Excigad

Exidzhad is a complexing drug.

Indications Excigad

It is indicated for the elimination of excess iron (in the chronic stage), which arises from multiple blood transfusions (transfusion siderosis) - to children aged more than 2 years, as well as adults.

[1]

Release form

Produced in tablet form (volume of 125, 250 or 500 mg). One blister plate contains 7 tablets. In one package 4 or 12 blisters.

Pharmacodynamics

Deferazirox is an oral triple ligand with a complexing effect. He has a powerful affinity with iron (III) and synthesis with it in the proportions 2k1. The medicine increases the rate of excretion of iron (mainly, along with feces). The substance has a weak affinity for copper with zinc, so it is not able to steadily reduce the level of these metals within the serum.

When testing iron metabolism in people with P-thalassemia and iron surplus after the use of drugs in daily dosages (10, 20, and 40 mg / kg), the average average excretion of iron per day was 0.0119, 0.329, and 0.445 mg of Fe / kg, respectively.

The effect of Eksidzhad on children aged more than 2 years and adults (with an overabundance of iron after transfusions to a chronic degree) was studied. Permanent transfusions are required in the following pathologies: sickle cell anemia, P-thalassemia, and in addition to other acquired and congenital forms of anemia (MDS, congenital Diamond-Blackfen syndrome (hypoplastic type of anemia), acquired aplastic anemia and other rare anemia ).

Everyday intake of drugs at dosages of 20 and 30 mg / kg for the period of year 1 in people suffering from β-thalassemia, which is accompanied by blood transfusions, causes a decrease in the level of iron stored in the body. The intrahepatic index of this substance decreased on average by almost 0.4, as well as 0.9 mg Fe / g of the dry liver element, respectively, and the serum ferritin values were practically 36, as well as 926 μg / l (according to the above figures ). In the case of drug use at the above dosages, the intake / excretion ratio of the Fe element was 1.02 (normal level), as well as 1.67 (elevated iron excretion level). These rates were observed with the use of drugs with patients with excess iron with other types of anemia.

Taking the medication during the first year in a daily amount of 10 mg / kg made it possible to maintain the optimal level of intrahepatic iron content, and at the same time the level of ferritin in the blood serum. This helped to achieve an equilibrium index between the numbers of excretion / intake of Fe in people who rarely had blood transfusions or performed transfusion transfusions.

Since inside the blood serum the ferritin values (determined every subsequent month) showed changes in the hepatic iron content, this shows that the dynamics of its concentration can be a criterion for evaluating the therapeutic effectiveness of Eksidzhad.

Pharmacokinetics

Absorption of the active component is quite high, the average peak plasma concentration is about 1.5-4 hours. The absolute bioavailability (AUC) of the active ingredient after oral administration is approximately 70% (in comparison with the I / O in the introduction).

The level of AUC increased approximately 2-fold in case of consumption together with food containing a high percentage of fat, and besides it increased by almost 50% in the case of reception with standard food. AUC-bioavailability of the active ingredient increased (by approximately 13-25%) when consumed half an hour before meals (moderate, as well as a high percentage of the presence of fats in food).

The total exposure (AUC) of the drug after use in the form of a suspension with the addition of juice from apples or oranges is approximately equal to the exposure of the drug when used in the form of an aqueous suspension (the corresponding relative AUC values will be equal to 103 as well as 90%).

At the equilibrium position, the peak concentration and AUC 0-24 hours of the substance increase along with the dosage practically linearly. Deferazirox is cumulated inside the body with a cumulative factor of 1.3-2.3.

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

The main metabolic pathway of the substance is glucuronization with further excretion together with bile. Deconjugation of glucuronates within the intestine with subsequent reabsorption (enterohepatic type of recirculation) is possible. Glucuronization of deferasirox is mainly carried out using the element UGT1A1, and in addition, less strongly, with the element UGT1A3. The oxidative process of substance exchange, mediated by element CYP450, is weakly expressed - approximately 8%. There is no information that demonstrates the inhibition or induction of enzymes in the case of drug use in medicinal dosages. Slowing metabolism of the active component of hydroxyurea during in vitro testing did not occur.

Deferazirox along with its decay products is excreted mainly along with feces (approximately 84% of the total dose). Through the kidneys excretion is weak - about 8% of the dosage. The average half-life is between 8-16 hours.

Dosing and administration

To drink tablets it is necessary on an empty stomach, 1 time for a day (approximately for half an hour before meal). It is recommended to take the medicine every day at about the same time.

Use the drug should be started after a 20+ red blood cell transfusion (approximately 100+ ml / kg) or in the presence of clinical indications that show chronic overabundance of iron (eg, if the serum ferritin component value exceeds 1000 μg / l).

The sizes of the required doses (in units of mg / kg) should be measured and rounded in the most approximate way to the dosage of the 1st whole tablet (125 or 250 or 500 mg).

The size of the required initial daily dosage is 20 mg / kg.

People who receive 14+ ml / kg of erythrocyte mass per month (approximately 4+ units / month to adults) are allowed to undergo a month's transfusion to consider the option of taking an initial daily dosage of 30 mg / kg.

Patients who are transfused less than 7 ml / kg of erythrocyte mass per month (less than 2 units / month to adult), with the purpose of maintaining optimum parameters of the substance, the option with the appointment of 10 mg / kg is considered.

When therapy with deferoxamine is used for patients with an acceptable curative effect, the initial dosage is prescribed at the rate of half of the previously taken (for example, a patient taking 40 mg / kg of medication per day (for 5 days a week or approximately equal number of days) allowed to begin treatment with a daily dosage of 20 mg / kg).

Selection of the optimal dose. Each month, monitor serum ferritin levels and adjust the dose rate of the drug every 3-6 months (if necessary - if changes in ferritin values are observed).

Correction is carried out in steps of 5-10 mg / kg. In this case, the direction of correction is selected depending on the therapeutic effect and therapeutic tasks provided on the patient (reduction or preservation of the existing level of iron).

If the drug does not give a result when taking 30 mg / kg (serum ferritin level remains ≥2500 μg / l), it is necessary to increase it to 40 mg / kg. Even more dosage is prohibited, because there are only limited information on the use of drugs in stronger doses.

To achieve the required serum ferritin index (a figure, usually in the range of 500-1000 μg / l), a stepwise (5-10 mg / kg) reduction in the dosage of drugs should be calculated - this will allow the level of the substance in the blood serum to remain in the above range.

If the ferritin index is much less than 500 μg / l, it is necessary to consult with the treating doctor about the interruption of the use of Eksidzhad.

[3]

Use Excigad during pregnancy

There is no clinical information about the use of the drug in pregnant women. Experimental tests have shown that the drug has a certain reproductive toxicity at dosages that exceed the recommended rate. There is no information about the risk of complications for the human body.

The drug is not recommended to be given to pregnant women, except for situations when the benefits for women are higher than the risk of potential development of side effects in the fetus.

Testing showed that the active substance quickly and in large quantities enters the breast milk. There was no drug exposure to the baby. There is no information about the excretion of the component together with the mother's milk. Lactating women who are treated with the help of Axidzhad, it is recommended for this period of time to refuse breastfeeding.

Contraindications

Among the contraindications: intolerance to the active component and the auxiliary elements of the medicine. Also, children's age is less than 2 years, since there is no information on the use of the drug in the above category of patients.

Side effects Excigad

The result of using Eksidzhad can be such side effects:

• Gastrointestinal organs: vomiting along with nausea, constipation, diarrhea, flatulence, abdominal pain, gastritis and dyspepsia;
• psyche: sleep disorders and anxiety;
• organs of the National Assembly: dizziness with headaches;
• visual organs: the appearance of maculopathy and early development of cataract;
• vestibular apparatus and auditory organs: transient loss of hearing;
• respiratory organs: pain in the larynx with a pharynx;
• liver: the development of hepatitis or CSF, as well as an increase in the level of transaminases;
• organs of the urinary system: proteinuria or an increase in creatinine;
• skin: itching or rashes, pigmentation disorder;
• others: puffiness, pyrexia, fatigue.

[2]

Overdose

As a result of a drug overdose, a subclinical form of hepatitis developed. After the withdrawal of the drug, the symptoms of hepatitis disappeared without further complications. Due to a single dose of 80 mg / kg in patients with an excess of iron and P-thalassemia, a slight diarrhea was observed along with nausea. At the same time, healthy volunteers tolerated a single dose of the drug at a dosage of no more than 40 mg / kg without complications.

In the case of an acute form of overdose, such manifestations can occur: headaches, vomiting along with nausea, and in addition diarrhea.

To eliminate these signs, you must induce vomiting or perform gastric lavage. Further symptomatic treatment is prescribed.

Interactions with other drugs

The combined use of drugs with antacids, which contain aluminum, has not been studied. Although Axidzhad has a weaker affinity for aluminum in comparison with iron, it is forbidden to use them together with aluminum-containing antacids.

There was no interaction of the drug with digoxin.

The interaction of drugs with vitamin C has not been studied, but with their combined use, one should avoid using vitamin D at a daily dosage of more than 200 mg.

The bioavailability of the active ingredient of the drug increases to a different extent when consumed with food.

[4], [5]

Storage conditions

The medicine is contained in a closed from small children, dry and dark place. Temperature is a maximum of 30 ° C.

Shelf life

Exidzhad is suitable for use for 3 years from the moment of its release.