Argeferr^® (Solution) Instructions for Use

Marketing Authorization Holder

Genfamedica S.A. (Switzerland)

Manufactured By

P.L. Rivero Y Cia, S.A. (Argentina)

Packaging and Quality Control Release

P.L. RIVERO Y CIA, S.A. (Argentina)

Or

PROTERA, LLC (Russia)

ATC Code

B03AC (Parenteral preparations of trivalent iron)

Active Substance

Iron sucrose (BAN accepted for use in the United Kingdom)

Dosage Form

Argeferr®

Solution for intravenous administration 20 mg/1 ml: amp. 5 ml 5 or 25 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration is a transparent brown solution.

Excipients : water for injections.

5 ml – ampoules of dark glass (5) – contour plastic packs (1) – cardboard boxes.
5 ml – ampoules of dark glass (25) – cardboard boxes.

Clinical-Pharmacological Group

Antianemic drug for parenteral administration

Pharmacotherapeutic Group

Iron preparation

Pharmacological Action

An iron preparation that regulates metabolic processes. It is a colloidal solution consisting of spheroidal iron-carbohydrate nanoparticles. The core (center) of each particle contains iron (III) hydroxide. The core is surrounded by a sucrose shell, which stabilizes the iron (III) hydroxide, slowly releases bioactive iron, and keeps the resulting particles in a colloidal solution. This results in a complex with a molecular weight of approximately 43 kDa, which prevents its excretion by the kidneys in unchanged form. The iron (III) in this complex is bound to structures similar to natural ferritin.

The active substance of the drug, iron (III) hydroxide sucrose complex, dissociates in the reticuloendothelial system into iron and sucrose upon entering the body. Due to the lower stability of iron saccharate compared to transferrin, a competitive exchange of iron in favor of transferrin is observed. As a result, about 31 g of iron is transferred within 24 hours. The polycyclic iron hydroxide is partially stored as ferritin after complexation with the protein ligand, apoferritin, from liver mitochondria.

The hemoglobin level increases faster and more reliably than after therapy with iron (II) containing drugs. Administration of 100 mg of iron (III) leads to an increase in hemoglobin by 2-3%; during pregnancy – by 2%. The toxicity of the drug is very low. The therapeutic index is 20 (200/7).

Pharmacokinetics

After a single intravenous administration of the drug, the C_max of iron (on average 538 µmol) in the blood is reached 10 minutes after the injection. The half-life is 6 hours. The V_d at steady state is approximately 8 L, indicating low distribution of iron in the body’s fluids.

Renal excretion of iron, observed in the first 4 hours after administration, is less than 5% of the total clearance. After 24 hours, the serum iron concentration returns to the initial (pre-administration) value and about 75% of the sucrose leaves the vascular bed.

Indications

• Iron deficiency conditions (including iron deficiency and acute posthemorrhagic anemia) in patients requiring rapid iron replenishment;
• In patients who do not tolerate oral iron preparations;
• Presence of gastrointestinal tract (GIT) diseases in which oral iron preparations cannot be used.

ICD codes

Dosage Regimen

Administration

Argeferr^® is administered only intravenously (slowly as a bolus or by drip), as well as into the venous portion of the dialysis system, and is not intended for intramuscular administration. Simultaneous administration of the full therapeutic dose of the drug is not allowed.

Before administering the first therapeutic dose, a test dose must be administered. If intolerance phenomena occur during the observation period, the drug administration should be stopped immediately.

Before opening the ampoule, it should be inspected for the presence of sediment and damage. Only the brown solution without sediment can be used.

Drip infusion

Argeferr^® is preferably administered by drip infusion to reduce the risk of a pronounced decrease in blood pressure and the danger of the solution entering the perivenous space. Immediately before infusion, the drug Argeferr^® should be diluted with 0.9% sodium chloride solution in a ratio of 1:20 [for example, 1 ml (20 mg of iron) in 20 ml of 0.9% sodium chloride solution]. The resulting solution is administered at the following rate: 100 mg of iron – in no less than 15 minutes; 200 mg of iron – over 30 minutes; 300 mg of iron – over 1.5 hours; 500 mg of iron – over 3.5 hours. Administration of the maximum tolerable single dose, which is 7 mg of iron/kg of body weight, should be carried out over at least 3.5 hours, regardless of the total dose of the drug.

Before the first drip administration of the therapeutic dose of the drug, a test dose must be administered; 1 ml of the drug (20 mg) of iron for adults and children with a body weight of less than 14 kg, over 15 minutes. In the absence of adverse events, the remaining part of the solution should be administered at the recommended rate.

Bolus injection

The drug Argeferr^® can also be administered as an undiluted solution intravenously slowly, at a rate of 1 ml of Argeferr^® (20 mg of iron) per minute (for example, 5 ml of Argeferr^® (100 mg of iron) is administered over 5 minutes). The maximum volume should not exceed 10 ml of Argeferr^® (200 mg of iron) per injection.

After the injection, the patient is recommended to keep the arm in an extended position for some time.

Before the first bolus injection of the therapeutic dose of Argeferr^®, a test dose should be administered: 1 ml of Argeferr^® (20 mg of iron) for adults and children with a body weight over 14 kg, and half the daily dose (1.5 mg of iron/kg) for children with a body weight of less than 14 kg over 1-2 minutes. In the absence of adverse events during the subsequent 15 minutes of observation, the remaining part of the solution should be administered at the recommended rate. After the injection, the patient is recommended to keep the arm in an extended position for some time.

Administration into the dialysis system

Argeferr^® can be administered directly into the venous portion of the dialysis system, strictly following the rules described for intravenous injection.

Dose calculation

The dose is calculated individually according to the total iron deficiency in the body using the formula

Total iron deficiency (mg) = body weight (kg) x (normal Hb – patient’s Hb) (g/L) x 0.24* + deposited iron (mg).

For patients with a body weight of less than 35 kg: normal Hb = 130 g/L, amount of deposited iron = 15 mg/kg of body weight.

For patients with a body weight of more than 35 kg: normal Hb = 150 g/L, amount of deposited iron = 500 mg.

Coefficient 0.24 = 0.0034 x 0.07 x 1000 (iron content in hemoglobin = 0.34%; blood volume = 7% of body weight; coefficient 1000 = conversion from “g” to “mg”),

The total volume (cumulative therapeutic dose) of Argeferr^® that needs to be administered (in ml) to replenish the iron deficiency in the body is equal to

Total iron deficiency (mg)

20mg/ml

¹Fe – iron

The frequency of administration is determined by the doctor, but not more often than every other day.

Standard dose

Adults, including elderly (over 65 years) patients: 5-10 ml of Argeferr^® (100-200 mg of iron) 1-3 times a week depending on the hemoglobin level.

Children: there are only limited data on the use of the drug in children. If necessary, it is recommended to administer no more than 0.15 ml of Argeferr^® (3 mg of iron) per kg of body weight 1-3 times a week depending on the hemoglobin level.

Maximum tolerable single dose

Adults, including elderly (over 65 years) patients

– For bolus injection: 10 ml of Argeferr^® (200 mg of iron), duration of administration not less than 10 minutes.

– For drip infusion: depending on the indications, a single dose can reach 500 mg of iron. The maximum allowable single dose is 7 mg of iron per kg of body weight and is administered once a week, but it should not exceed 500 mg of iron.

If the total therapeutic dose exceeds the maximum allowable single dose, fractional administration of the drug is recommended.

If no improvement in hematological parameters occurs 1-2 weeks after starting treatment with Argeferr^®, the initial diagnosis should be reconsidered. As a rule, larger doses are associated with a higher frequency of adverse events.

Dose calculation for replenishing iron content after blood loss or autologous blood donation

The dose of Argeferr^® required to compensate for the iron deficiency is calculated using the following formula

If the amount of blood lost is known

Intravenous administration of 200 mg of iron (= 10 ml of Argeferr^®) leads to the same increase in Hb concentration as transfusion of 1 unit of blood (= 400 ml with Hb concentration of 150 g/L).

Amount of iron to be replenished (mg) = number of units of blood lost x 200 or required volume of Argeferr^® (ml) = number of units of blood lost x 10.

If Hb content is decreased: use the previous formula provided that iron stores do not need to be replenished.

Amount of iron to be replenished [mg] = body weight [kg] x 0.24 x (normal Hb – patient’s Hb) (g/L).

For example: body weight 60 kg, Hb deficit = 10 g/L => required amount of iron ~ 150 mg => required volume of Argeferr^® = 7.5 ml.

Treatment of patients with chronic renal diseases on hemodialysis and receiving additional treatment with erythropoietin

The drug is administered strictly intravenously. The injection is performed as slowly as possible, with the duration of administration increasing as the dose increases. The procedure is not particularly difficult for patients on hemodialysis, as they usually have suitable intravenous access. The drug is administered in 0.9% sodium chloride solution over at least 15 minutes during the last 2 hours of the hemodialysis session.

Absolute iron deficiency (anemia correction phase)

– 30-50 mg of iron/dialysis session or

– 1000 mg of iron over 6 – 10 weeks.

Maintenance therapy phase

Various doses are prescribed in various regimens

– 10-25 mg of iron/dialysis session

Or

– 100 mg of iron/once a month (depending on serum ferritin concentration).

Hemoglobin correction phase

– 150 mg of iron to increase the concentration by 10 g/L.

Adverse Reactions

The following adverse events, having a temporary and possible causal relationship to the administration of Argeferr^®, are currently known. All symptoms were observed very rarely (frequency of occurrence less than 0.01% and greater than or equal to 0.001%).

Nervous system disorders: dizziness, headache, loss of consciousness, paresthesia.

Cardiovascular system disorders: palpitations, tachycardia, decreased blood pressure, collapse-like states, feeling of heat, “flushing” of blood to the face, peripheral edema.

Respiratory system disorders: bronchospasm, shortness of breath.

Gastrointestinal tract disorders: diffuse abdominal pain, pain in the epigastric region, diarrhea, taste perversion, nausea, vomiting, transient taste sensations (especially, a “metallic” taste in the mouth).

Skin and subcutaneous tissue disorders: erythema, itching, rash, pigmentation disorder, increased sweating.

Musculoskeletal and connective tissue disorders: arthralgia, back pain, joint swelling, myalgia, limb pain.

Immune system disorders: allergic, anaphylactoid reactions, including facial edema, laryngeal edema.

General disorders and administration site conditions: asthenia, chest and back pain, feeling of heaviness in the chest, weakness, pallor of the skin, malaise, increased body temperature, chills.

Local reactions: pain and swelling at the injection site (especially with extravasal entry of the drug), phlebitis, burning sensation, hematoma.

Contraindications

Use of the drug is contraindicated in case of

• Anemia not associated with iron deficiency;
• Signs of iron overload (hemosiderosis, hemochromatosis) or impaired utilization process;
• Hypersensitivity to Argeferr^® or its components;
• First trimester of pregnancy (see section “Use in Pregnancy and Lactation”).

With caution: patients with bronchial asthma, eczema, polyvalent allergy, allergic reactions to other parenteral iron preparations (due to the high risk of developing allergic reactions (see section “Special Precautions”)). Caution is also required when administering iron preparations to patients with hepatic insufficiency, diabetes mellitus (see section “Special Precautions”), with acute infectious diseases and individuals with low iron-binding capacity of serum and/or folic acid deficiency, pediatric patients (under 18 years) (due to insufficient data on safety and efficacy).

Use in Pregnancy and Lactation

Contraindicated in the first trimester of pregnancy. In the second and third trimesters of pregnancy, the drug is prescribed if the expected benefit of use outweighs the possible risk to the fetus. During lactation, the safety of the drug use has not been established. It is recommended to discontinue breastfeeding (if it is necessary to use the drug) or to discontinue the drug.

Use in Hepatic Impairment

Caution is required when administering iron preparations to patients with hepatic insufficiency.

Pediatric Use

With caution: pediatric patients (under 18 years) (due to insufficient data on safety and efficacy).

Geriatric Use

Use is possible according to the dosing regimen.

Special Precautions

Argeferr^® should be prescribed only to those patients in whom the diagnosis of anemia is confirmed by appropriate laboratory data (for example, results of serum ferritin or hemoglobin and hematocrit determination, red blood cell count and their parameters – mean corpuscular volume or mean corpuscular hemoglobin). Intravenous iron preparations can cause allergic or anaphylactoid reactions, which can be potentially life-threatening.

The administration rate of Argeferr^® must be strictly observed (rapid administration of the drug may cause a decrease in blood pressure). A higher frequency of adverse events (especially – decreased blood pressure), including severe ones, is associated with an increase in dose. Thus, the administration time given in the “Dosage Regimen” section must be strictly observed, even if the patient is not receiving the drug at the maximum tolerable single dose.

During the administration of Argeferr^®, hemodynamic parameters must be monitored.

Intravenous iron preparations can cause allergic or anaphylactoid reactions, which can be potentially life-threatening. Patients with bronchial asthma, eczema, atopic diseases, polyvalent allergy, allergic reactions to other iron preparations, as well as individuals with low iron-binding capacity of serum and/or folic acid deficiency, have an increased risk of developing allergic or anaphylactoid reactions (see section “With caution”).

Studies conducted in patients with hypersensitivity reactions to iron dextran showed no complications during treatment with the drug.

It is necessary to avoid the penetration of the drug into the perivenous space, as the entry of Argeferr^® outside the vessel leads to tissue necrosis and brown discoloration of the skin. In case this complication develops, it is recommended (if the needle is still in the vessel) to inject a small amount of 0.9% sodium chloride solution. To accelerate the elimination of iron and prevent its further penetration into the surrounding tissues, the application of heparin-containing preparations (gel or ointment is applied with light movements, without rubbing) to the injection site is recommended.

Administration of the drug in the presence of sediment is unacceptable.

1 ml of Argeferr^® contains from 260 to 340 mg of sucrose. This data must be taken into account in patients with diabetes mellitus. During drip infusion of the drug, depending on the indications, the maximum tolerable single dose can reach 500 mg of iron, which corresponds to the administration of 8.5 g of sucrose. When converting this amount of carbohydrates to bread units (BU) (1 BU = 12 g of carbohydrates), it corresponds to 0.7 BU.

During therapy with erythropoiesis stimulants, iron metabolism is monitored using such indicators as serum ferritin concentration and transferrin iron saturation (TSAT). Determining the number of hypochromic red blood cells and the hemoglobin concentration in reticulocytes helps in making the decision to prescribe intravenous iron preparations when there is hyperferritinemia and low TSAT. The risk of iron overload is compensated by blood losses during procedures related to dialysis (1-3 g of iron is lost per year). Serum ferritin concentration should be monitored regularly. A serum ferritin concentration above 500 µg/L (with a normal C-reactive protein level) persisting for a long time may indicate iatrogenic iron overload. In such cases, iron preparations should be discontinued (therapy with the erythropoiesis stimulant should continue). Since iron stimulates the growth of most microorganisms, iron preparations should be discontinued if acute bacterial infections develop. Also, therapy with iron preparations should be conducted with caution in patients with permanent dialysis catheters.

Effect on the ability to drive vehicles and operate machinery

The safety of the drug regarding the ability to drive a vehicle or operate potentially dangerous machinery has not been established.

Caution is recommended when driving a vehicle or operating potentially dangerous machinery.

Overdose

Symptoms: decrease in blood pressure (signs of collapse appear within 30 min), symptoms of hemosiderosis.

Treatment: symptomatic, if necessary – iron-binding medications (chelates), for example, deferoxamine.

Drug Interactions

The drug should not be prescribed simultaneously with oral iron dosage forms, as it contributes to a decrease in iron absorption from the gastrointestinal tract. Treatment with oral iron preparations can be started no earlier than 5 days after the last injection.

Argeferr^® can be mixed in the same syringe only with 0.9% sodium chloride solution. The addition of any other solutions for intravenous administration and therapeutic drugs is not permitted, as there is a risk of precipitation and/or other pharmaceutical interaction. Compatibility with containers made of materials other than glass, polyethylene, and polyvinyl chloride has not been studied.

Storage Conditions

The drug should be stored in a light-protected place at a temperature from 4°C (39.2°F) to 25°C (77°F). Do not freeze. Keep out of reach of children.

Shelf Life

The shelf life is 3 years. Do not use the drug after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

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.