rash, therapy may be resumed at a lower dose with gradual dose escalation after the rash has resolved. In severe cases, such re-initiation may be combined with short-term use of oral corticosteroids. Serious skin adverse reactions have been reported, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), which may be fatal. If a serious skin adverse reaction is suspected, the medicinal product should be discontinued immediately and not restarted. Patients should be informed about symptoms of serious skin reactions, which should be closely monitored.
Hypersensitivity reactions.
Serious hypersensitivity reactions (such as anaphylaxis and angioedema) have been reported in patients receiving deferasirox, predominantly during the first month of treatment. If such reactions occur, the medicinal product should be discontinued and appropriate medical treatment initiated. Re-administration of deferasirox should not be attempted 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 (including fundoscopy) should be assessed before starting treatment and at regular intervals (every 12 months). If disturbances occur during treatment, dose reduction or discontinuation of therapy should be considered.
Blood disorders.
Cases of leukopenia, thrombocytopenia, or pancytopenia (or exacerbation thereof), as well as worsening anemia, have been reported in patients receiving deferasirox. Most of these patients already had hematological disorders, often associated with bone marrow insufficiency. However, a contributory or aggravating role of this medicinal product cannot be excluded. Treatment interruption should be considered in patients who develop cytopenia of unknown etiology.
Other factors.
Monthly monitoring of serum ferritin levels is recommended to assess patient response to therapy and to avoid overdosing. Dose reduction or careful monitoring of renal and hepatic function and serum ferritin levels is recommended during periods of high-dose treatment and when serum ferritin levels approach the target 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 clinical studies, growth and sexual development in children treated with deferasirox 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 deferasirox for transfusion-related 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 deferasirox.
Concomitant use of deferasirox with aluminum-containing antacids is not recommended. Concomitant use of deferasirox with repaglinide (a CYP2C8 substrate) or with CYP1A2 substrates that have a narrow therapeutic index, such as theophylline, clozapine, or tizanidine, is not recommended. Important information on excipients.
This medicinal product contains lactose. If the patient has been diagnosed with an intolerance to certain sugars, consultation with a physician is required before taking this medicinal product.
Use during pregnancy or breastfeeding.
Pregnancy.
Clinical data on the effects of deferasirox during pregnancy are lacking. Animal studies have shown reproductive toxicity when administered at maternally toxic doses. The potential risk in humans is unknown.
Therefore, deferasirox is not recommended during pregnancy unless there are life-threatening indications.
The medicinal product may reduce the efficacy of hormonal contraceptives (see section "Special precautions for use"). Therefore, women of reproductive potential are advised to use additional or alternative non-hormonal contraceptive methods during treatment with deferasirox.
Breastfeeding period.
Animal studies have shown that deferasirox is rapidly and extensively excreted into breast milk. No effects on offspring were observed. It is unknown whether deferasirox is excreted in human breast milk. Breastfeeding during treatment with deferasirox 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 reaction speed when driving vehicles or operating machinery.
Studies on the effect of deferasirox on the ability to drive vehicles or operate machinery have not been conducted. Patients who experience adverse effects such as dizziness should refrain from driving or operating machinery.
Dosage and administration.
Transfusional iron overload.
Initiation and maintenance therapy with deferasirox should be performed by physicians experienced in the treatment of chronic iron overload. Treatment is recommended to begin after approximately 20 units (≈100 mL/kg) of transfused red blood cells 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 iron introduced via transfusions and, if necessary, to reduce existing iron stores.
Table 3.
Recommended doses for transfusional iron overload.
| Tablets, film-coated |
Transfusions |
Serum ferritin levels |
||
| Initial dose |
14 mg/kg per day |
After 20 units (approximately 100 mL/kg) of packed red blood cells (PRBC) |
or |
> 1,000 µg/L |
| Alternative initial doses |
21 mg/kg per day |
> 14 mL/kg/month PRBC (approximately > 4 units/month for adults) |
||
| 7 mg/kg per day |
< 7 mL/kg/month PRBC (approximately < 2 units/month for adults) |
|||
| For patients previously well-controlled with deferoxamine therapy |
1/3 of deferoxamine dose |
|||
| Monitoring |
Monthly |
|||
| Target range |
500–1,000 µg/L |
|||
| Dose adjustment steps (every 3–6 months) |
Dose increase |
> 2,500 µg/L |
||
| 3.5–7 mg/kg per day Up to 28 mg/kg per day |
||||
| Dose reduction |
||||
| 3.5–7 mg/kg per day |
< 2,500 µg/L |
|||
| In patients previously receiving doses > 21 mg/kg per day |
||||
| Target range achieved |
500–1,000 µg/L |
|||
| Maximum dose |
28 mg/kg per day |
|||
| Considering treatment interruption |
< 500 µg/L |
|||
Dosage.
Initial dose.
The recommended initial daily dose of deferasirox is 14 mg/kg body weight. For patients requiring reduction of elevated iron levels who receive more than 14 mL/kg/month of packed red blood cells (approximately > 4 units/month for an adult patient), the initial daily dose may be 21 mg/kg.
For patients who do not require reduction of elevated iron levels and who receive less than 7 mL/kg/month of packed red blood cells (approximately < 2 units/month for an adult patient), the initial daily dose may be 7 mg/kg.
Patient response should be monitored, and dose escalation should be considered if an adequate response is not achieved.
Patients who have responded well to deferoxamine therapy may be started on a deferasirox dose of 1/3 the deferoxamine dose (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 deferasirox of 14 mg/kg/day). If the daily dose is less than 14 mg/kg body weight, clinical response should be monitored and dose escalation considered if an adequate response is not achieved.
Dose adjustment.
Serum ferritin levels should be monitored monthly, and deferasirox dosage should be adjusted every 3–6 months based on changes in serum ferritin levels, as needed. Dose adjustments should be made incrementally by 3.5–7 mg/kg, according to individual patient response and therapeutic goals (maintenance or reduction of iron levels). For patients in whom treatment with 21 mg/kg does not provide adequate control (e.g., serum ferritin levels consistently exceed 2500 µg/L and show no tendency to decrease over time), doses up to 28 mg/kg may be considered. Data on the long-term efficacy and safety of deferasirox at doses exceeding 30 mg/kg are 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 28 mg/kg) may not provide adequate control, and alternative treatment options should be considered. If adequate control is not achieved with doses above 21 mg/kg, treatment at such doses should not be continued, and alternative treatment options should be considered. Doses exceeding 28 mg/kg are not recommended due to limited experience with such regimens. Patients receiving doses above 21 mg/kg should have their dose reduced gradually by 3.5–7 mg/kg upon achieving control (e.g., serum ferritin levels consistently below 2500 µg/L and showing a decreasing trend over time). For patients who achieve the desired serum ferritin level (typically between 500 and 1000 µg/L), the dose should be reduced gradually by 3.5–7 mg/kg to maintain serum ferritin levels within the desired range. If serum ferritin levels decrease consistently to below 500 µg/L, treatment should be discontinued.
Transfusion-independent thalassemia syndromes.
Chelation therapy should only be initiated in the presence of iron overload (liver iron concentration [LIC] ≥ 5 mg Fe/g dry weight or consistently elevated serum ferritin levels > 800 µg/L). LIC is the preferred parameter for assessing iron overload and should be used whenever possible. Caution should be exercised when administering chelation therapy to all patients to minimize the risk of chelator overdose.
Table 4.
Recommended dosing in transfusion-independent thalassemia syndromes.
| Tablets, film-coated |
Liver iron concentration (LIC)* |
Serum ferritin levels |
||
| Initial dose |
7 mg/kg per day |
≥ 5 mg iron / g dry weight |
or |
> 800 μg/L |
| Monitoring |
Monthly |
|||
| Dose adjustment stages (every 3–6 months) |
Dose increase 3.5–7 mg/kg per day |
≥ 7 mg iron / g dry weight |
or |
> 2000 μg/L |
| Dose reduction 3.5–7 mg/kg per day |
< 7 mg iron / g dry weight |
or |
≤ 2000 μg/L |
|
| Maximum dose |
14 mg/kg per day |
|||
| 7 mg/kg per day |
||||
| For adults For children |
Not evaluated |
and |
≤ 2000 μg/L |
|
| Discontinuation of treatment |
< 3 mg iron / g dry weight |
or |
< 300 μg/L |
|
| Resumption of treatment |
Not recommended |
|||
*Determination of liver iron concentration is the preferred method for assessing the level of iron overload.
Initial dose.
The recommended initial daily dose of deferasirox for patients with transfusion-independent thalassemia syndromes is 7 mg/kg body weight.
Dose adjustment.
Serum ferritin levels should be monitored monthly. After 3–6 months of treatment, a stepwise dose increase by 3.5–7 mg/kg should be considered if the patient's LIC is ≥ 7 mg Fe/g dry weight or serum ferritin levels remain consistently > 2000 µg/L without showing a declining trend over time, and the patient tolerates the medication well. Doses exceeding 14 mg/kg are not recommended, as there is no experience with higher doses in transfusion-independent thalassemia patients.
For patients in whom LIC has not been measured and serum ferritin levels are ≤ 2000 µg/L, doses should not exceed 7 mg/kg.
For patients whose dose has been increased to > 7 mg/kg, dose reduction to 7 mg/kg or lower is recommended when LIC < 7 mg Fe/g dry weight or serum ferritin levels ≤ 2000 µg/L.
Treatment discontinuation.
Treatment should be discontinued once an acceptable body iron level is achieved (LIC < 3 mg Fe/g dry weight or serum ferritin levels < 300 µg/L). There are no data on reinitiating treatment in patients who experience iron re-accumulation after achieving acceptable 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. In clinical studies, elderly patients had a higher frequency 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 deferasirox 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 the drug 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 such patients. Liver function should be monitored every 2 weeks during the first month and then monthly in all patients.
Method of administration.
Film-coated tablets should be swallowed whole with water. For patients unable to swallow whole tablets, they may be crushed and mixed with soft food such as yogurt or apple puree. The medication should be taken immediately and completely, and not stored for later use.
Take once daily, preferably at the same time each day; may be taken with or without food.
Children.
Dosing recommendations for children aged 2 to 17 years are the same as for adult patients. Dose calculations should take into account changes in children's body weight over time. Exposure in children aged 2 to 5 years 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 and subsequently individually titrated.
For children with transfusion-independent thalassemia syndromes, the dose should not exceed 7 mg/kg. In these patients, careful monitoring of LIC and serum ferritin levels is essential to avoid chelator overload: in addition to monthly assessment of serum ferritin levels, LIC should be closely monitored every 3 months if serum ferritin levels are ≤ 800 µg/L. Monthly monitoring of serum ferritin levels is recommended to assess patient response to therapy and to minimize the risk of chelator overload.
The safety and efficacy of the drug in children from birth to 23 months of age have not yet been established.
Overdose.
Symptoms. Early signs of acute overdose are gastrointestinal effects such as abdominal pain, diarrhea, nausea, and vomiting. Hepatic and renal disorders have been reported, including cases of elevated liver enzymes and creatinine levels, which return to normal after discontinuation of treatment. A single accidental dose of 90 mg/kg caused Fanconi syndrome, which resolves upon discontinuation of treatment. Treatment. There is no specific antidote for deferasirox overdose. Standard overdose management procedures and symptomatic treatment may be applied as medically appropriate.
Adverse Reactions
During treatment with deferasirox, gastrointestinal (GI) adverse reactions were most commonly observed in both adults and children: mainly nausea, vomiting, diarrhea, abdominal pain, and skin rash. Diarrhea was more frequently reported 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 while continuing the medication. In clinical studies, dose-dependent increases in serum creatinine concentration were observed in patients, although such elevations remained within normal limits in most cases. A decrease 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 suggests that no further decline in mean creatinine clearance occurred in subsequent years. Elevations in liver transaminases have been reported. Regular monitoring of renal and hepatic function tests is recommended. Hearing impairment (hearing loss) and visual disturbances (lens opacities) were observed infrequently; annual examinations are also recommended. Serious skin reactions have been reported with the use of this medication, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). The frequency categories of adverse reactions are defined as follows: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); frequency not known (cannot be estimated from available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Blood and lymphatic system disorders: frequency not known — pancytopenia^1, thrombocytopenia^1, worsening of anemia^1, neutropenia^1.
Immune system disorders: frequency not known — hypersensitivity reactions (including anaphylaxis and angioedema)^1.
Metabolism and nutrition disorders: frequency not known — metabolic acidosis^1.
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 system 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; frequency not known — gastrointestinal perforation^1, acute pancreatitis^1.
Hepatobiliary disorders: common — increased transaminase levels; uncommon — hepatitis, cholelithiasis; frequency not known — hepatic failure^1,^2.
Skin and subcutaneous tissue disorders: common — rash, pruritus; uncommon — pigmentary disturbances; rare — drug reaction with eosinophilia and systemic symptoms (DRESS syndrome); frequency not known — Stevens-Johnson syndrome^1, hypersensitivity vasculitis^1, urticaria^1, erythema multiforme^1, alopecia^1, toxic epidermal necrolysis (TEN)^1.
Renal and urinary disorders: very common — increased blood creatinine levels; common — proteinuria; uncommon — tubular dysfunction^2 (acquired Fanconi syndrome), glucosuria; frequency not known — acute renal failure^1, tubulointerstitial nephritis^1, nephrolithiasis^1, acute tubular necrosis^1.
General disorders and administration site conditions: uncommon — increased body temperature, swelling, fatigue.
^1 Adverse reactions reported from spontaneous reports, for which frequency or causal relationship to the drug cannot always be reliably established.
^2 Severe cases have been reported, associated with altered consciousness due to hyperammonemic encephalopathy.
In 2% of cases, gallstones and related disorders of the biliary tract were observed. In another 2% of cases, increased activity of hepatic transaminases was observed. In some cases (0.3% of patients), liver transaminase levels increased more than 10-fold above the upper limit of normal, indicating possible development of hepatitis. Cases of hepatic failure, sometimes fatal, have been reported, particularly in patients with pre-existing liver cirrhosis. Cases of metabolic acidosis have been reported during studies. Most of these patients had renal dysfunction, 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 2102 adults and children with β-thalassemia and transfusion-dependent iron overload (including various parameters such as transfusion intensity, route of administration, and duration of treatment), who were treated in two randomized clinical trials and four open-label studies up to 5 years, 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 = 1142) in children during the first year of treatment. In the subpopulation of patients treated for more than 1 year (n = 250 for over 5 years), no further decline in mean creatinine clearance was observed in subsequent years.
In patients with non-transfusion-dependent thalassemia syndromes and iron overload receiving deferasirox at a dose of 10 mg/kg/day, the most common drug-related adverse events were diarrhea (9.1%), rash (9.1%), and nausea (7.3%). Abnormalities in serum creatinine and creatinine clearance were recorded in 5.5% and 1.8% of patients, respectively, receiving deferasirox at 10 mg/kg/day. Elevations in liver transaminases exceeding twice the baseline level and five times the upper limit of normal were recorded in 1.8% of patients receiving deferasirox at 10 mg/kg/day.
Children.
Growth and sexual development in children treated with deferasirox for up to 5 years were not impaired.
Diarrhea occurred 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 receiving the medication.
Data indicate a higher incidence of metabolic acidosis in children associated with Fanconi syndrome. Acute pancreatitis has been reported, particularly in children and adolescents.
Reporting of suspected adverse reactions.
Reporting of adverse reactions after marketing authorization of the medicinal product is of great importance. It enables ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua
**Shelf life. **3 years.
Storage conditions. No special storage conditions are required for this medicinal product. Keep out of reach of children.
Packaging. 10 tablets in a blister pack, 3 blisters in a cardboard box.
Prescription status. Prescription only.
Manufacturer. Sandoz Spain, S.L.
Manufacturer's address and place of business. C/Castello, n° 1, Sant Boi de Llobregat, Barcelona, 08830, Spain