Zeno
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT ZENO (ZENO)
Composition:
Active substance: deferasirox;
1 tablet contains: deferasirox 90 mg, 180 mg, or 360 mg;
Excipients:
tablets of 90 mg: microcrystalline cellulose*, crospovidone, povidone, poloxamer, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Blue 85F205018 coating**;
* microcrystalline cellulose PH 101, PH 102;
**Opadry II Blue 85F205018 coating: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, indigo carmine lake (E 132).
tablets of 180 mg: microcrystalline cellulose*, crospovidone, povidone, poloxamer, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Blue 85F20694**;
* microcrystalline cellulose PH 101, PH 102;
**Opadry II Blue 85F20694 coating: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, indigo carmine lake (E 132).
tablets of 360 mg: microcrystalline cellulose*, crospovidone, povidone, poloxamer, colloidal anhydrous silicon dioxide, magnesium stearate, Opadry II Blue 85F20578**;
* microcrystalline cellulose PH 101, PH 102;
**Opadry II Blue 85F20578 coating: polyvinyl alcohol, titanium dioxide (E 171), polyethylene glycol, talc, indigo carmine lake (E 132), yellow iron oxide (E 172).
Pharmaceutical form. Film-coated tablets.
Main physicochemical properties:
tablets of 90 mg: pale blue, oval-shaped, biconvex film-coated tablets, with imprint «90» on one side and company logo on the other side;
tablets of 180 mg: blue, oval-shaped, biconvex film-coated tablets, with imprint «180» on one side and company logo on the other side;
tablets of 360 mg: dark blue, oval-shaped, biconvex film-coated tablets, with imprint «360» on one side and company logo on the other side.
Pharmacotherapeutic group.
Agents forming chelate compounds with iron.
ATC code V03A C03.
Pharmacological Properties.
Pharmacodynamics.
Deferasirox is an oral active chelating agent 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 lead to persistent low serum levels of these metals.
In an iron balance metabolic study in adult patients with transfusion-dependent 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.
Deferasirox was studied in 411 adults (aged ≥16 years) 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, Diamond-Blackfan syndrome, aplastic anemia, and other very rare anemias).
Treatment with doses of 20 and 30 mg/kg body weight per day over 1 year in adults and children with beta-thalassemia receiving frequent blood transfusions led to a reduction in total body iron levels; liver iron concentration decreased on average to approximately –0.4 and –8.9 mg iron/g dry weight of liver, 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 1 year may maintain liver iron concentration and serum ferritin levels and induce net iron balance in patients receiving infrequent transfusions or exchange transfusions. Monthly assessment of serum ferritin levels reflected changes in liver iron concentration. Changes in serum ferritin levels can be used to monitor the corresponding response to therapy. Limited clinical data (29 patients with normal cardiac function at baseline) using MRI show that treatment with deferasirox at doses of 10–30 mg/kg per day over 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 transfusion-related iron overload did not demonstrate superiority of deferasirox over deferoxamine in the overall patient population. According to analysis of the results of this study, in the subgroup of patients with liver iron concentration ≥7 mg iron/g dry weight of liver receiving 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 receiving 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 was higher than the dose specified in the protocol. A total of 56 patients aged under 6 years participated in this pivotal study, 28 of whom received deferasirox.
Based on preclinical and clinical studies, deferasirox may be as effective as deferoxamine when administered at a 2:1 dose ratio (i.e., deferasirox dose numerically equal to 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 dry weight of liver with various rare anemias or sickle cell anemia, deferasirox at doses up to 20 and 30 mg/kg led to reductions in liver iron concentration and serum ferritin levels 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 hemosiderosis received deferasirox. No clinically significant differences in the safety profile and tolerability of deferasirox were observed in children aged 2 to <6 years compared to the overall population of adult patients and older children, including increases in serum creatinine >33% above the upper limit of normal in ≥2 consecutive assessments (3.1%) and increases in alanine aminotransferase (ALT) >5 times the upper limit of normal (4.3%). Isolated elevations in 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 between film-coated tablets and dispersible tablets.
In patients with non-transfusion-dependent thalassemia syndromes and iron overload, deferasirox treatment 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 per day, 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 per day, deferasirox 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 deferasirox (initial dose 10 mg/kg per 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 deferasirox (initial dose 10 mg/kg per day) and increased by 115 µg/L in patients receiving placebo (p < 0.001).
Pharmacokinetics.
After administration of deferasirox in the form of film-coated tablets, higher bioavailability was observed compared to deferasirox in the form of 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 500 mg dispersible tablets. The maximum concentration (Cmax) increased by 30% (90% CI: 20.3–40.0%), but clinical analysis did not show a clinically significant effect of this increase.
Absorption.
After oral administration of deferasirox in the form of 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. The absolute bioavailability (AUC) of film-coated tablets has not been determined. The bioavailability of deferasirox in film-coated tablets was 36% higher than that of dispersible tablets.
In a study evaluating the effect of food on the 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 values 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 values increased (by 18% and 29%, respectively). The increase in Cmax may be due to a combined effect of formulation and food intake 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; the 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) likely occurs: in a study involving healthy volunteers, administration of cholestyramine after a single dose of deferasirox resulted in a 45% reduction in its 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.
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). The mean elimination half-life (t1/2) ranges from 8 to 16 hours. Transporters MRP2 and MXR (BCRP) are involved in the 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 cumulative 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. The pharmacokinetics of deferasirox in elderly patients (aged ≥65 years) have not been studied.
Renal or Hepatic Impairment. The pharmacokinetics of deferasirox in patients with renal or hepatic impairment have not been studied. There is no effect on the pharmacokinetics of deferasirox with increases in liver transaminases 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. The mean Cmax of deferasirox in patients with mild or moderate hepatic impairment increased by 22%. Exposure increased 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 transfusional iron overload 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 of the medicinal product.
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 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, film-coated tablets, increased by 29% when administered 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 dependent on UDP-glucuronosyltransferase enzymes. In a study involving healthy volunteers, concomitant administration of deferasirox (single 30 mg/kg dose) and rifampicin, a strong inducer of UDP-glucuronosyltransferase (repeated 600 mg/day dose), resulted in a 44% reduction in deferasirox exposure (90% CI: 37–51%). Thus, concomitant use of deferasirox with strong UDP-glucuronosyltransferase inducers (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 dose adjustment should be considered if necessary.
Cholestyramine significantly reduced deferasirox exposure in a mechanistic study assessing intrahepatic utilization.
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%). This effect may be more pronounced under clinical conditions. Therefore, deferasirox should be used with caution in combination with substances metabolized via CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptives, bepridil, ergotamine), due to the potential for reduced efficacy.
In a study involving healthy volunteers, concomitant administration of deferasirox, as 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 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 as a CYP1A2 inhibitor (repeated 30 mg/kg/day dose) and theophylline, a CYP1A2 substrate (single 120 mg dose), resulted in an 84% increase in theophylline AUC (90% CI: 73% to 95%). Cmax after a single dose was not significantly affected, but increased Cmax of theophylline is expected with long-term administration. Therefore, concomitant use of deferasirox with theophylline is not recommended. If deferasirox and theophylline are used together, theophylline concentrations should be monitored and dose reduction considered. Interactions between deferasirox 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 the medicinal product with antacids containing aluminum has not been formally studied. Although deferasirox has lower affinity for aluminum than for iron, it is not recommended to administer the product together with antacids containing aluminum.
Concomitant use of deferasirox 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 the medicinal product with anticoagulants may also increase the risk of gastrointestinal bleeding. Careful clinical monitoring is required when combining deferasirox with these agents.
Concomitant administration of deferasirox and busulfan increases busulfan AUC, but the mechanism of interaction remains unclear. If possible, pharmacokinetic parameters (AUC, clearance) of the administered busulfan dose should be evaluated to allow 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 age.
During clinical trials, approximately 36% of patients experienced a dose-dependent increase in serum creatinine levels of >33% on ≥2 consecutive occasions, sometimes exceeding the upper limit of normal. Approximately two-thirds of patients with elevated serum creatinine returned to levels below 33% without dose adjustment. In the remaining third, elevated serum creatinine did not always respond to dose reduction or discontinuation of the drug. Cases of acute renal failure have been reported during 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 established. Particular attention should be paid to monitoring serum creatinine in patients receiving concomitant medications that impair renal function, and in patients receiving high doses of the drug and/or having low transfusion rates (<7 mL/kg/month of packed red blood cells or <2 units/month for adults). Although an increase in renal adverse events was not observed after dose escalation to 30 mg/kg in clinical trials, the possibility of an increased risk of renal adverse events with deferasirox film-coated tablets at doses exceeding 21 mg/kg cannot be excluded.
Serum creatinine should be assessed prior to initiation of therapy and re-evaluated after starting treatment. Serum creatinine, creatinine clearance (calculated using the Cockcroft–Gault or MDRD formula 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 then 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 post-marketing experience in patients treated with deferasirox. Most of these patients had evidence of impaired renal function, renal tubulopathy (e.g., 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 mental status in the setting of hyperammonemic encephalopathy have been reported in patients receiving deferasirox, particularly in children. Hyperammonemic encephalopathy should be considered and plasma ammonia levels should be measured in patients who develop unexplained changes in mental status during deferasirox therapy.
Table 1
| 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 mean value |
and |
decrease < ULN* (< 90 mL/min) |
| Children |
> age-appropriate normal range ** |
and/or |
decrease < ULN* (< 90 mL/min) |
| After dose reduction, discontinue treatment if |
|||
| Adults and children |
Remains >33% above the pre-treatment mean value |
and/or |
decrease < ULN* (<90 mL/min) |
Dose adjustment and treatment interruption for monitoring kidney function.
*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 case of abnormalities in markers of renal tubular function and/or according to clinical indications:
- proteinuria (testing should be performed prior to starting therapy and monthly thereafter);
- glucosuria in patients without diabetes mellitus, and low serum levels of potassium, phosphate, magnesium, or urate, as well as phosphaturia, aminoaciduria (monitoring as needed).
Renal tubulopathy has been mainly reported in children and adolescents with beta-thalassemia who were treated with the medicinal product.
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 kidney functions are observed (e.g., proteinuria, Fanconi syndrome).
Liver function.
Elevations in liver function tests have been observed in patients treated with 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 serum ammonia levels should be measured in patients who develop unexplained mental status changes during deferasirox therapy. Adequate hydration should be maintained in patients experiencing volume-depleting conditions (such as diarrhea or vomiting), especially in children with acute illnesses. Most reports of liver failure involved patients with significant comorbidities, including pre-existing liver cirrhosis. However, a contributory or aggravating role of deferasirox cannot be excluded (see section "Adverse Reactions").
It is recommended to monitor serum transaminases, bilirubin, and alkaline phosphatase levels prior to starting treatment, every 2 weeks during the first month, and then once monthly. If there is a persistent and progressive increase in serum transaminases that cannot be attributed to other causes, deferasirox should be discontinued. After identifying the cause of liver function test abnormalities or once values return to normal, re-initiation of deferasirox therapy at a lower dose with gradual dose escalation may be considered.
Deferasirox is not recommended in patients with severe hepatic impairment (Child–Pugh class C).
Table 2
Recommendations for safety monitoring
| Parameter |
Frequency |
| Serum creatinine |
Double the baseline value. Weekly during the first month of therapy and during the first month after dose adjustment. Then monthly. |
| Creatinine clearance and/or serum cystatin C level |
Prior to initiation of therapy. Weekly during the first month of therapy and during the first month after dose adjustment. Then monthly. |
| Proteinuria |
Prior to initiation of 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 |
Prior to initiation of therapy. Every 2 weeks during the first month of therapy. Then monthly. |
| Hearing and vision testing |
Prior to initiation of therapy. Then annually. |
| Body weight, height and sexual development |
Prior to initiation of therapy. Annually in children. |
In patients with a predicted short life expectancy (e.g., with a high risk of myelodysplastic syndrome), particularly when comorbidities may increase the risk of adverse events, the benefit of deferasirox therapy may be limited and may be outweighed by the risks. Consequently, the use of deferasirox in such patients is not recommended.
Deferasirox should be used with caution in elderly patients due to a higher frequency of adverse reactions (particularly diarrhea).
Limited data are available in children with non-transfusion-dependent thalassemia. Therefore, treatment with the medicinal product should be accompanied by monitoring of the patient for adverse reactions and assessment of iron levels. In addition, before initiating deferasirox therapy in children with severe iron overload due to non-transfusion-dependent thalassemia, physicians should be aware that the long-term consequences in such patients are currently unknown.
Gastrointestinal tract.
Ulcers and gastrointestinal bleeding from the upper gastrointestinal tract have been reported in patients, including children and adolescents, treated with deferasirox. 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 deferasirox therapy and the need for timely additional evaluation and treatment if serious gastrointestinal adverse events are suspected. Caution should be exercised in patients receiving deferasirox 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 × 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 resolves. In severe cases, such resumption may be combined with short-term use of oral steroids. Serious skin adverse reactions (SSARs), 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 serious skin adverse reactions are suspected, deferasirox therapy should be immediately discontinued and not restarted. Patients should be informed about the symptoms of serious 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 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.
Eye and ear disorders.
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.
Blood disorders.
Cases of leukopenia, thrombocytopenia, or pancytopenia (or exacerbation of these conditions), as well as worsening anemia, have been reported in patients receiving deferasirox. 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 overdosing. Dose reduction or careful monitoring of renal and hepatic function and serum ferritin levels is recommended during high-dose treatment periods 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. Results should also be documented in the patient's medical record.
In clinical studies, growth and sexual development in children treated with deferasirox for up to 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 undergoing treatment 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 deferasirox therapy.
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.
Use during pregnancy or breastfeeding.
Pregnancy
Clinical data on the effects of deferasirox on pregnancy are lacking. In animal studies, no toxic effects on reproductive function were observed at maternally toxic doses. The potential risk to humans is unknown.
As a precautionary measure, deferasirox should not be used during pregnancy unless there are life-threatening indications.
The medicinal product may reduce the efficacy of hormonal contraceptives; therefore, women of reproductive potential are advised to use additional or alternative non-hormonal contraceptive methods during treatment with deferasirox.
Breastfeeding
In animal studies, deferasirox was 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 deferasirox treatment is not recommended.
Fertility
There are no data on fertility in humans. In animals, no adverse effects on fertility in males or females were observed.
Ability to affect reaction speed when driving or operating machinery.
Studies on the effect of deferasirox on the ability to drive or operate machinery have not been conducted. Patients experiencing adverse effects such as dizziness should refrain from driving or operating machinery.
Method of administration and dosage.
Transfusional iron overload.
Initial and maintenance treatment with deferasirox should be administered by physicians experienced in managing chronic iron overload. Initiation of treatment is recommended 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 through transfusions and, if necessary, to reduce existing iron stores.
Table 3
Recommended doses for iron overload due to blood transfusions
| 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 of PRBC (approximately >4 units/month for adults) |
||
| 7 mg/kg per day |
<7 mL/kg/month of 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/day Up to 28 mg/kg/day |
||||
| Dose reduction |
||||
| 3.5–7 mg/kg/day |
<2,500 µg/L |
|||
| For patients receiving doses >21 mg/kg/day |
||||
| Target range achieved |
500–1,000 µg/L |
|||
| Maximum dose |
28 mg/kg per day |
|||
| Considering treatment interruption |
<500 µg/L |
|||
Dosing.
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.
The patient's response should be monitored, and dose escalation should be considered if an adequate effect is not achieved.
Patients who have shown a good clinical response to deferoxamine therapy may be started on a deferasirox dose equivalent to one-third of their 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 at 14 mg/kg/day).
If the daily dose is less than 14 mg/kg body weight, the patient's clinical response should be monitored and dose escalation considered if an adequate effect is not achieved.
Dose adjustment
Serum ferritin levels should be monitored monthly, and the deferasirox dose adjusted every 3–6 months as needed based on changes in serum ferritin levels. Dose adjustments should be made incrementally by 3.5–7 mg/kg according to the individual patient's response and therapeutic goals (maintenance or reduction of iron levels). For patients in whom treatment with deferasirox at 21 mg/kg does not provide adequate control (e.g., serum ferritin levels consistently exceed 2500 µg/L and show no trend toward decline 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 increases, 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, as clinical experience is limited.
Patients receiving deferasirox at 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 declining trend over time). Patients who achieve the desired serum ferritin level (typically between 500 and 1000 µg/L) should have their dose reduced gradually by 3.5–7 mg/kg to maintain serum ferritin levels within the desired range. If serum ferritin levels decline consistently 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 [dw] or serum ferritin levels consistently >800 µg/L). LIC is the preferred parameter for determining 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-induced toxicity.
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 assessed |
and |
≤2000 μg/L |
|
| Discontinuation of treatment |
<3 mg iron/g dry weight |
or |
<300 μg/L |
|
| Resumption of treatment |
Not recommended |
|||
*Measurement 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 non-transfusion-dependent thalassemia syndromes is 7 mg/kg body weight.
Dose adjustment.
Serum ferritin levels should be monitored monthly. After 3–6 months of treatment, a gradual dose increase by 3.5–7 mg/kg should be considered if the patient's LIC value is ≥ 7 mg Fe/g dry weight or serum ferritin levels remain persistently > 2000 µg/L without showing a downward 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 patients with non-transfusion-dependent thalassemia syndromes.
For patients who have not had LIC measured and whose serum ferritin level is ≤ 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 is < 7 mg Fe/g dry weight or serum ferritin level is ≤ 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 re-initiating treatment in patients who experience iron re-accumulation after achieving acceptable body 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 experienced a higher frequency of adverse reactions compared to younger patients (particularly diarrhea), so 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 in all patients every 2 weeks during the first month and then monthly.
Administration method.
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; do not store for later use.
Administer once daily, preferably at the same time each day. It can be taken on an empty stomach or with a light meal.
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 body weight over time. Children aged 2 to 5 years have lower exposure compared to adults. Therefore, this age group may require higher doses than adults. However, the initial dose should be the same as for adults, followed by individual dose titration.
For children with non-transfusion-dependent 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 overuse: in addition to monthly assessment of serum ferritin levels, LIC should be carefully monitored every 3 months if serum ferritin is ≤ 800 µg/L.
The safety and efficacy of the drug in children from birth to 23 months of age have not yet been established.
Overdose.
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 returned to normal after discontinuation of treatment. A single accidental dose of 90 mg/kg led to Fanconi syndrome, which resolved upon treatment discontinuation.
There is no specific antidote for deferasirox overdose. Standard overdose management procedures and symptomatic treatment may be used if medically indicated.
Adverse Reactions.
During treatment with deferasirox in adults and children, the most commonly reported adverse reactions were gastrointestinal (GI) in nature: mainly nausea, vomiting, diarrhea, or 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.
During clinical studies, dose-dependent increases in serum creatinine concentration were observed in patients, although such increases remained within the normal range in most patients. 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 there was no further decline in mean creatinine clearance in subsequent years. Elevations in liver transaminases have been reported. Regular monitoring of renal and hepatic function tests is recommended. Hearing disorders (hearing loss) and visual disturbances (lens opacities) were infrequent; annual examinations are also recommended.
Serious skin adverse reactions (SSARs) have been reported during use of the medicinal product, including Stevens-Johnson syndrome, toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS).
The frequency category of adverse reactions is 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); frequency not known (cannot be estimated based on available data). Within each frequency group, adverse reactions are listed in order of decreasing severity.
Blood and lymphatic system disorders: frequency not known – pancytopenia1, thrombocytopenia1, worsening of anemia1, neutropenia1.
Immune system disorders: frequency not known – hypersensitivity reactions (including anaphylaxis and angioedema)1.
Metabolism and nutrition disorders: frequency 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 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 perforation1, acute pancreatitis1.
Hepatobiliary disorders: common – increased transaminase levels; uncommon – hepatitis, cholelithiasis; frequency not known – hepatic failure1,2.
Skin and subcutaneous tissue disorders: common – rash, pruritus; uncommon – pigment disorders; rare – drug reaction with eosinophilia and systemic symptoms (DRESS); frequency 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; frequency not known – acute renal failure1, tubulointerstitial nephritis1, nephrolithiasis1, acute tubular necrosis1.
General disorders and administration site conditions: uncommon – increased body temperature, edema, fatigue.
1 Adverse reactions identified from spontaneous reports during clinical trials, for which the frequency or causal relationship to drug exposure cannot always be reliably established.
2 Severe cases have been reported, associated with altered consciousness in the setting of hyperammonemic encephalopathy.
Gallstones and related biliary tract disorders were observed in 2% of cases. Additionally, elevated liver transaminase activity was observed in 2% of cases. In some cases (0.3%), liver transaminase levels increased more than 10-fold above the upper limit of normal, indicating 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 clinical studies. Most of these patients had renal impairment, renal tubulopathy (Fanconi syndrome), diarrhea, or conditions disrupting 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 β-thalassemia and transfusional iron overload (including various parameters such as transfusion intensity, route of administration, and duration of treatment), treated in two randomized clinical trials and four open-label studies with up to 5 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 subpopulation of patients treated for more than 1 year (n=250 treated for over 5 years), no further decline in mean creatinine clearance was observed in subsequent years.
In transfusion-independent patients with thalassemia syndromes and iron overload, diarrhea (9.1%), rash (9.1%), and nausea (7.3%) were the most common drug-related adverse events observed in patients receiving deferasirox at a dose of 10 mg/kg/day. 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. Increases in liver transaminase levels 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 who received 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 receiving the medicinal product.
Data indicate a higher frequency of reported cases of metabolic acidosis in children associated with Fanconi syndrome. Acute pancreatitis has been reported, particularly in children and adolescents.
Shelf life. 2 years.
Storage conditions.
Store at temperatures not exceeding 25 °C in the original packaging.
Keep out of reach and sight of children.
Packaging.
10 tablets per blister, 3 blisters per cardboard pack.
Prescription category.
Prescription only.
Manufacturer.
Nobel Ilac Sanai ve Ticaret A.S.
Manufacturer's address and location of business operations.
Sankaklar Quarter, Eskisehir Yolu Akcakoca Street No: 299, 81100 Duzce, Turkey.