Eksidzhad - instructions for use, dose, side effects, contraindications

Active substanceDeferaziroxDeferazirox

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Jaden

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Novartis Pharma AG Switzerland

Eksidzhad®

pills inwards

Novartis Pharma AG Switzerland

Dosage form: & nbspTablets are dispersible.

Composition:1 tablet is dispersible contains: active substance: deferazirox 125 mg, 250 mg or 500 mg; Excipients: crospovidone 85 mg, 170 mg, 340 mg, lactose monohydrate (200 bases) 72.6 mg, 145.2 mg, 290.4 mg, lactose monohydrate (dry aerosol) 63.3 mg, 126.6 mg, 253.2 mg, cellulose, microcrystalline 63.3 mg, 126.6 mg, 253.2 mg, povidone K 30 12.8 mg, 25.6 mg, 51.2 mg, sodium lauryl sulfate 2.1 mg, 4.2 mg, 8 , 4 mg, silicon dioxide colloidal anhydrous 0.9 mg, 1.8 mg, 3.6 mg, magnesium stearate (traces).

Description:

Tablets dispersible 125 mg: round, flat cylindrical tablets of almost white color with bevelled edge and impression J 125 / NVR.

Tablets dispersible 250 mg: round, flat cylindrical tablets of almost white color with bevelled edge and impression J 250 / NVR.

Tablets dispersible 500 mg: round, flat-cylindrical tablets of almost white color with bevelled edge and impression J 500 / NVR.

Pharmacotherapeutic group:Complexing agent.

ATX: & nbsp

V.03.A.C Iron-binding preparations

Pharmacodynamics:

Deferazirox is a complexing triple ligand for ingestion, which has a high affinity for iron (III) and binds it in a ratio of 2: 1. The drug increases the excretion of iron, mainly through the intestine. Deferazirox has a low affinity for zinc and copper, and does not cause a persistent decrease in the content of these metals in the blood serum.

In the study of iron exchange in adult patients with β-thalassemia with post-transfusion iron overload (Fe) deferasirox in the application in daily doses of 10 mg / kg, 20 mg / kg and 40 mg / kg (in the form of dispersible tablets) average effective iron excretion averaged 0.0119 mg Fe/ kg, 0.329 mg Fe/ kg and 0.445 mg Fe/ kg of body weight per day, respectively.

The use of deferazirox was studied in adult patients and children > 2 years with chronic transfusion transfusion with iron. Major diseases which require regular blood transfusions include: β-thalassemia, sickle cell anemia, and other congenital and acquired anemia (myelodysplastic syndromes, congenital aplastic anemia, Diamond-Blekfana acquired aplastic anemia and other rare forms of anemia).

Daily use of deferazirox at doses of 20 mg / kg and 30 mg / kg in the form of dispersible tablets for one year in adults and children with β-thalassemia on the background of ongoing blood transfusions led to a decrease in total iron stores in the body; the content of iron in the liver (SZHP) decreased on average by almost 0.4 mg Fe/g and 8.9 mg Fe/g dry substance of the liver, serum ferritin concentration decreased on average by almost 36 μg / l and 926 μg / l, respectively.

When using the drug in the same doses, the ratio of excretion of iron to iron intake in the body was 1.02 (which is an indicator of the normal iron balance) and 1.67 (which corresponds to increased excretion of iron from the body). A similar therapeutic response was observed with the use of deferasirox in patients with iron overload and with other types of anemia. The use of deferazirox in a daily dose of 10 mg / kg in the form of dispersible tablets for one year allowed to maintain the normal iron content in the liver, serum ferritin concentration and contributed to the balance of iron (the balance between iron intake and excretion) in patients who rarely receive blood transfusion or exchange blood transfusions. Since the concentration of serum ferritin, determined monthly, reflected changes in the iron content in the liver, the dynamics of serum ferritin concentration may be a criterion for evaluating the effectiveness of therapy.

With the use of deferazirox in a dose of 20-30 mg / kg / day for 1 year in patients aged> 2 years with β-thalassemia and chronic post-transfusion overload with iron and initial SZP> 7 mg Fe/r dry substance of the liver, the decrease in SSP was 5.3 ± 8.0 mg Fe/r dry matter of the liver and was similar to that of deferoxamine (4.3 ± 5.8). Reduction of SSP to a value of 7 mg Fe/r dry substance of the liver was noted in 58.6% of patients who received deferazirox (with initial SZHP > 7 mg Fe/r dry substance of the liver). When using deferaziroxa at a dose of 20-30 mg / kg / day in patients with β-thalassemia and chronic post-transfusion overload with iron with initial SZHP > 7 mg Fe/g dry substance of the liver, which could not be treated with deferoxamine, a decrease in SFS was 5.5 ± 7.4 mg Fe/r dry substance of the liver. Decrease of SMP to the value < 7 mg Fe/g dry substance of the liver was noted in 58.5% of patients receiving deferazirox (with initial SZHP > 7 mg Fe/g dry substance of the liver).

The effect of deferasirox on serum ferritin concentration and the ratio of iron excretion to its entry into the body was dose-dependent in the dose range 5-30 mg / kg / day.

In patients with sickle-cell anemia and chronic post-transfusion iron overload, the mean decrease in PCI was 1.3 and 0.7 mg Fe/g dry matter liver for deferazirox and deferoxamine, respectively.

With the use of deferazirox in a dose of 30 to 40 mg / kg / day for 1 year in patients with p-thalassemia with chronic post-transfusion overload with iron with myocardial damage (left ventricular ejection fraction (LVEF) > 56%, the transverse relaxation time (T2 *), determined by magnetic resonance imaging of the myocardium, was 5-20 ms), myocardial function was improved (an increase in T2 * by 16% of the original). The use of deferazirox in a dose of 20 to 40 mg / kg / day for 1 year in patients from β- thalassemia with chronic post-transfusion overload with iron without myocardial damage (LVEF > 56%, T2 * > 20 ms) promoted the preservation of normal myocardial function (T2 * 32.0-32.5 ms).

In patients with iron overload and myocardial infarction (T2 * <20 ms), treatment with Eksidzhad® resulted in a decrease in the iron content in the myocardium and

progressive improvement in T2 * values over three years of follow-up.In patients with

with iron overload without myocardial damage, the use of the Eksidzhad® prevented the accumulation of iron in the heart (the T2 * value was maintained at a level of more than 20 ms) for more than a year of observation, despite the ongoing transfusion therapy. In patients with thalassemia and chronic non-transfusion iron overload, therapy with Eksidzhad® at a dose of 10 mg / kg of body weight for 1 year leads to a decrease in the SSP from the baseline by 3.80 mg on average Fe/g of dry substance of the liver, while in patients receiving placebo, SSP increases by 0.38 mg Fe/r dry substance of the liver. AT addition, therapy with Eksidzhad® at a dose of 10 mg / kg of body weight for 1 year leads

to a decrease in serum ferritin concentration by 222.0 μg / l from the initial values, and

patients receiving a placebo serum ferritin concentration increases by 114.5 μg / l.

Pharmacokinetics:

Suction

Deferazirox is well absorbed after ingestion in the form of dispersible tablets, the average time to reach the maximum concentration in the blood plasma (t_max) is about 1.5-4 hours. Absolute bioavailability (area under the pharmacokinetic curve "concentration-time", AUC) Deferasiroksa at ingestion is about 70% compared with intravenous administration. AUC increased approximately 2-fold when taken at breakfast with high-fat food and almost 50% when taken during a standard breakfast.

Bioavailability (AUC) deferaziroxa moderately (approximately 13-25%) increased when taken 30 minutes before a meal with a normal or high fat content. General exposition (on AUC) deferaziroxa when administered as a suspension with orange or apple juice was equivalent to the exposure of the drug when applied as an aqueous suspension (relative values AUC 103% and 90% respectively).

In the equilibrium state, the maximum concentration (C_m_Oh) and AUCo-24 h deferaziroxa increase almost linearly with a dose. Deferazirox accumulates in the body, the accumulation factor is 1.3-2.3. Distribution

Deferazirox binds to a high degree with blood plasma proteins (99%), almost exclusively with albumin; has a small apparent volume of distribution - approximately 14 liters in adults. Metabolism

The main way of metabolism of deferasirox is glucuronidation followed by excretion with bile. Deferazirox is subjected to enterohepatic recirculation.Deconjugation of glucuronates in the intestine and their subsequent reabsorption occurs. In healthy patients who received colestramine after a single administration of deferasirox, AUC deferazirox decreased by 45%.

Deferazirox undergoes glucuronation mainly by means of UGT1A1 (uridine-diphosphate-glucuronyltransferase (UGT) family 1, polypeptide A1) and to a lesser extent - UGT1 A3 (family UGT1, polypeptide A3).

Oxidative metabolism of deferasirox, mediated by isoenzymes of cytochrome P450, is expressed to a small extent (about 8%).

In vitro There was no inhibition of metabolism of deferasirox with hydroxycarbamide.

Excretion

Deferazirox and its metabolites are excreted mainly through the intestine (84% of the dose). Renal excretion of deferazirox and its metabolites is minimal (8% of the dose). Average half-life (ti/ g) varies from 8 to 16 hours.

Pharmacokinetics in special clinical cases.

The general bioavailability of deferasirox in adolescents (12 to 17 years) and children (2 to 12 years) after a single and multiple doses was lower than in adult patients. In children younger than 6 years, bioavailability is lower by 50% than in adults, but this is not clinically important, since the dosage regimen is set individually.

The pharmacokinetics of deferasierox in patients aged> 65 years have not been studied. In patients with impaired liver or kidney function, the pharmacokinetics of deferasierox have not been studied. Average AUC deferasirox in patients with impaired hepatic class A and B liver function according to the Child-Pugh classification was higher than in patients with normal liver function by 16% and 76%, respectively. Average C_m_Oh in patients with impaired liver function of mild and moderate severity exceeded by 22% the value of this parameter in patients with normal liver function.

An increase in the activity of "hepatic" transaminases up to 5 times in comparison with the upper limit of the norm does not affect the pharmacokinetics of deferasirox.

Indications:

Chronic posttransfusion overload with iron in adults and children aged 2 years and older.

Chronic nontransfusion overload with iron in patients with thalassemia aged 10 years and older.

Contraindications:

Hypersensitivity to the active substance and any other component of the drug.

Creatinine clearance (CK) <60 ml / min or serum creatinine concentration is 2 or more times higher than the upper limit of the age norm.

Patients with myelodysplastic high-risk syndrome or other hemoblastoses and non-hematological malignancies, in whom chelation therapy is ineffective due to rapid disease progression. Violations of liver function of a serious degree (class C according to the Child-Pugh classification). Rare hereditary disorders associated with intolerance to galactose, severe lactase deficiency, or glucose-galactose malabsorption. Pregnancy and the period of breastfeeding.

Experience with the use of the drug Eksidzhad ® in children younger than 2 years is absent.

Carefully:

Use with caution in elderly patients aged> 65 years; patients with a serum creatinine concentration greater than the age limit, especially if there are additional risk factors, such as simultaneous use of drugs capable of causing renal dysfunction; dehydration or severe infections; care should be taken when using the drug in patients with impaired liver function (the use of the drug Eksidzhad ® in this category of patients has not been studied),while the use of anticoagulants and other drugs having ulcerogenic effect (nonsteroidal anti-inflammatory drugs, glkzhokortikosteroidami, bisphosphonates for oral administration); use the drug with caution in patients with a reduction in the number of platelets <50x10⁹/ l.

Pregnancy and lactation:

There are no clinical data on the use of deferasirox during pregnancy. In experimental studies, some reproductive toxicity of the drug in doses toxic to the mother organism is shown. The potential risk to humans is unknown.

Do not use Eksidzhad® the drug in pregnant women except in cases of extreme necessity.

In studies deferazirox quickly and in a significant amount penetrated into the milk of lactating animals. Influence of the drug on the offspring was not noted. It is not known whether the deferazirox in human milk. Women receiving treatment with Eksidzhad®, it is not recommended to continue breastfeeding.

Dosing and Administration:

Chronic posttransfusonic overload with iron

ExiJad® therapy is recommended to begin after transfusion of approximately 20 units (about 100 ml / kg) of erythrocytic mass and more, or in the presence of clinical data indicative of the development of chronic iron overload (for example, at a serum ferritin concentration of more than 1000 μg / L) .

The dose (in mg / kg) should be calculated and rounded as close as possible to the dose of the whole tablet (125 mg, 250 mg, 500 mg).

Eksidzhad® should be taken orally once a day on an empty stomach, no later than 30 minutes before meals, preferably at the same time.

Initial dose

The recommended initial daily dose of Eksidzhad® is 20 mg / kg body weight. For patients receiving transfusions of erythrocyte mass in excess of 14 ml / kg / month (approximately more than 4 blood units per month for adults), an initial 30 mg / kg dose may be used to reduce the iron content in the body.

For patients receiving less than 7 ml / kg / month of erythrocyte mass (approximately less than 2 blood units per month for adults), an initial 10 mg / kg dose may be considered to maintain a normal iron content in the body.

For patients with good clinical effect during the treatment with deferoxamine initial dose of drug Eksidzhad® should be half of the previously used dose deferoxamine (e.g., in a patient who received 40 mg / kg / day of deferoxamine for 5 days per week or the equivalent amount, therapy with Eksidzhad ® can be started with 20 mg / kg per day). Dose selection

It recommended monthly monitoring the concentration of serum ferritin and if necessary to conduct correction Eksidzhad® dose every 3-6 months, based on the change in serum ferritin concentration. Dose correction should be carried out in stages in increments of 5-10 mg / kg body weight according to the individual response to therapy, and depending on the purpose of the therapy (maintaining or reducing the iron content).

With the ineffectiveness of treatment at a dose of 30 mg / kg body weight (concentration of serum ferritin is kept at> 2500 g / L), the dose should be increased to 40 mg / kg body weight. Not recommended to use a dose of 40 mg / kg, as experience with the drug at higher doses is limited.

When the target serum ferritin concentration is reached (usually from 500 μg / l to 1000 μg / l), it is necessary to provide a gradual (with a "step" of 5-10 mg / kg) reduction in the dose of the drug in order to maintain serum ferritin concentration in this target range .

If serum ferritin concentration is well below 500 μg / l, discontinuation of treatment with Exidzhad® should be considered.

In patients with an insignificant degree of iron overload or a slightly elevated serum ferritin concentration, the risk of toxic effect of the drug Eksidzhad⁴, as well as other iron chelators, can increase with an unreasonably high dose of the drug.

Chronic nontransfusonic overload with iron in patients with thalassemia

Helicotherapy with Exidzhad® in this category of patients is only possible with proven iron overload (SZHP > 5 mg Fe/r dry matter liver or serum ferritin concentration> 800 μg / l). If the definition of SSP is not available, chelation therapy should be conducted with caution to minimize the risk of excessive chelation. Initial dose

The recommended initial daily dose of Eksidzhad® is 10 mg / kg body weight. Dose selection

It is recommended to monitor the concentration of serum ferritin every month. Every 3-6 months, a step-by-step increase in the dose of the drug by 5-10 mg / kg is possible. Correction of the dose is possible with the preservation of SFA at the level > 7 mg Fe/g dry matter of the liver or persisting (without a tendency to decrease) serum ferritin concentration> 2000 μg / l and with good tolerability of therapy. The use of Eksidzhad® in patients with thalassemia at a dose of more than 20 mg / kg body weight is not recommended (due to a lack of data on efficacy and safety of use in this dosage). In patients with a serum ferritin concentration of <2000 mcg / l without the definition of SFS, the dose of Eksidzhad® should not exceed 10 mg / kg of body weight.

In patients receiving therapy at a dose of more than 10 mg / kg body weight, it is recommended to reduce the dose of the drug Exidzhad® when achieving an SSI <7 mg Fe/g dry matter liver or ferritin concentration < 2000 μg / l.

Therapy with Exidzhad® should be completed when the LVS is reached <3 mg Fe/g dry substance of the liver or ferritin concentration <300 μg / l. In the future, it is possible to resume therapy if there is a therapeutic need.

Patients aged> 65 years

Patients in this category do not need a dosage adjustment. Since in clinical studies in patients aged >For 65 years, there has been an increase in the incidence of adverse events (AEs) compared to patients less than 65 years of age, in this category of patients, close monitoring of AEs should be performed and, if necessary, the dose of the drug should be reduced.

Children and adolescents (from 2 to 17 years old)

For children and adolescents aged from 2 to 17 years, correction of the dosing regimen is not required. When calculating the dose for patients of this category, one should take into account the change in body weight over time.

Patients with impaired function of the nights

It is necessary to use with caution the preparation of Eksidzhad® in patients with a serum creatinine concentration higher than the norm, especially if there are additional risk factors such as simultaneous use of drugs capable of causing renal dysfunction in patients with dehydration or severe infections.It is not necessary to correct the initial dose in patients with impaired renal function. Concentration of serum creatinine should be monitored once a month; If necessary, the daily dose should be reduced by 10 mg / kg.

Patients with hepatic impairment

In patients with impaired liver function, the drug was not used. In patients with impaired hepatic function of the middle degree (class B according to the Child-Pugh classification), the initial dose should be reduced by approximately 50%. The drug should not be used in patients with severe liver function disorders (Child-Pugh class C).

Control of liver function should be performed before treatment, every 2 weeks during the first month of treatment and then monthly. Application rules

When taken during a meal, the bioavailability of deferazirox increases to different degrees, so the Eksidzhad® should be taken on an empty stomach no later than 30 minutes before a meal, preferably at the same time of day.

A suspension is prepared from the dispersible tablets. Tablets are placed in a glass with water or orange or apple juice (100-200 ml) and stirred in a liquid until a homogeneous suspension is obtained.The prepared suspension is taken orally, after which a small amount of water or juice is added to its residues in a glass, mixed and drink the resulting liquid.

Dispersible tablets can not be chewed or swallowed whole.

Since in the carbonated beverages or milk dispersible tablets dissolve slowly to form a foam, the Eksidzhad® preparation is not recommended for dilution in carbonated beverages or milk.

Side effects:

In patients with chronic post-transfusion iron overload, the most frequent AEs reported during long-term therapy with the Eksjad® drug in adults and children include: gastrointestinal disorders (26%): nausea, vomiting, diarrhea, abdominal pain and dermatological disorders (7%) - skin rash. These reactions are dose-dependent, mostly mild or moderate, have a transitory character, and in most cases are resolved independently even after continuing treatment. A slight non-progressive increase in serum creatinine concentration, mostly within normal limits, was observed in almost 36% of patients,was dose-dependent and often resolved independently, it is possible to reduce the concentration of creatinine in the blood plasma with a decrease in the dose of the drug. In patients with chronic post-transfusion iron overload, an increase in the activity of "hepatic" transaminases, independent of the dose of the drug, was noted in 2% of cases. In most patients, an increase in the activity of "hepatic" transaminases was observed before the drug started treatment. Infrequently (0.3%) there was an increase in the activity of "liver" transaminases more than 10 times higher than the upper limit of the norm, suggesting the development of hepatitis.

In a clinical trial in patients with thalassemia and iron overload, in which patients received the 10 mg / kg dose of Eksidzhad®, the most frequent AEs were diarrhea (9.1%), rash (9.1%), nausea (7 , 3%). An increase in serum creatinine and a decrease in creatinine clearance was noted in 5.5% and 1.8% of cases, respectively. Increase in the activity of "liver" transaminases more than 2 times compared with baseline and more than 5 times higher than normal was observed in 1.8% of patients.

As well as in the treatment with other iron chelators, in patients who received the Eksidzhad® preparation,infringement of hearing (in the form of disturbance of perception of high-frequency sounds) and a clouding of a lens (an early cataract) was infrequent noted.

To assess the frequency of occurrence, the following criteria were used (according to the WHO classification (World Health Organization)): very often (>1/10); often (>1/100, <1/10); infrequently (>1/1000, <1/100); rarely (>1/10000, <1/1000); very rarely (<1/10000); frequency unknown: individual reports of the following AEs (establishing a link between drug use and the development of AE data is not always possible).

Immune system disorders: frequency is unknown - hypersensitivity reactions (including anaphylactic reactions and angioedema). In most cases, hypersensitivity reactions were observed in the first months of treatment with the drug.

Disorders of the psyche: infrequently - anxiety, sleep disturbances.

Impaired nervous system: often - headache; infrequently - dizziness. Disorders from the side of the organ of vision: infrequently - early cataract, maculopathy; rarely - optic neuritis.

Hearing disorders and labyrinthine disturbances: infrequently - hearing loss.

Disturbances from the respiratory system, chest and mediastinal organs: infrequently - pain in the larynx and pharynx.

Disorders from the digestive system: often - diarrhea, constipation, vomiting, nausea, abdominal pain, bloating, dyspepsia; infrequently - gastrointestinal bleeding, gastric ulcer (including plural) and duodenal ulcers, gastritis; rarely - esophagitis; frequency unknown - ulcerative lesion of the gastrointestinal tract with perforation.

Disorders from the liver and bile ducts: infrequently - hepatitis, cholelithiasis; frequency unknown - hepatic insufficiency.

Disturbances from the skin and subcutaneous tissues: often - skin rash, itchy skin; infrequently - a violation of pigmentation; rarely erythema multiforme; frequency unknown - Stevens-Johnson syndrome, leukocytoclastic vasculitis, hives, alopecia.

Disorders from the kidneys and urinary tract: frequency unknown - acute necrosis of renal tubules, acute renal failure (in most cases, there was an increase in the serum creatinine concentration >2 times above the upper limit of the norm, after discontinuation of therapy with the drug, normalization of this indicator was usually noted), tubulointerstitial nephritis.

Laboratory and instrumental data: very often - an increase in the concentration of creatinine in the blood serum; often - increased activity of "hepatic" transaminases, proteinuria; infrequently - tubulopathy (acquired Fanconi syndrome), glucosuria.

General disorders and disorders at the site of administration: infrequently - fever, swelling, fatigue.

When using the drug Eksidzhad ®, there were cases of development of cytopenia, including neutropenia, thrombocytopenia and aggravation of the severity of anemia. In most cases, cytopenia was observed in patients with an initial failure of bone marrow function. Causal relationship between the data of AEs and the use of the drug is not revealed.

With the use of the drug Eksidzhad ® in clinical practice, separate reports on the development of hepatic insufficiency (including cases with fatal outcome) were obtained. AT In most cases, liver failure was developed in patients with severe concomitant diseases, including liver cirrhosis and multiple organ failure. There are rare reports of the development of gastrointestinal bleeding with a lethal outcome on the background of therapy with Eksidzhad® in elderly patients,patients with progressive hemoblastoses and / or with a decrease in the number of platelets. Against the background of drug therapy, cases of renal tubulopathy (in most cases in children and adolescents with β-thalassemia and serum ferritin concentration <1500 μg / l) were noted.

Overdose:

There have been cases of overdose with deferasirox (intake for several weeks at a dose 2-3 times higher than recommended). In one case, an overdose led to the development of subclinical hepatitis. At the termination of therapy by the drug, manifestations of hepatitis were stopped without the development of complications in the long-term period. With a single admission of 80 mg / kg body weight, patients with β-thalassemia with iron overload had good tolerability with the development of mild nausea and diarrhea. Healthy volunteers well tolerated a single dose at a dose of up to 40 mg / kg. In case of an overdose, the following acute symptoms may develop: nausea, vomiting, headache, diarrhea.

Treatment: inducing vomiting or rinsing the stomach; symptomatic therapy.

Interaction:

Special studies on the simultaneous use of the drug Exidzhad® with aluminum-containing antacid preparations were not carried out. Although deferazirox has a lower affinity for aluminum than for iron, the Eksidzhad® preparation should not be used simultaneously with aluminum-containing antacids.

The efficacy and safety of the use of Eksidzhad® with other iron chelators have not been studied, and therefore the Eksidzhad® preparation should not be used with other iron chelators.

In healthy volunteers, when deferazirox was administered concomitantly with midazolam, the substrate of the CYP3A4 isoenzyme, the systemic bioavailability of the latter decreased by 17%. Since in patients with chronic iron overload, a decrease in the systemic bioavailability of drugs that are substrates of the CYP3A4 isoenzyme may be more pronounced, caution should be exercised with the preparation of Eksidzhad® along with preparations metabolized with CYP3A4 (eg, cyclosporine, simvastatin, hormonal contraceptives, bepridil, ergotamine).

In healthy volunteers, when deferazirox was administered simultaneously with active inducers of uridine diphosphate glucuronyltransferase (CGT), rifampicin (repeated administration of 600 mg per day), the systemic bioavailability of the latter was reduced by 44%.In this regard, concomitant therapy with potent inductors of UGT (for example, rifampicin, phenytoin, phenobarbital, ritonavir) may lead to a decrease in the effectiveness of the drug Exidzhad®. Therefore, it is necessary to provide for an increase in the dose of the Eksidzhad® drug when it is used simultaneously with the active inductors of the CGT, based on the clinical response to therapy. In healthy volunteers, with the simultaneous use of deferazirox (repeated administration at a dose of 30 mg / kg per day) with a substrate of the isoenzyme CYP2C8, repaglinide (a single dose of 0.5 mg), AUC and Cmax increased by 131% and 62%, respectively. Since the interaction of deferasirox with repaglinitide in a dose of 0.5 mg has not been studied, it is necessary to exclude the simultaneous use of the drug Exidzhad® with repaglininide. Do not exclude the interaction between deferasirox and another substrate of the isoenzyme CYP2C8, paclitaxel. Cholestyramine significantly reduces the bioavailability of deferasirox (probably due to decreased enterohepatic recirculation).

In healthy volunteers, with simultaneous application of deferasirox (repeated administration at a dose of 30 mg / kg per day) with the substrate of the isoenzyme CYP1A2 with theophylline (a single dose of 120 mg), the AUC increased by 84%.With a single application of Cmax theophylline did not change, however, with prolonged use, it is possible to increase this index. The simultaneous use of the drug Exidzhad® with theophylline is undesirable. However, if these drugs are used simultaneously, careful monitoring of theophylline concentration in the blood with a possible dose reduction with simultaneous therapy with the Exidzhad® preparation is necessary. Do not exclude the possibility of the interaction of deferasirox with other substrates of the isoenzyme CYP1A2. In healthy volunteers, there was no interaction of deferazirox with digoxin. Special studies on the simultaneous use of deferazirox and ascorbic acid have not been conducted. The use of ascorbic acid in a dose up to 200 mg / day simultaneously with deferaziroxom was not accompanied by undesirable consequences. Since the simultaneous use of deferazirox with anticoagulants and drugs that have ulcerogenic effects (nonsteroidal anti-inflammatory drugs, glucocorticosteroids, bisphosphonates for oral administration) may increase the risk of serious AEs from the digestive tract(bleeding, ulcerative lesions), it is necessary to use with caution the preparation of Eksidzhad® in patients receiving the above preparations.

With the simultaneous use of deferazirox with hormonal contraceptives, which are metabolized with the participation of the isoenzyme CYP3A4, the effectiveness of the latter may be reduced.

Special instructions:

creatinine in serum, usually within normal limits. Approximately one-third of patients remained elevated in creatinine, despite a reduction in dose or discontinuation of the drug. With the use of the drug Eksidzhad® in the post-marketing period, cases of development of acute renal failure are noted. In some cases, with the use of the drug Eksidzhad® in the post-expiratory period, impaired renal function led to the development of renal failure requiring temporary or permanent dialysis.

In adults, the daily dose of Eksidzhad® should be reduced by 10 mg / kg if, in two consecutive studies, the increase in serum creatinine is more than 33% compared to the mean before treatment,or calculated KK reaches values below the lower limit of the norm (less than 90 ml / min) in the absence of communication with other causes, except for the use of the drug. In children, the dose of the drug should be reduced by 10 mg / kg, if the calculated CK reaches values below the lower limit of the norm (less than 90 ml / min) or in two consecutive studies, the creatinine concentration in the blood plasma exceeds the upper limit of the age norm. If there is an increase in serum creatinine concentration by more than 33% compared to the average before treatment and / or calculated serum CC reaches less than the lower limit of the norm, ExiJad® therapy should be discontinued. The decision to resume treatment with the drug is taken individually, based on the clinical situation.

Given the increased risk of complications when using Eksidzhad® in patients with impaired renal function, or receiving drugs that have a negative effect on kidney function, it is recommended to determine serum creatinine and / or CC serum concentrations weekly during the first month of therapy, and then monthly.It is recommended to double the serum creatinine concentration before starting therapy. Further it is recommended to determine the concentration of creatinine in the blood plasma, CK (calculated by Cockcroft-Gault formula or according to the MDRD formula in adults and according to the Schwartz formula in children) and / or the concentration of cystatin C in the blood plasma weekly after the initiation of therapy or dose change of Eksidzhad®, and then monthly. When using the Eksidzhad® drug, the level of proteinuria should be monitored on a monthly basis. In some cases, kidney tubular function should also be monitored regularly (indicators such as glucosuria in patients without diabetes mellitus, low potassium, phosphate, magnesium or uric acid salts, as well as phosphaturia, aminoaciduria). If abnormalities of these indicators of tubular renal function are detected from normal values, the dose should be reduced or temporarily ExiJad® should be administered by doctors with experience in the management of chronic post-transfusion overload with iron, only after assessing the possible risks and benefits of chelation therapy.

When applying an inadequately high dose of Eksidzhad® in patients with a low degree of iron overload or with a slight increase in serum ferritin concentration, the toxic effect of the drug may increase. It is recommended that the concentration of serum ferritin be determined on a monthly basis to assess the effectiveness of therapy. If the concentration of serum ferritin is reduced to less than 500 μg / l (with iron overload due to blood transfusions) or less than 300 μg / l (with thalassemia), therapy should be discontinued.

Disorders from the gastrointestinal tract

When using the drug in both adults and children, it is possible to develop such serious complications on the part of the digestive system, such as gastrointestinal bleeding, ulcerative lesions of the stomach and duodenum. There were rare cases of bleeding from the organs of the gastrointestinal tract with a lethal outcome, especially in elderly patients with severe hematologic oncological diseases and / or a low number of platelets.

In some patients, multiple ulcerative lesions of the gastrointestinal tract were noted.

The doctor and the patient should be especially wary of the symptoms of peptic ulcer or duodenal ulcers, as well as signs of bleeding from the gastrointestinal tract (GI tract). If suspected of developing gastrointestinal bleeding, appropriate diagnostic and therapeutic measures should be taken. There were also reports of cases of ulcerative lesions of the gastrointestinal tract with perforation (including fatal outcome).

Impaired renal function

Treatment with the drug Exidzhad® was carried out only in patients with serum creatinine concentration within the limits of the age norm.

In clinical trials, in about 36% of patients treated with Exidzhad®, there was a slight non-progressive increase in concentration of Exixjad®. In the event that, despite a reduction in dose or discontinuation of the drug, the concentration of serum creatinine remains significantly elevated and is accompanied by a persistent impairment of some other indicator of renal function (eg, proteinuria,Fanconi syndrome) should be referred to the nephrologist for consultation and subsequent specialized examination (eg, kidney biopsy).

With the development of diarrhea and / or vomiting in the background of therapy with the drug Exidzhad®, adequate hydration of the patients should be ensured.

With the use of the drug in the postregistered period, cases of metabolic acidosis development have been described. In most cases, the condition developed in patients with impaired renal function, dysfunction of the proximal renal tubules (Fanconi syndrome) or diarrhea, as well as conditions whose complication is a violation of the acid-base balance. In such patients, the acid-base balance should be monitored for clinical reasons. With the development of metabolic acidosis, consideration should be given to the possibility of discontinuing therapy with Exidzhad®.

Impaired liver function

Treatment with Eksidzhad ® was carried out only in patients with activity values of "liver" transaminases, which exceed the upper limit of the norm by no more than 5 times. It is recommended to conduct preliminary, in the first month - two-fold,and further monthly monitoring of liver function (activity of "liver" transaminases, bilirubin concentration, activity of alkaline phosphatase). With the progression of an increase in the activity of "liver" transaminases, which is not associated with any other causes, therapy with Exidzhad® should be discontinued. Immediately after determining the cause of biochemical changes, or after the normalization of the indicators, one may consider the question of a cautious resumption of therapy with a lower dose of Exidzhad®, followed by a gradual increase. When using the drug Eksidzhad ® in the post-registration period, cases of hepatic insufficiency (including fatal outcome) were noted. Although in most cases hepatic insufficiency has developed in patients with concomitant diseases (including cirrhosis), the role of Eksidzhad® as an additional or potentiating factor can not be ruled out. It is not recommended to use the drug in patients with severe liver failure (class C according to the Child-Pugh classification).

Hypersensitivity reactions

There have been reports of the development of hypersensitivity reactions to deferasirox (including anaphylactic reactions and angioedema). In most cases, hypersensitivity reactions were observed in the first months of treatment with the drug. With the development of severe hypersensitivity reactions, treatment with the drug should be canceled and appropriate medical measures taken.

Disturbances from the skin

There is evidence of the development of Stevens-Johnson syndrome with the drug

Excidzhad®. It is impossible to exclude the risk of developing more severe skin reactions (toxic epidermal necrolysis, drug rash with eosinophilia and systemic manifestations (DRESS-syndrome)). If suspected of developing these conditions, taking the drug should be stopped immediately; resume therapy with the drug should not be. In patients with Eksidzhad®, skin rashes may occur. Since spontaneous disappearance of the rash is often observed, with the mild to moderate severity of this complication, treatment with Exidzad® can be continued without dose adjustment.When developing a more severe rash, it is necessary to temporarily stop the treatment with the drug. After resolving the rash, the Eksidzhad® preparation can be used repeatedly, at a lower dose and then increased.

Visual and auditory disorders

Since hearing and vision impairment was not often noted against the background of Exidzhad® treatment, it is recommended that hearing acuity be determined and an ophthalmological examination (including the eye fundus examination) should be performed before starting treatment with Exidzhad® and during further therapy at regular intervals of 12 months. In the case of hearing or visual impairment, consideration should be given to reducing the dose or stopping treatment with the drug.

Hematologic disorders

When using the drug, a regular determination of hematological parameters should be made. In case of development of cytopenia against the background of the use of the drug Eksidzhad ® treatment with the drug should be temporarily suspended. After normalization of hematological parameters, therapy with Exidzad® can be resumed.

When using the drug Eksidzhad ® in children with post-transfusion overload of iron for 5 years is not accompanied by a delay in growth.As a precautionary measure, the growth, weight, and degree of puberty of children receiving drug therapy should be monitored annually.

Severe overload with iron can lead to heart dysfunction. Cardiac function should be evaluated regularly in patients who receive long-term therapy with Exidzhad® for severe iron overload.

The drug Eksidzhad® can not be used in combination with other medicines, which form complexes with iron ions, since the safety of the use of such combination therapy has not been established.

Effect on the ability to drive transp. cf. and fur:

The study of the effect of the drug on the ability to drive vehicles and mechanisms was not carried out. When there is such an infrequent side effect as dizziness, patients should be careful when carrying out these activities.

Form release / dosage:

Tablets are dispersible 125 mg, 250 mg and 500 mg.

Packaging:

For 7 dispersible tablets of 125 mg, 250 mg, 500 mg in a blister of PVC / PE / PVDC and PA / Al / PVC.

For 4 or 12 blisters in a cardboard box together with instructions for use.

Storage conditions:Store in a dry place at a temperature not exceeding 30 ° C, out of the reach of children

Shelf life:3 years. The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-001925/07

Date of registration:03.08.2007/04.02.2016

The owner of the registration certificate:Novartis Pharma AGNovartis Pharma AG Switzerland

Manufacturer: & nbsp

NOVARTIS PHARMA, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp23.04.2016

Illustrated instructions

Instructions

Eksidzhad® (Exjade®)