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

Active substanceDeferaziroxDeferazirox

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Jaden

pills inwards

Novartis Pharma AG Switzerland

Eksidzhad®

pills inwards

Novartis Pharma AG Switzerland

Dosage form: & nbsptfilm-covered laths

Composition:

1 tablet, film-coated, contains:

active substance: deferazirox - 90/180/360 mg;

Excipients: cellulose microcrystalline - 53,61 / 107,22 / 214,44 mg, crospovidone - 1 1,34 / 22,68 / 45,36 mg, povidone-K30 - 3,65 / 7,30 / 14.60 mg, magnesium stearate - 2.43 / 4.86 / 9.72 mg, silicon dioxide colloid - 0.81 / 1.62 / 3.24 mg, poloxamer 188 - 0.16 / 0.32 / 0.64 mg;

shell: opadraj blue 00F105007 (hypromellose - 3,570 mg, titanium dioxide (E 171) - 0,679 mg, macrogol-4000 - 0,358 mg, talc-0,358 mg, indigokarmin (E 132) - 0,037 mg)) - 5,00 mg / 00F105009 (hypromellose - 7,140 mg, titanium dioxide (E 171) - 1,330 mg, macrogol 4000 to 0,715 mg, talc 0,715 mg, indigokarmin (E 132) 0.100 mg)) - 10.00 mg / 00F105003 (hypromellose 13.566 mg, titanium dioxide (E171) 2.417 mg, macrogol 4000 to 1.359 mg, talc 1.359 mg, indigocarmine (E 132) 0.300 mg)) 19.00 mg.

Description:

Tablets, film-coated, 90 mg

Oval, biconvex tablets covered with a film membrane, light-blue, with bevelled edges. On one side between the two curved lines is engraved "90", on the other - "NVR".

Tablets, film-coated, 180 mg

Oval, biconvex tablets covered with a film membrane, blue, with bevelled edges. On one side between the two curved lines is engraved "180", on the other - "NVR".

Tablets, film-coated, 360 mg

Oval biconvex tablets covered with a film membrane, dark blue, with beveled edges. On one side between the two curved lines is engraved "360", on the other - "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. Deferazirox 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 overload with iron (Fe) with the use of deferazirox in daily doses of 10 mg / kg, 20 mg / kg and 40 mg / kg (in the form of dispersible tablets), the average effective excretion of iron 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 post-transfusion overload with iron.

The main diseases requiring regular blood transfusions included: β-thalassemia, sickle-cell anemia and other congenital and acquired anemia (myelodysplastic syndromes, congenital hypo-plastic anemia of Diamond-Blackfen, 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 in the form of dispersible tablets for 1 year in patients aged ≥2 years with β-thalassemia and chronic post-transfusion overload with iron and initial SZHP ≥7 mg Fe/ g dry substance of the liver, the decrease in SSP was 5.3 ± 8.0 mg Fe/ g 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/ g dry substance of the liver was noted in 58.6% of patients who received deferazirox (with initial SZHP ≥7 mg Fe/ g dry substance of the liver).

With the use of deferazirox in a dose of 20-30 mg / kg / day in the form of dispersible tablets 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/ g dry substance of the liver. Reduction of SSP to ≤7 mg Fe/ g dry substance of the liver was noted in 58.5% of patients who received deferazirox (with initial SZHP ≥7 mg Fe/ g dry substance of the liver).

The effect of the use of deferazirox in the form of dispersible tablets on serum ferritin concentration and the ratio of iron excretion to its entry into the body was dose-dependent in the dose range of 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.

When using deferazirox in a dose of 30 to 40 mg / kg / day in the form of dispersible tablets for 1 year in patients with β-thalassemia with chronic post-transfusion overload with iron with myocardial damage (left ventricular ejection fraction (LVEF) ≥56%the transverse relaxation time (T2 *), determined in the course of magnetic resonance imaging of the myocardium, remained 5-20 ms), the myocardial function improved (an increase in T2 * by 16% of the original).

The use of deferazirox in a dose of 20 to 40 mg / kg / day in the form of dispersible tablets for 1 year in patients with β-talassemia with chronic post-transfusion iron overload without myocardial damage (LVEF ≥56%, T2 * ≥20 ms) promoted preservation of normal myocardial function (T2 * 32.0-32.5 ms).

In patients with iron overload and myocardial damage (T2 * <20 ms), deferasierox treatment resulted in a decrease in iron content in the myocardium and a progressive improvement in T2 * values over three years of follow-up.

In patients with iron overload without myocardial damage, deferasierox administration prevented the accumulation of iron in the heart (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, deferaziroxome therapy in the form of dispersible tablets at a dose of 10 mg / kg of body weight for 1 year leads to a decrease in the SMP from the baseline by an average of 3.80 mg Fe/ g of dry substance of the liver, while in patients receiving placebo, SSP increases by 0.38 mg Fe/ g dry substance of the liver.

In addition, deferasierox therapy in the form of dispersible tablets 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 baseline, and in patients receiving placebo, serum ferritin concentration increases at 114.5 μg / l.

Pharmacokinetics:

The drug Jaden, film-coated tablets, is a drug form of deferazirox with greater bioavailability compared with the drug Exidzhad^® (deferazirox), dispersible tablets.

The drug Jaden, film-coated tablets, at a dosage of 360 mg is equivalent to the drug Exidzhad® (deferazirox), dispersible tablets at a dosage of 500 mg, with respect to the area under the concentration-time curve (AUC), determined on an empty stomach.

The maximum concentration (C_mOh) increased by 30% (90% CI: 20.3% -40.0%), but there were no clinically significant effects.

Suction

Deferazirox in the form of dispersible tablets is well absorbed after ingestion, the mean time to reach the maximum concentration in the blood plasma (t_max) is about 1.5-4 hours.Absolute bioavailability according to AUC deferaziroxa in the form of dispersible tablets for oral administration is about 70% compared with intravenous administration. Absolute bioavailability of deferazirox in the form of tablets coated with a film membrane has not been studied. Bioavailability of deferazirox in the form of tablets coated with a film coat, is higher by 36% compared with deferaziroxom in the form of dispersible tablets.

When using deferaziroxa, film-coated tablets in healthy volunteers on an empty stomach together with low-fat food (fat content <10% of calories), AUC and C_max slightly decreased (by 11% and 16% respectively); with food high in fat (fat content> 50% of calories), AUC and C_maxincreased by 18% and 29%, respectively. The effect of increasing C_max due to a change in dosage form and use with food containing a high percentage of fat, can be added up, so the medication must be administered to Jaden on an empty stomach or with light food.

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 volunteers who received cholestyramine after a single dose 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 - UGT1A3 (UST family 1, 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). The mean half-life (T_1/2) varies from 8 to 16 hours.

Pharmacokinetics in special clinical cases

Total bioavailability of deferazirox in adolescents (from 12 to 17 years) and children (from 2 to 12 years) after a single and multiple doses was lower than in adult patients.

Children under 6 years bioavailability is lower by 50% than in adults, however this has no clinical significance, since the dosage regimen is set individually.

Pharmacokinetics of deferazirox in patients ≥65 years of age not studied.

In patients with impaired liver or kidney function the pharmacokinetics of deferasirox 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_max in patients with violations of 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 high-risk myelodysplastic syndrome or other hemoblastoses and non-hematological malignancies, in whom chelation therapy will be ineffective due to rapid progression of the disease.

- Dysfunction of the liver of a severe 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 in the use of deferaziroxa in children younger than 2 years is absent.

Carefully:

Age> 65 years; the serum creatinine concentration is higher than the norm, especially if there are additional risk factors, such as simultaneous use of drugs capable of causing kidney dysfunction, dehydration or severe infections; violations of liver function (the use of the drug Jaden in patients of this category has not been studied),simultaneous use with anticoagulants and other drugs that have ulcerogenic effects (nonsteroidal anti-inflammatory drugs, glucocorticosteroids, bisphosphonates for oral administration); decrease in the number of platelets <50 x 10⁹/ 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. According to studies in animals deferazirox does not affect male or female fertility.

Do not use the drug Jaden in pregnant women, except in cases of extreme necessity.

In studies in animals 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 Jaden should not continue breastfeeding.

Dosing and Administration:

Tablets drug Jadena, coated with a film sheath, should be swallowed whole, washed down with a small amount of water. For patients who can not swallow the whole tablet, as well as for children under 3 years old, it is recommended to break the tablet and sprinkle powdered powder, for example yoghurt or apple sauce (mashed potatoes) with the resulting powder. The resulting powder should be taken completely and immediately, without storing it for later use.

The drug Jaden should be taken orally once a day on an empty stomach or with light food, preferably at the same time.

Chronic posttransfusion overload with iron

Jaden therapy is recommended to begin after transfusion of approximately 20 units (about 100 ml / kg) of erythrocyte mass and more or in the presence of clinical data indicating 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.

The goal of iron chelator therapy is to remove iron supplied with transfusions of erythrocyte mass, and, if necessary, reduce the iron content in the body.The decision to remove accumulated iron should be taken individually, based on an assessment of the expected benefits and risks from chelation therapy.

The drug Jaden, film-coated tablets, is a dosage form of deferazirox with a higher bioavailability compared with the drug

Excigad^®, dispersible tablets. When replacing therapy with the drug Eksidzhad^® on therapy with Jaden's drug, the dose should be reduced by 30% and rounded as close as possible to the dose of the whole film-coated tablet.

The correspondence of the doses of both dosage forms is shown in Table 1.

Table 1. Dosage in the therapy of chronic post-transfusion overload with iron

	Jadena, film-coated tablets	Excidzhad®, dispersible tablets
Initial dose	14 mg / kg / day	20 mg / kg / day
Alternative	7 mg / kg / day	10 mg / kg / day
initial dose	21 mg / kg / day	30 mg / kg / day
Dose selection	3,5-7 mg / kg / day	5-10 mg / kg / day
The maximum dose	28 mg / kg / day	40 mg / kg / day

Initial dose

The recommended initial daily dose of Jaden is 14 mg / kg body weight.

For patients receiving transfusion of erythrocyte mass inmore than 14 ml / kg / month (approximately more than 4 blood units per month for adults), an initial daily dose of 21 mg / kg is possible to reduce the iron content in the body.

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

For patients with a good clinical effect against deferoxamine, the initial dose of Jaden should be one third of the previously used dose of deferoxamine (for example, in a patient who received 40 mg / kg / day of deferoxamine 5 days a week or the equivalent, start with 14 mg / kg per day).

Dose selection

It is recommended to monitor the concentration of serum ferritin every month and, if necessary, adjust the dosage of the drug to Jaden every 3-6 months, based on the change in serum ferritin concentration. Dose adjustment should be carried out in stages, in steps of 3.5-7 mg / kg body weight, according to the individual response to therapy and depending on the purpose of the therapy (maintenance or reduction of iron content).

If the drug is ineffective at a dose of 21 mg / kg body weight (serum ferritin concentration remains at ≥ 2500 μg / l), the dose should be increased to 28 mg / kg body weight. It is not recommended to use the dose more than 28 mg / kg, since the experience of using the drug in 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 reduction (with a "step" of 3.5-7 mg / kg) of the dose to maintain serum ferritin concentration in this target range.

If serum ferritin concentration is significantly below 500 μg / l, discontinuation of treatment with Jaden should be considered.

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

Chronic nontransfusion overload with iron in patients with thalassemia

Chelation therapy with Jaden in patients in this category is only possiblewith proven iron overload (SIF ≥5 mg Fe / g dry substance 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.

The drug Jaden, film-coated tablets, is a dosage form of deferazirox with a higher bioavailability compared with the preparation of Eksidzhad®, dispersible tablets.

When replacing therapy with the drug Eksidzhad® on therapy with Jaden's drug, the dose should be reduced by 30% and rounded as close as possible to the dose of the whole film-coated tablet.

The correspondence of the doses of both forms of release is presented in Table 2.

Table 2. Dosage in the therapy of chronic nontransfusion overload with iron in patients with thalassemia

	Jadena, film-coated tablets	Excidzhad®, dispersible tablets
Initial dose	7 mg / kg / day	10 mg / kg / day
Dose selection	3,5-7 mg / kg / day	5-10 mg / kg / day
The maximum dose	14 mg / kg / day	20 mg / kg / day

Initial dose

The recommended initial daily dose of Jaden is 7 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 is possible at 3.5-7 mg / kg. Correction of the dose is possible with the preservation of SMP at a level of ≥ 7 mg Fe/ g of dry liver substance or persisting (without a tendency to decrease) serum ferritin concentration> 2000 μg / l and with good tolerability of therapy.

The use of Jaden in patients with thalassemia at a dose of more than 14 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 μg / l without definition of FGP, the dose of Jaden should not exceed 7 mg / kg of body weight.

In patients receiving therapy at a dose of more than 7 mg / kg of body weight, it is recommended to reduce the dose of the drug to Jaden before achieving SFA ≤7 mg Fe/ g dry substance of the liver or ferritin concentration ≤2000 μg / l.

Therapy with Jaden's drug should be completed when the SMP 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 trials in patients aged ≥65 years there was an increase in the incidence of adverse events (AEs) compared with patients less than 65 years of age, in this category of patients should be carefully monitored AEs and, if necessary, reduce the dose of the drug.

Children and teenagers (from 2 to 17 years)

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.

The use of the drug in the form of film-coated tablets has not been studied in clinical studies in patients younger than 10 years (see section "Pharmacological properties").

Patients with impaired renal function

It is necessary to use with caution the drug Jaden in patients with a serum creatinine concentration above the age limit in the presence of additional risk factors, such as simultaneous use of drugs capable of causing renal dysfunction, for example, 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 7 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.

Side effects:

In patients with chronic post-transfusion iron overload, the most frequent adverse events reported during prolonged therapy with deferazirox in the form of dispersible tablets in adults and children include: gastrointestinal disturbances (26%): nausea, vomiting , diarrhea, abdominal pain and dermatological disorders (7%) - skin rash.These reactions are dose-dependent, mostly mild or moderately expressed, are transient in nature and in most cases are resolved independently even with continued treatment.

A slight non-progressive increase in serum creatinine concentration, mainly within normal limits, was observed in almost 36% of patients, was dose-dependent and was often resolved on its own, a decrease in creatinine concentration in the blood plasma was possible with a decrease in the dose of the drug.

In patients with chronic post-transfusion iron overload with deferazirox in the form of dispersible tablets, 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 deferazirox in the form of dispersible tablets at a dose of 10 mg / kg body weight, the most frequent AEs were diarrhea (9.1%), skin rashes (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 with other iron chelators, patients who received deferazirox, 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 - reactions Hypersensitivity (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.

Disturbances from the nervous system: often - headache; infrequently - dizziness.

Disturbances on the part of the organ of sight: infrequently - early cataract, maculopathy; rarely - optic neuritis.

Hearing disorders and labyrinthine disorders: 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.

Disturbances from the liver and bile ducts: often - increased activity of "liver" transaminases; 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: very often - an increase in the concentration of creatinine in the blood serum; often - proteinuria; infrequently - tubulopathy (acquired Fanconi syndrome), glucosuria; frequency is unknown - acute necrosis of renal tubules, acute renal failure (in most cases, an increase in serum creatinine> 2 times higher than the upper limit of the norm was observed, after normalization of the drug, normalization of this index was noted), tubulointerstitial nephritis.

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

With the use of deferaziroxa, there have been 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 deferaziroxa in clinical practice, separate reports were received on the development of hepatic insufficiency (including cases with fatal outcome). In most cases, liver failure was developed in patients with severe comorbidities, including liver cirrhosis and multiple organ failure.

There are rare reports of the development of gastrointestinal hemorrhage with a lethal outcome with deferaziroxome therapy in elderly patients, patients with progressive hemoblastosis 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.

If any of the side effects listed in the manual are aggravated, or if you notice any other side effects not listed in the instructions, inform the doctor about it.

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. At a single administration of deferazirox in the form of dispersible tablets at a dose of 80 mg / kg of body weight (corresponding to a dose of 56 mg / kg deferasirox in the form of film-coated tablets), patients with P-thalassemia with iron overload were well tolerated with development of mild nausea and diarrhea.

Healthy volunteers well tolerated a single dose of deferazirox in the form of dispersible tablets at a dose of up to 40 mg / kg (which corresponds to a dose of 28 mg / kg deferaziroxa in the form of film-coated tablets).

In case of an overdose, the following acute symptoms: nausea, vomiting, headache, diarrhea.

Treatment: inducing vomiting or gastric lavage; symptomatic therapy.

Interaction:

Medicinal products, capable of lowering the system exposure of deferazirox

In healthy volunteers, with a single application of deferazirox at a dose of 30 mg / kg in the form of dispersible tablets simultaneously with the active inducers of uridine diphosphate glucuronyltransferase (CGT), rifampicin (repeated administration of 600 mg per day),a decrease in the systemic bioavailability of the latter by 44% was noted. In this regard, concomitant therapy with potent UHT inducers (for example, rifampicin, phenytoin, phenobarbital, ritonavir) can lead to a decrease in the effectiveness of the drug to Jaden. Thus, it is necessary to provide for an increase in the dose of the drug to Jaden when it is used simultaneously with the active inductors of the UGT, based on the clinical response to therapy.

Cholestyramine significantly reduces the bioavailability of deferasirox (probably due to decreased enterohepatic recirculation).

Interaction with food

The deferasirox stan in the form of tablets coated with a film membrane significantly increases (by 29%) when applied with food with a high fat content. The drug can be used as an empty stomach or with light food.

Interaction with midazolam and other drugs metabolized with the participation of isoenzyme CYP3A4

In healthy volunteers, when using deferazirox in the form of dispersible tablets simultaneously with midazolam, substrate isoenzyme CYP3A4, there was a decrease in the systemic bioavailability of the latter by 17%.Since in patients with chronic iron overload, a decrease in the systemic bioavailability of drugs that are substrates of the isoenzyme CYP3A4, may be more pronounced, caution should be applied to the preparation of Jaden along with drugs metabolized with participation CYP3A4 (e.g., cyclosporine, simvastatin, hormonal contraceptives, bepridilom, ergotamine).

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

Interaction with repaglinide and other drugs, metabolized with the participation of the isoenzyme CYP2C8

In healthy volunteers with simultaneous application of deferasirox (repeated administration in the form of dispersible tablets at a dose of 30 mg / kg per day) with a substrate of isoenzyme CYP2C8, repaglinide (a single dose of 0.5 mg), there was an increase AUC and C_mOh the latter by 131% and 62%, respectively. Since the interaction of deferazirox with repaglinitide at a dose of 0.5 mg has not been studied, it is necessary to exclude the simultaneous use of the drug Jaden with repaglitinide. Do not exclude the interaction between deferasirox and other isoenzyme substrates CYP2C8 with paclitaxel.

Interaction with theophylline and other drugs, metabolized with the participation of the isoenzyme CYP1A2

In healthy volunteers with simultaneous application of deferasirox (repeated administration in the form of dispersible tablets at a dose of 30 mg / kg per day) with a substrate of isoenzyme CYP1A2 theophylline (a single dose of 120 mg), there was an increase AUC the latter by 84%. With a single application of C_mOh Theophylline did not change, however, with prolonged use, it is possible to increase this index. The simultaneous use of the drug Jaden with theophylline is undesirable, but if these drugs are used simultaneously, careful monitoring of theophylline concentration in the blood with a possible dose reduction with simultaneous therapy with the drug Juden is necessary. We should not exclude the possibility of the interaction of deferazirox with other isoenzyme substrates CYP1A2.

Other interactions

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.

Unrecommended combinations

Special studies on the simultaneous use of the drug Jaden with aluminum-containing antacids have not been carried out. Although deferazirox has a lower affinity for aluminum than for iron, the drug Jaden should not be used simultaneously with aluminum-containing antacids.

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 gastrointestinal tract (bleeding, ulcerative lesions), it is necessary to use with caution the drug Jaden in patients , receiving the above drugs.

The effectiveness and safety of the use of the drug Jaden with other iron chelators have not been studied, and therefore the drug Jaden should not be used with other iron chelators.

Special instructions:

When using an inadequately high dose of Jaden 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

Deferasierox treatment was performed only in patients with serum creatinine concentration within the limits of the age norm.

In clinical studies, in about 36% of patients treated with deferasierox, there was a slight non-progressive increase in serum creatinine, 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 deferaziroxa in the post-marketing period, cases of development of acute renal failure are noted.

In adult patients, the daily dose of Jaden should be reduced by 7 mg / kg if, in two consecutive studies, an increase in serum creatinine levels is greater than 33% compared with the mean before treatment, or calculated CC (creatinine clearance) reaches values less than the lower limit 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 7 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 with the average before treatment and / or calculated serum CC reaches less than the lower limit of the norm, treatment with Jaden 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 in the use of the drug Jaden in patients with impaired renal function, or receiving drugs that have a negative effect on kidney function,It is recommended to determine the concentration of creatinine in the blood serum and / or CC 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, KK (calculated by the Cockcroft-Gault formula or by formula MDRD in adults and according to formula Schwartz in children) and / or the concentration of cystatin C in the blood plasma weekly after initiation of therapy or dose change of the drug to Jaden, and then monthly.

When using the drug, Jaden should monitor the proteinuria level 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 phosphaguria, aminoaciduria). If abnormalities of these indicators of tubular renal function are detected from normal values, dose should be reduced or the drug should be temporarily discontinued.

With the development of diarrhea and / or vomiting on the background of therapy with the drug, Jaden should provide adequate hydration of patients.

Impaired liver function

Deferasierox treatment was performed 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 carry out preliminary, in the first month - two-fold, and then monthly monitoring of liver function (activity of "liver" transaminases, bilirubin concentration, alkaline phosphatase activity). With the progression of an increase in the activity of "liver" transaminases, not associated with any other causes, treatment with Jaden should be discontinued.

Immediately after determining the cause of the biochemical changes, or after the normalization of the indicators, one can consider the question of a cautious resumption of therapy with the drug Jaden at a lower dose, followed by a gradual increase.

With the use of deferaziroxa in the post-marketing period, cases of hepatic insufficiency (including fatal outcome) were noted. Although in most cases, liver failure has developed in patients with concomitant diseases (including cirrhosis), the role of deferasirox 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 use of deferasirox. If you suspect a development of this condition, taking the drug should be stopped immediately; resume therapy with the drug should not be. There are reports of rare cases of development of erythema multiforme against the background of application of deferazirox.

In the application of deferaziroxa in patients can occur skin rashes. Since spontaneous disappearance of skin rash is often noted, with a mild to moderate severity of the complication, treatment with Jaden can be continued without dose adjustment.With the development of more severe skin rash, it is necessary to temporarily stop the treatment with the drug. After resolving the rash, the Jaden drug can be used repeatedly, at a lower dose and then increased.

Visual and auditory disorders

Since deferasiroxom was rarely treated with hearing and vision impairment (clouding of the lens), it is recommended that hearing acuity be determined and an ophthalmological examination (including ocular fundus examination) should be performed before starting treatment with Jaden 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 the case of the development of cytopenia against the background of the use of the drug Jaden, treatment with the drug should be temporarily suspended. After normalization of hematological parameters, the therapy with Jaden can be resumed.

The use of deferazirox in the form of dispersible tablets in children with post-transfusion overload with iron for five years was not accompanied by growth retardation.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. Heart function should be evaluated regularly in patients who receive long-term therapy with Jaden's drug due to heavy iron overload.

The drug Jaden can not be used in combination with other drugs that 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 Jaden 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:Film coated tablets, 90 mg, 180 mg and 360 mg.

Packaging:

For 10 tablets, in a blister of PVC / PVDC and aluminum foil.

For 3 or 9 blisters together with instructions for medical use in a cardboard box.

Storage conditions:

Store in the original packaging at a temperature not exceeding 30 ° C.

Protect from moisture.

Keep out of the reach of children.

Shelf life:

2 years.

The drug should not be used after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-003935

Date of registration:03.11.2016

Expiration Date:03.11.2021

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

Manufacturer: & nbsp

NOVARTIS PHARMA STEIN, AG Switzerland

Representation: & nbspNOVARTIS PHARMA LLCNOVARTIS PHARMA LLC

Information update date: & nbsp27.03.2017

Illustrated instructions

Instructions

Jaden (Dzhadenu)