Exjade^® (Tablets) Instructions for Use

ATC Code

V03AC03 (Deferasirox)

Active Substance

Deferasirox (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Chelating agent

Pharmacotherapeutic Group

Chelating agent

Pharmacological Action

Complexing agent. It is a tridentate ligand with high affinity for iron (III) and binds to it in a 2:1 ratio.

It enhances iron excretion, primarily in the feces. Deferasirox has low affinity for zinc and copper and does not cause a persistent decrease in the serum levels of these metals.

It has been shown that with daily use of deferasirox at doses of 20 mg/kg and 30 mg/kg for 1 year in adults and children with β-thalassemia receiving ongoing blood transfusions, total body iron stores were reduced; liver iron concentration decreased on average by almost 0.4 mg Fe/g and 0.9 mg Fe/g of liver dry weight, respectively, and serum ferritin concentration decreased on average by almost 36 µg/L and 926 µg/L, respectively. When used at the same doses, the ratio of iron excretion to iron intake was 1.02 (which is an indicator of normal iron balance) and 1.67 (which corresponds to increased iron excretion from the body). A similar therapeutic response was observed with the use of deferasirox in patients with iron overload and other types of anemia. The use of deferasirox at a daily dose of 10 mg/kg for 1 year maintained normal liver iron content, serum ferritin concentration, and contributed to the achievement of iron balance (equilibrium between iron intake and excretion) in patients who rarely receive blood transfusions or exchange transfusions.

Pharmacokinetics

Deferasirox is well absorbed after oral administration, the mean T_max in plasma is about 1.5-4 hours. The absolute bioavailability (by AUC) of deferasirox after oral administration is about 70% compared to intravenous administration. At steady state, the C_max and AUC_0-24h of deferasirox increase almost linearly with the dose. Deferasirox accumulates in the body, the accumulation factor is 1.3-2.3. Deferasirox is highly bound to plasma proteins (99%), almost exclusively to albumin; it has a small apparent V_d – approximately 14 L in adults.

When taken with food, the bioavailability of deferasirox increases to varying degrees.

The main pathway of deferasirox metabolism is glucuronidation followed by biliary excretion. Deconjugation of glucuronides in the intestine and subsequent reabsorption (enterohepatic recirculation) probably occurs. CYP450-mediated oxidative metabolism of deferasirox in humans is less pronounced (about 8%). There is no evidence of enzyme induction or inhibition when the drug is used at therapeutic doses.

In vitro, no inhibition of deferasirox metabolism by hydroxyurea was observed.

Deferasirox and its metabolites are excreted primarily in the feces (84% of the dose). Renal excretion of deferasirox and its metabolites is minimal (8% of the dose). The mean T_1/2 ranges from 8 to 16 hours.

The overall bioavailability of deferasirox in adolescents (from 12 to 17 years) and children (from 2 to 12 years) after single and multiple doses was lower than in adult patients. In children under 6 years of age, bioavailability is 50% lower than in adults. However, this is not clinically significant, as the dosage regimen of the drug is established individually.

Indications

Chronic post-transfusion iron overload in adults and children aged 2 years and older.

ICD codes

Dosage Regimen

Tablets

Therapy with deferasirox is recommended to be started after transfusion of more than 20 units (about 100 ml/kg) of packed red blood cells or in the presence of clinical data indicating the development of chronic iron overload (for example, with a serum ferritin concentration of more than 1000 µg/L).

For oral administration. The recommended initial dose is 10-30 mg/kg/day, depending on the amount of packed red blood cells the patient received per month. It is recommended to monitor serum ferritin concentration monthly and, if necessary, adjust the dose of deferasirox every 3-6 months, based on changes in serum ferritin levels. Dose adjustment should be carried out gradually, increasing or decreasing the dose at one time by 5-10 mg/kg. The direction of dose adjustment is determined by the individual effectiveness of treatment and therapeutic goals (maintaining or reducing iron content). The use of a dose of more than 30 mg/kg is not recommended, as experience with higher doses is limited. If the serum ferritin concentration is significantly below 500 µg/L, consideration should be given to interrupting treatment with deferasirox.

Adverse Reactions

From the CNS: frequent – headache; sometimes – dizziness, anxiety, sleep disorders.

From the digestive system: frequent – diarrhea, constipation, vomiting, nausea, abdominal pain, abdominal distension, dyspepsia, increased activity of hepatic transaminases; sometimes – gastritis, hepatitis, cholelithiasis.

From the urinary system: very often – increased serum creatinine concentration; frequent – proteinuria; regardless of causality – acute renal failure (increase in serum creatinine to 2 times above the ULN; after discontinuation of therapy, normalization of creatinine levels was usually noted).

From the sense organs: sometimes – early cataract, maculopathy, hearing loss.

From the respiratory system: sometimes – pain in the larynx and pharynx.

Dermatological reactions: frequent – rash, itching; sometimes – pigmentation disorder; regardless of causality – leukocytoclastic vasculitis, urticaria.

Allergic reactions regardless of causality – in most cases, hypersensitivity reactions (including anaphylactic reactions and angioedema) were observed in the first months of treatment.

Other: sometimes – increased body temperature, edema, feeling of tiredness. Cases of cytopenia (mainly in patients with pre-existing bone marrow dysfunction) have been reported, including neutropenia and thrombocytopenia (causal relationship not established).

Contraindications

Hypersensitivity to deferasirox.

Use in Pregnancy and Lactation

There are no clinical data on the use of deferasirox during pregnancy. Experimental studies have shown some reproductive toxicity of deferasirox at doses toxic to the maternal body. The potential risk to humans is unknown.

It is not recommended to use Deferasirox during pregnancy, except in cases where the expected benefit to the mother outweighs the possible risk to the fetus.

In experimental studies, it was found that Deferasirox is rapidly and significantly excreted in breast milk, with no effect on offspring noted.

It is not known whether Deferasirox is excreted in human breast milk. Deferasirox should not be used during lactation (breastfeeding).

Use in Hepatic Impairment

Use with caution in patients with impaired liver function.

Monthly monitoring of liver function is recommended. If progressive increase in hepatic transaminase activity occurs, not associated with any other causes, deferasirox therapy should be interrupted. Immediately after determining the cause of the biochemical changes or after normalization of indicators, consideration can be given to cautiously resuming deferasirox therapy at a lower dose with subsequent gradual increase.

Use in Renal Impairment

Use with caution in patients with impaired renal function.

Given the increased risk of complications, when using deferasirox in patients with impaired renal function or receiving drugs that have a negative effect on renal function, it is recommended to determine serum creatinine levels weekly during the first month of therapy, and then monthly.

During treatment with deferasirox, proteinuria levels should be monitored monthly.

Pediatric Use

The use of deferasirox is not accompanied by growth retardation in children. However, as a precaution, the child’s body weight and height should be regularly monitored (every 12 months) during treatment.

There is no experience with the use of deferasirox in children under 2 years of age.

Special Precautions

Use with caution in patients with impaired renal or liver function.

Deferasirox has been used only in patients with serum creatinine levels within the age-specific normal range and with hepatic transaminase activity not exceeding the ULN by more than 5 times.

In case of severe hypersensitivity reactions, Deferasirox should be discontinued immediately and appropriate therapy initiated.

It is recommended to determine serum creatinine levels twice before starting treatment and monitor this indicator monthly during therapy. The dose of deferasirox should be adjusted according to changes in serum creatinine. In case of a progressive increase in serum creatinine exceeding the ULN, deferasirox therapy should be interrupted. The decision to resume treatment is made based on the specific clinical situation.

Given the increased risk of complications, when using deferasirox in patients with impaired renal function or receiving drugs that have a negative effect on renal function, it is recommended to determine serum creatinine levels weekly during the first month of therapy, and then monthly.

During treatment with deferasirox, proteinuria levels should be monitored monthly.

Monthly monitoring of liver function is recommended. If progressive increase in hepatic transaminase activity occurs, not associated with any other causes, deferasirox therapy should be interrupted. Immediately after determining the cause of the biochemical changes or after normalization of indicators, consideration can be given to cautiously resuming deferasirox therapy at a lower dose with subsequent gradual increase.

Since skin rash often resolves spontaneously, if a mild to moderate skin rash develops, treatment with deferasirox can be continued without dose adjustment. If a more severe rash develops, treatment should be temporarily discontinued. After the rash disappears, deferasirox can be started at a lower dose with subsequent increase.

If diarrhea and/or vomiting develop during therapy with deferasirox, adequate hydration should be ensured.

During treatment, it is recommended to determine hearing acuity and conduct an ophthalmological examination (including fundus ophthalmoscopy) before starting deferasirox and during further therapy with the drug, at regular intervals of 12 months. If hearing or vision disorders develop, consideration should be given to reducing the dose or discontinuing treatment.

Hematological parameters should be monitored during treatment. If cytopenia of unclear etiology develops, treatment should be temporarily suspended. After normalization of hematological parameters, deferasirox therapy can be resumed.

To assess the effectiveness of deferasirox therapy, it is recommended to determine serum ferritin concentration every month. If the serum ferritin concentration consistently decreases to a value of less than 500 µg/L, consideration should be given to interrupting treatment.

Do not use Deferasirox in combination with other drugs that form complexes with iron ions, as the safety of using such a combination has not been established.

Use in pediatrics

The use of deferasirox is not accompanied by growth retardation in children. However, as a precaution, the child’s body weight and height should be regularly monitored (every 12 months) during treatment.

There is no experience with the use of deferasirox in children under 2 years of age.

Effect on ability to drive vehicles and operate machinery

If dizziness occurs during treatment, patients should exercise caution when driving vehicles and operating machinery.

Drug Interactions

Deferasirox should not be used simultaneously with aluminum-containing antacid preparations.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.