Exijad

Exjade is a chelating drug.

Indications Exijad

It is indicated for the elimination of excess iron (in the chronic stage) arising from multiple blood transfusions (transfusion siderosis) – for children over 2 years of age, as well as adults.

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Release form

Available in tablet form (volume 125, 250 or 500 mg). One blister contains 7 tablets. One package contains 4 or 12 blisters.

Pharmacodynamics

Deferasirox is an oral triple ligand with a complexing effect. It has a strong affinity for iron (III) and synthesis with it in proportions of 2:1. The drug increases the rate of iron excretion (mainly with feces). The substance has a weak affinity for copper and zinc, so it is not able to consistently reduce the level of these metals in the serum.

When testing iron metabolism in people with β-thalassemia and iron overload after taking the drug in daily doses (10, 20, and 40 mg/kg), the average effective iron excretion per day was 0.0119, 0.329, and 0.445 mg Fe/kg, respectively.

The effect of Exjade on children over 2 years of age and adults (with iron overload after transfusions in a chronic degree) was studied. Constant transfusions are required in the following pathologies: sickle cell anemia, β-thalassemia, and in addition to this, in other acquired and congenital forms of anemia (MDS, congenital Diamond-Blackfan syndrome (hypoplastic type of anemia), acquired aplastic anemia and other rare types of anemia).

Daily intake of the drug in doses of 20 and 30 mg/kg for a period of 1 year in people suffering from β-thalassemia, which is accompanied by blood transfusions, causes a decrease in the level of iron accumulated in the body. The intrahepatic indicator of this substance decreased on average by almost 0.4 and 0.9 mg Fe/g dry liver element, respectively, and the ferritin indicators in the blood serum - by almost 36 and 926 mcg/l (in accordance with the above figures). In the case of taking the drug in the above doses, the proportions of intake/excretion of the Fe element were 1.02 (normal level), and 1.67 (increased level of iron excretion). These indicators were observed when taking the drug by patients with excess iron in other types of anemia.

Taking the drug for 1 year at a daily dose of 10 mg/kg made it possible to maintain intrahepatic iron levels at an optimal level, and along with this, the level of the substance ferritin in the blood serum. This helped to achieve an equilibrium indicator between the figures of Fe excretion/intake in people who rarely received blood transfusions or underwent exchange transfusions.

Since serum ferritin levels (measured every subsequent month) showed changes in hepatic iron content, this indicates that the dynamics of its concentration can be a criterion for assessing the therapeutic efficacy of Exjade.

Pharmacokinetics

The absorption of the active component is quite high, the average rate of reaching the peak plasma concentration is approximately 1.5-4 hours. The absolute bioavailability (AUC) of the active substance after oral administration is approximately 70% (compared to intravenous administration).

The AUC level increased approximately 2-fold when taken with food containing a high percentage of fat, and also increased by almost 50% when taken with standard food. The AUC bioavailability of the active ingredient increased (by approximately 13-25%) when taken half an hour before a meal (moderate as well as high percentage of fat in food).

The total exposure (AUC) of the drug after administration in the form of a suspension with the addition of apple or orange juice is approximately equal to the exposure of the drug when administered in the form of an aqueous suspension (in this case, the corresponding relative AUC values will be equal to 103 and 90%).

At steady state, peak concentration and AUC 0-24 hours of the substance increase with dosage almost linearly. Deferasirox accumulates in the body with a cumulative factor of 1.3-2.3.

The active ingredient is well synthesized with plasma protein (99%, almost all – with albumin). It has a small apparent distribution volume – about 14 liters for an adult.

The main metabolic pathway of the substance is glucuronidation with subsequent excretion with bile. Deconjugation of glucuronates inside the intestine with subsequent reabsorption (enterohepatic type of recirculation) is possible. Glucuronidation of deferasirox is mainly carried out by the UGT1A1 element, and also, to a lesser extent, by the UGT1A3 element. The oxidative process of metabolism mediated by the CYP450 element is weakly expressed - approximately 8%. There is no information demonstrating inhibition or induction of enzymes in the case of taking the drug in medicinal doses. Slowing down of the metabolism of the active component by hydroxyurea did not occur during in vitro testing.

Deferasirox and its breakdown products are excreted primarily in the feces (approximately 84% of the total dose). Renal excretion is weak, accounting for approximately 8% of the dose. The average half-life ranges from 8 to 16 hours.

Dosing and administration

The tablets should be taken on an empty stomach, once a day (about half an hour before meals). It is recommended to take the medicine at about the same time every day.

The drug should be used after transfusion of 20+ U of red blood cells (approximately 100+ ml/kg) or in the presence of clinical indications that demonstrate the occurrence of chronic iron excess (for example, if the serum ferritin component exceeds 1000 μg/L).

The required dose sizes (in units of mg/kg) must be measured and rounded as close as possible to the dosage of 1 whole tablet (125 or 250 or 500 mg).

The required initial daily dosage is 20 mg/kg.

For people who receive 14+ ml/kg of red blood cell transfusions per month (approximately 4+ U/month for an adult), the option of taking an initial daily dose of 30 mg/kg may be considered to lower the levels.

For patients who receive less than 7 ml/kg of red blood cell mass per month (less than 2 U/month for an adult), the option of prescribing 10 mg/kg is considered in order to maintain optimal levels of the substance.

When using deferoxamine for therapy in patients with an acceptable therapeutic effect, the initial dosage is prescribed at half the previously taken dose (for example, a patient who took 40 mg/kg of the drug per day (for 5 days per week or approximately an equal number of days) is allowed to begin treatment with a daily dosage of 20 mg/kg).

Selection of the optimal dose. Serum ferritin levels should be monitored monthly and the dose of the drug adjusted every 3-6 months (if necessary – if changes in ferritin levels are observed).

The correction is performed step by step – in parts of 5–10 mg/kg. The direction of correction is selected depending on the therapeutic effect on the patient and the treatment objectives (reduction or maintenance of the existing iron level).

If the drug does not produce results when taken at 30 mg/kg (serum ferritin level remains ≥2500 mcg/l), it is necessary to increase it to 40 mg/kg. It is prohibited to increase the dosage even more, because there is only limited information on the use of the drug in stronger doses.

To achieve the required serum ferritin level (the figure is usually within 500-1000 mcg/l), a step-by-step (by 5-10 mg/kg) reduction in the drug dosage should be calculated - this will allow the level of the substance in the blood serum to remain in the above range.

If the ferritin level is much less than 500 mcg/L, you should consult your doctor about stopping the use of Exjade.

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Use Exijad during pregnancy

There is no clinical data on the use of the drug in pregnant women. Experimental tests have shown that the drug has some reproductive toxicity at doses that exceed the recommended norm. There is no information on the risk of complications for the human body.

The drug is not recommended for use in pregnant women, except in situations where the benefit to the woman outweighs the risk of potential side effects in the fetus.

Tests have shown that the active substance quickly and in large quantities gets into breast milk. No effect of the drug on the child was observed. There is no information on the excretion of the component with breast milk. Lactating women who are treated with Exjade are advised to stop breastfeeding for this period of time.

Contraindications

Contraindications include: intolerance to the active component and auxiliary elements of the drug. Also, children under 2 years of age, since there is no information on the use of the drug in the above-mentioned category of patients.

Side effects Exijad

The following side effects may result from using Exjade:

• gastrointestinal tract: vomiting with nausea, constipation, diarrhea, flatulence, abdominal pain, gastritis and dyspeptic symptoms;
• psyche: sleep disorders and anxiety;
• nervous system organs: dizziness with headaches;
• visual organs: the appearance of maculopathy and early development of cataracts;
• vestibular apparatus and auditory organs: transient hearing loss;
• respiratory organs: pain in the larynx and pharynx;
• liver: development of hepatitis or cholelithiasis, as well as increased levels of transaminases;
• urinary system organs: proteinuria or increased creatinine levels;
• skin: itching or rash, pigmentation disorders;
• others: swelling, pyrexia, feeling of fatigue.

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Overdose

As a result of the drug overdose, a subclinical form of hepatitis developed. After the drug was discontinued, the symptoms of hepatitis disappeared without further complications. As a result of a single use of the drug at a dosage of 80 mg/kg, patients with iron overload and β-thalassemia experienced mild diarrhea along with nausea. At the same time, healthy volunteers tolerated a single use of the drug at a dosage of no more than 40 mg/kg without complications.

In case of acute overdose, the following symptoms may occur: headaches, vomiting along with nausea, and in addition, diarrhea.

To eliminate these symptoms, you need to induce vomiting or perform gastric lavage. Then symptomatic treatment is prescribed.

Interactions with other drugs

The combined use of the drug with antacids that contain aluminum has not been studied. Although Exjade has a weaker affinity for aluminum compared to iron, it is prohibited to use them together with aluminum-containing antacids.

No interaction of the drug with digoxin has been noted.

The interaction of the drug with vitamin C has not been studied, but when using them in combination, one should avoid taking the vitamin in a daily dose of more than 200 mg.

The bioavailability of the active component of the drug increases to varying degrees when taken with food.

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Storage conditions

The medicine is kept in a dry and dark place, out of the reach of small children. The temperature is a maximum of 30°C.

Shelf life

Exjade is good for use for 3 years from the date of its release.