EKSIZHAD

Active material: Deferasirox
When ATH: V03AC03
CCF: Complexing the drug
ICD-10 codes (testimony): T45.4, T80
When CSF: 32.01.01
Manufacturer: NOVARTIS PHARMA AG (Switzerland)

PHARMACEUTICAL FORM, COMPOSITION AND PACKAGING

Dispersible tablets round, Valium, nearly white, with a beveled edge and stamp “J 125/NVR”.

Excipients: lactose monohydrate (200 grounds), lactose monohydrate (Dry Spray), krospovydon, microcrystalline cellulose, povidone K30, sodium lauryl, Colloidal anhydrous silica, magnesium stearate.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (12) – packs cardboard.

Dispersible tablets round, Valium, nearly white, with a beveled edge and stamp “J 250/NVR”.

Excipients: lactose monohydrate (200 grounds), lactose monohydrate (Dry Spray), krospovydon, microcrystalline cellulose, povidone K30, sodium lauryl, Colloidal anhydrous silica, magnesium stearate.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (12) – packs cardboard.

Dispersible tablets round, Valium, nearly white, with a beveled edge and stamp “J 500/NVR”.

Excipients: lactose monohydrate (200 grounds), lactose monohydrate (Dry Spray), krospovydon, microcrystalline cellulose, povidone K30, sodium lauryl, Colloidal anhydrous silica, magnesium stearate.

7 PC. – blisters (4) – packs cardboard.
7 PC. – blisters (12) – packs cardboard.

Pharmacological action

Complexing the drug. Is triple ligand, having a high affinity for iron (III) and connecting it to the ratio 2:1.

The drug increases the excretion of iron, predominantly in the feces. Deferasirox has low affinity for zinc and copper and does not cause a persistent reduction of these metals in the serum.

In a study of iron metabolism in adult patients with β-thalassemia major with iron overload posttransfusion when using Exjade at daily doses 10 mg / kg, 20 mg / kg 40 mg / kg, the average effective iron excretion averaged 0.0119 Fe mg / kg, 0.329 Fe mg / kg 0.445 mg Fe / kg body weight per day, respectively.

Application Exjade has been studied in adults and children older than 2 years with chronic post-transfusion iron overload. Major diseases, require regular transfusions, включали b-талассемию, sickle cell disease and other congenital and acquired anemias (myelodysplastic syndromes, congenital aplastic anemia Diamond-Blekfena, Acquired aplastic anemia and other rare forms of anemia).

Daily use of Exjade doses 20 mg / kg 30 mg / kg for 1 year for adults and children with β-thalassemia amid continuing blood transfusions led to a decrease in the total reserves of iron in the body; the iron content in the liver decreased on average, nearly 0.4 mg Fe / g, and 0.9 mg Fe / g liver dry matter, ferritin concentration in serum decreased an average of almost 36 mg / l 926 g / L, respectively. In applying the drug at the same dose ratio of iron excretion to intake of iron in the body is 1.02 (which is indicative of a normal iron balance) and 1.67 (which corresponds to an increased excretion of iron from the body). Such therapeutic response observed when using Exjade in patients with iron overload and other types of anemias. Use of the drug in a daily dose of 10 mg / kg for 1 Year allowed to maintain normal iron content in the liver, the concentration of serum ferritin levels and contributed to the balance of iron (balance between intake and excretion of iron) patients, rarely receiving blood transfusion or exchange transfusion. As the level of serum ferritin, determined monthly, It reflects changes in the content of iron in the liver, dynamics of the concentration of serum ferritin levels may be a criterion for assessing the effectiveness of therapy.

Pharmacokinetics

Absorption

Deferasirox is well absorbed after oral administration, average T_max in the blood plasma is about 1.5-4 no. The absolute bioavailability (by AUC) deferasirox when taken orally is about 70% compared to / in the introduction. AUC increased approximately 2 times at the reception during the breakfast high in fat (fat causes >50% energy value) and almost 50% at reception during standard breakfast. Bioavailability (by AUC) deferasirox moderately (about 13-25%) increased when taking over 30 minutes before meals with normal or high fat.

The total exposure (AUC) deferasirox when receiving a suspension of orange or apple juice was equivalent to the exposure of the drug when used in the form of an aqueous slurry (Relative AUC values 103% and 90% respectively).

In equilibrium C_max и AUC_{0 -24 no} deferasirox increase approximately linearly with dose. Deferasirox accumulates in the body, factor cumulation – 1.3-2.3.

Distribution

Deferasirox is highly bound to plasma proteins (99%), almost exclusively to albumin; It has little apparent V_d – about 14 l in adults.

Metabolism

The main route of metabolism is deferasirox glucuronidation, followed by excretion in the bile. Probably, deconjugation glucuronate occurs in the intestine and subsequent reabsorption (énterogepatïçeskaya recycling). Deferasirox undergoes glucuronidation mainly by UGT1A1 and less – UGT1A3.

Metabolism (Oxidative) deferasirox, CYP450 mediated, in humans is less pronounced (about 8%). Evidence, evidencing the induction or inhibition of enzymes when used in therapeutic doses, not available.

In vitro metabolism was not observed inhibition deferasirox hydroxyurea.

Deduction

Deferasirox and its metabolites are excreted mainly in the faeces (84% dose). Renal excretion of deferasirox and its metabolites is minimal (8% dose). Average T_1/2 It varies between 8 to 16 no.

Pharmacokinetics in special clinical situations.

The total bioavailability of deferasirox in adolescents (from 12 to 17 years) and children (from 2 to 12 years) after single and multiple administration were below, than in adults. Children younger than 6 years bioavailability below 50%, than in adults. However, it has no clinical significance, because the drug dosing regimen set individually.

The pharmacokinetics of deferasirox in elderly patients (senior 65 years) It has not been studied.

In patients with impaired liver function IPT kidney pharmacokinetics of deferasirox have not been studied. Increased levels of hepatic transaminases to 5 times compared to the ULN no effect on the pharmacokinetics of deferasirox.

Testimony

- Post-transfusion chronic iron overload in adults and children 2 and older.

Dosage regimen

Exjade therapy is recommended to start over after transfusion 20 units (about 100 ml / kg) red blood cells or the presence of clinical data, indicating the development of chronic iron overload (eg, at a concentration of serum ferritin more 1000 ug / l).

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

Exjade should be taken into 1 times / day on an empty stomach, at least, for 30 minutes before eating, preferably at the same time of the day every day.

The initial dose

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

Patient, receiving the introduction of more 14 ml / kg / month of packed red blood cells (approximately more than 4 transfusions per month for adults), to reduce the body's iron overload may be considered the use of an initial daily dose 30 mg / kg.

Patients, receiving less 7 ml / kg / month of packed red blood cells (approximately more than 2 blood transfusions per month for adults), in order to maintain a normal level of iron in the body can be considered the use of an initial daily dose 10 mg / kg.

In patients with a good clinical effect during the treatment with deferoxamine, initial dose of Exjade should be half of the previously used dose deferoxamine (eg, patient, Gets 40 mg / kg / day for deferoxamine 5 days per week or the equivalent amount, Exjade therapy can be initiated with a dose 20 mg / kg / day).

Maintenance dose

It recommended monthly monitor the concentration of serum ferritin and, if necessary, to carry out the correction dose every Exjade 3-6 months, based on changes in the level of serum ferritin. Dose adjustment should be “steps”; “move” is 5-10 mg / kg. Direction dose adjustment is determined by the individual effectiveness of treatment, and therapeutic goals (maintenance or reduction of iron). We do not recommend the use of a dose 30 mg / kg, as experience with the drug at higher doses is limited. If the concentration of serum ferritin is significantly lower 500 ug / l, should consider interrupting treatment Exjade.

To elderly patients (senior 65 years) It does not require correction dosing regimen.

To children and adolescents between the ages of 2 to 17 years correction dosing regime is not required. In the calculation of the dose for these patients should take into account the change in body weight over time.

Applications have Exjade patients with impaired renal function It has not been studied. Exjade treatment should be carried out with caution in patients with a serum creatinine above the age norm. No initial dose adjustment is required for patients with impaired renal function. Creatinine in serum should be monitored 1 once a month; if necessary, the daily dose should be reduced by 10 mg / kg.

Applications have Exjade patients with impaired liver function It has not been studied; in these patients the drug should be used with caution. No initial dose adjustment is required in patients with impaired hepatic function. Monitoring of liver function should be 1 once a month.

Terms of use of the drug

Because dispersible tablets are prepared suspension. Tablets were placed in a glass of water or orange or apple juice (100-200 ml) and stirred into the liquid until a homogeneous suspension. The suspension is taken orally, after which its residues in the beaker was added small quantity of water or juice, stirred and then also drink the liquid.

It is not recommended to dilute dispersible tablets carbonated beverages or milk.

Dispersible tablets should not be chewed or swallowed whole.

Side effect

Most common adverse reactions, It reported during prolonged therapy Exjade in adult and children, include disorders of the digestive system (26% patients) – nausea, vomiting, diarrhea, stomach ache, and dermatological disorders (7%) – skin rash. These reactions are dose-dependent, mainly mild or moderate, They are transient and disappear in most cases even with continued treatment. Easy non-progressive increase in serum creatinine concentration, substantially within the confines of standards, there was almost 34% patients. This undesirable phenomenon is dose-dependent, often resolve spontaneously and can sometimes be reduced at lower doses.

IN 2% of cases there was an increase in liver transaminases, independent of dose. In most patients, an increase of transaminases was observed before receiving Exjade. Sometimes (0.3%) there was an increase in liver transaminases over 10 times the ULN, suggests the development of hepatitis. As well as in the treatment of other iron chelators, patients, treated with Exjade, There is a high frequency hearing loss and lens opacities (rannyaya cataracts).

To determine the incidence of adverse reactions, the following criteria: Often (≥1/10); often (≥1/100, <1/10); sometimes (≥1/1000, <1/100), rarely (<1/10000).

CNS: often – headache; sometimes – dizziness, alarm, sleep disorders.

On the part of the organ of vision: sometimes – rannyaya cataracts, makulopatija.

On the part of the organ of hearing: sometimes – hearing loss.

On the part of the respiratory system: sometimes – pain in the larynx and pharynx.

From the digestive system: often – diarrhea, constipation, vomiting, nausea, stomach ache, abdominal distention, dyspepsia, increase in liver transaminases; sometimes – gastritis, hepatitis, cholelithiasis.

Dermatological reactions: often – rash, itch; sometimes – pigmentation disorders.

From the urinary system: very often - increasing the concentration of serum creatinine; often – proteinuria.

Other: sometimes – fever, swelling, feeling tired.

On Exjade therapy in clinical practice include the following adverse events irrespective of a causal connection with the use of the drug:

From the urinary system: acute renal failure; in most cases, there was an increase in serum creatinine in 2 times the ULN; after the cessation of drug therapy is usually observed normal levels of creatinine.

Dermatological reactions: leykotsitoklasticheskiy vasculitis, hives.

Allergic and immunopathological reactions: most in the first few months of treatment were observed hypersensitivity reactions (including anaphylaxis and angioedema).

When using Exjade been cases of cytopenia, including neutropenia and thrombocytopenia. In most cases, cytopenia observed in patients with baseline impairment of bone marrow function. The causal relationship between the adverse events and the use of the drug was not found.

Contraindications

- Increased sensitivity to the active agent and any other ingredients of the formulation.

Experience with children under the age of Exjade 2 years of absence.

FROM caution should be prescribed to patients with impaired renal or hepatic function, since the use of Exjade in these patients has not been studied.

Exjade treatment was performed only in patients with serum creatinine within the boundaries of age norms and the value of liver transaminases, ULN exceeding no more than 5 time.

In case of severe hypersensitivity reactions to the drug Exjade should be lifted immediately and start appropriate therapy.

Pregnancy and lactation

Clinical data on the use of deferasirox during pregnancy is not. IN experimental studies shown some reproductive toxicity of the drug in doses, maternal toxicity. The potential risk for humans is unknown.

Exjade is not recommended for pregnant women, except, the expected benefit to the mother outweighs the potential risk to the fetus.

IN experimental studies It was found, that deferasirox quickly and in large numbers enters the mother's milk. The effects of the drug on the offspring were observed.

Unknown, if deferasirox is allocated with breast milk in humans. Women, receiving treatment with Exjade, it is not recommended to continue breastfeeding.

Cautions

Exjade therapy must begin and carry out doctors, with experience in the treatment of chronic iron overload posttransfusion.

It is recommended to determine the level of serum creatinine twice before treatment and to monitor this index on a monthly basis during therapy. Some patients, Exjade treated, nonprogressive mentioned increase of serum creatinine, usually within limit of normal. In adult patients, the daily dose can be reduced by Exjade 10 mg / kg, if for two consecutive visits, non-progressive increase in serum creatinine was more than 33% compared to the average pre-treatment, and could not be attributed to other causes. In children, the dose can be reduced by 10 mg / kg, if for two consecutive visits, serum creatinine greater than the upper limit of age norm. If there is a progressive increase in serum creatinine in excess of CAH, Exjade therapy should be interrupted. The decision to resume taking Exjade treatment based on the specific clinical situation.

Given the increased risk of complications, when using Exjade in patients with impaired renal function or receiving drugs, having a negative impact on renal function, It is recommended to determine the level of serum creatinine weekly during the first month of therapy, and then monthly.

When using Exjade should be on a monthly basis to monitor the level of proteinuria.

It is recommended that the monthly monitoring of liver function. With the progression of increase in liver transaminases, not related to any other causes, Exjade therapy should be interrupted. Immediately after the determination of the causes biochemical changes or after normalization can consider cautious resumption of Exjade treatment at a lower dose followed by gradual increase in its.

Because patients often marked by the spontaneous disappearance of the rash, the development of skin rashes of mild to moderate severity treatment Exjade may be continued without dose adjustment. With the development of more severe rash is necessary to temporarily stop treatment with. After the disappearance of the rash Exjade can be assigned again, at a lower dose followed by its increase. In severe cases, the resumption of drug therapy can be carried out in combination with short-term use of corticosteroids.

With the development of diarrhea and / or vomiting during therapy with Exjade should ensure adequate hydration of patients.

Because treatment with Exjade marked deterioration in hearing and vision (cataract), It is recommended to determine the acuteness of hearing and conduct eye examination (ophthalmoscopy including fundus) Exjade use before and during subsequent therapy with, at regular intervals 12 Months. In the case of hearing or visual impairment should consider dose reduction or cessation of drug treatment.

In applying the drug, periodic determination of hematological parameters. In the case of unknown etiology cytopenia during treatment with Exjade treatment praparatom should suspend. After normalization of hematologic parameters Exjade therapy can be resumed.

To assess the effectiveness of Exjade therapy is recommended to determine the concentration of serum ferritin monthly. If the concentration of serum ferritin permanently reduced to a value less than 500 ug / l, should consider interrupting treatment Exjade.

Application of Exjade is not accompanied by growth retardation in children. However, as a precautionary measure when using the drug regularly (every 12 Months) control body weight and growth of the child.

Exjade should not be prescribed in combination with other drugs, form complexes with iron ions, because the safety of this combination therapy has not been established.

The preparation includes lactose (1.1 mg lactose for each mg of deferasirox). The drug is not recommended for use in patients with rare hereditary disorders, associated with galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption.

Effects on ability to drive vehicles and management mechanisms

Influence of Exjade on the ability to drive vehicles and use machines is not installed. If you experience dizziness during treatment with Exjade, patients should be careful when driving and operating machinery.

Overdose

Symptoms: an overdose of Exjade noted the development of subclinical hepatitis. Upon termination of therapy with symptoms of hepatitis stoped without complications in the long term. In single dose of the drug at a dose of 80 mg / kg of patients with β-thalassemia major with iron overload observed mild nausea and diarrhea. Healthy persons tolerated single dose to dose 40 mg / kg. In acute overdosage the following symptoms may develop: nausea, vomiting, headache, diarrhea.

Treatment: induction of vomiting or gastric lavage; simptomaticheskaya therapy.

Drug Interactions

Special studies on the use of Exjade with aluminum-containing antacid preparations has not been. Although deferasirox has a low affinity to aluminum, than to iron, Exjade should not be used simultaneously with an aluminum antacids.

In healthy volunteers, there was no interaction between Exjade and digoxin.

Special studies on the simultaneous use of Exjade and ascorbic acid has not been. The use of ascorbic acid in doses up to 200 mg / day with Exjade was not accompanied by undesirable effects.

While taking the drug during the meal increases the bioavailability of deferasirox in varying degrees.

Conditions of supply of pharmacies

The drug prescription.

Conditions and terms

The drug should be stored in a dry, out of reach of children at or above 30 ° C. Shelf life – 3 year.