VISTAFERUM

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VISTAFERUM (VISTAFERUM)

Composition:

Active ingredient: 1 ml of solution contains 20 mg of iron (as iron (III) hydroxide sucrose complex);

Excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Solution for intravenous injection.

Main physicochemical properties: dark brown-red solution in amber-colored ampoules.

Pharmacotherapeutic group. Antianaemic agents. Iron preparations. ATC code B03AC.

Pharmacological Properties.

Pharmacodynamics.

The active component of the medicinal product VISTAFERUM iron sucrose consists of polynuclear iron (III) hydroxide cores surrounded externally by a large number of non-covalently bound sucrose molecules. The average molecular mass of the complex is approximately 43 kDa. The polynuclear iron core has a structure similar to that of the core of ferritin, which is the physiological iron-containing protein. The complex is designed to deliver iron in a controlled manner to proteins responsible for its transport and storage in the body (transferrin and ferritin, respectively). After intravenous administration, the polynuclear iron core of the complex is taken up predominantly by the reticuloendothelial system of the liver, spleen, and bone marrow. In the second phase, iron is used for the synthesis of hemoglobin, myoglobin, and other iron-containing enzymes or is stored in the liver in the form of ferritin.

Pharmacokinetics.

Distribution. Ferrokinetic assessment of iron sucrose labeled with 52Fe and 59Fe was performed in 6 patients with anemia and chronic renal insufficiency. Within the first 6–8 hours, 52Fe is taken up by the liver, spleen, and bone marrow. Radioactive uptake of iron occurs in macrophages of the reticuloendothelial system of the spleen. After intravenous administration to healthy volunteers of a single dose of VISTAFERUM containing 100 mg of iron, maximum iron concentration was observed 10 minutes after administration, reaching a mean value of 538 mmol/L. The volume of distribution in the central compartment corresponded to plasma volume (approximately 3 liters).

Metabolism. After injection, sucrose is almost completely metabolized, and the polynuclear iron core is taken up predominantly by the reticuloendothelial system of the liver, spleen, and bone marrow. Iron uptake by erythrocytes during the 4 weeks following administration ranges from 68% to 97%.

Elimination. The average molecular mass of the complex is approximately 43 kDa, which is sufficiently large to prevent renal excretion. Renal elimination of iron within the first 4 hours after injection of 100 mg of iron accounts for less than 5% of the administered dose. Within 24 hours, total serum iron concentration returns to baseline levels (pre-dose), and renal excretion of sucrose amounts to approximately 75% of the administered dose. Pharmacokinetics in specific patient populations. It is currently unknown whether renal or hepatic impairment affects the pharmacological properties of iron (III) hydroxide sucrose complex (see section "Special Warnings and Precautions for Use").

Clinical characteristics.

Indications.

The medicinal product should be administered to patients with iron deficiency in the following cases:

• intolerance to oral iron preparations;
• presence of inflammatory gastrointestinal disorders (e.g., ulcerative colitis) that may exacerbate during therapy with oral iron preparations;
• iron-deficiency states resistant to treatment, when control of these conditions with oral iron preparations is inadequate;
• in chronic kidney disease, when the use of oral iron preparations is ineffective.

The medicinal product VISTAFERUM should be used only when indications are based on appropriate laboratory tests, specifically parameters such as hemoglobin level, serum ferritin, and transferrin iron saturation.

Contraindications.

• Hypersensitivity to the active substance or to any of the excipients of the medicinal product;
• anemia not associated with iron deficiency (e.g., hemolytic anemia, megaloblastic anemia due to vitamin B12 deficiency, disorders of erythropoiesis, bone marrow hypoplasia, anemia caused by lead poisoning);
• iron overload (hemosiderosis, hemochromatosis) or inherited disorders of iron metabolism (e.g., sideroblastic anemia, cutaneous porphyria, thalassemia);
• severe intolerance to other parenteral iron-containing medicinal products;
• first trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

VISTAFERUM is indicated for patients who cannot be prescribed oral iron preparations due to intolerance, inefficacy, or presence of gastrointestinal disorders. VISTAFERUM should not be administered simultaneously with oral iron-containing products, as absorption of orally administered iron is reduced. Therefore, oral treatment with iron preparations should not be initiated earlier than 5 days after the last injection of the product.

Special precautions for use.

Intravenous administration of iron-containing drugs may lead to immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions), which can be fatal. Such reactions have been reported even when previous administration of parenteral iron preparations was uncomplicated. VISTAFERUM should be administered to patients with a history of hypersensitivity reactions to iron dextran only in cases of extreme necessity and under strict precautionary measures.

Treatment with VISTAFERUM should be prescribed only by a physician after precise determination of the indication.

VISTAFERUM may be administered only if medical personnel experienced in the assessment and management of anaphylactic reactions are immediately available and if the facility is adequately equipped with resuscitation equipment. Prior to each administration of VISTAFERUM, the patient should be questioned about any previous adverse reactions associated with intravenous iron preparations.

Hypersensitivity reactions.

Typical symptoms of acute hypersensitivity reactions include: decreased blood pressure, tachycardia (including severe and potentially life-threatening anaphylactic/anaphylactoid reactions and even anaphylactic shock), respiratory symptoms (including bronchospasm, laryngeal edema, and pharyngeal edema), gastrointestinal symptoms (including abdominal cramps, vomiting), or skin manifestations (including urticaria, erythema, pruritus). Hypersensitivity reactions have also been reported after parenteral administration of iron complexes that previously did not cause complications. Cases of hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm that may lead to myocardial infarction, see section "Adverse reactions") have been reported.

Each patient should be monitored for adverse reactions for at least 30 minutes after each intravenous administration of iron-containing drugs. If any allergic reactions or signs of intolerance occur during administration, the infusion must be stopped immediately.

For emergency treatment of acute anaphylactic/anaphylactoid reactions, adrenaline (e.g., 0.3 mg intramuscularly) is recommended as the first-line therapy, followed by antihistamines and/or corticosteroids (which have a delayed onset of action).

Patients with existing allergies, including drug intolerance, severe bronchial asthma in medical history, eczema, and other forms of atopy, as well as patients with immunological and inflammatory diseases (such as systemic lupus erythematosus, rheumatoid arthritis), are at high risk of developing hypersensitivity reactions.

Parenteral administration of iron preparations in patients with liver dysfunction should be performed only after careful risk/benefit assessment. Parenteral administration of iron preparations should be avoided in patients with liver dysfunction when iron overload could act as a triggering factor. To prevent iron overload, close monitoring of iron levels in the body is recommended.

Parenteral iron administration may negatively affect the course of bacterial or viral infections.

Parenteral iron-containing medicinal products should be used with caution in patients with acute or chronic infections.

In patients with chronic infection, a benefit/risk assessment should be performed. It is recommended to discontinue VISTAFERUM in patients with bacteremia. Paravenous leakage should be avoided, as extravasation of VISTAFERUM at the injection site may lead to pain, inflammation, tissue necrosis, and brown discoloration of the skin. In case of paravenous leakage, administration should be stopped immediately.

Decreased blood pressure is commonly observed during intravenous administration of iron preparations. Therefore, the drug should be used with caution. The recommended infusion rate must be strictly followed to avoid the development of arterial hypotension. A higher incidence of adverse events (particularly hypotension) is associated with higher doses or faster infusion rates.

Special caution is required when administering VISTAFERUM to patients with hepatic insufficiency, decompensated liver cirrhosis, epidemic hepatitis, Rendu-Osler disease, acute-phase infectious kidney diseases, and uncontrolled hyperparathyroidism.

Important information about excipients.

This medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

There is limited data on the use of iron sucrose complex in pregnant women during the first trimester of pregnancy. Data on the use of the drug in pregnant women during the second and third trimesters of pregnancy showed no adverse effects on maternal or fetal health.

It is currently unknown whether iron (III) hydroxide sucrose complex crosses the placenta. Iron bound to transferrin does not cross the placental barrier. Iron bound to lactoferrin passes into breast milk.

Fetal bradycardia may occur after parenteral administration of iron preparations. This phenomenon is usually transient and is a consequence of maternal hypersensitivity reaction. Close fetal monitoring is required during intravenous parenteral administration of iron preparations to pregnant women.

Studies on the impact on iron levels in newborns have not been conducted. VISTAFERUM is contraindicated during the first trimester of pregnancy (see section "Contraindications"). Use of the drug during the second and third trimesters of pregnancy is possible only under strict indications.

A risk/benefit assessment should be performed before administering the drug during pregnancy, as hypersensitivity reactions pose certain risks to both mother and child (see section "Special precautions for use"). Pre-pregnancy body weight should be considered when calculating the required iron dose to avoid overdose.

Data on the excretion of iron into human breast milk after intravenous administration of iron sucrose are limited. In a clinical study, 10 healthy breastfeeding women with iron deficiency received 100 mg of iron as a sucrose complex. After four days of treatment, iron levels in breast milk were not elevated and did not differ from those in the control group (n = 5). The potential impact of iron from breast milk on the newborn/infant cannot be excluded; therefore, a risk/benefit assessment should be performed before administering the drug.

Ability to influence the speed of reaction while driving or operating machinery.

No relevant studies have been conducted. The effect of the medicinal product on reaction speed while driving or operating machinery is unlikely. However, if adverse reactions such as dizziness or confusion occur, patients should refrain from driving or operating machinery until symptoms resolve.

Method of Administration and Dosage

The medicinal product is administered intravenously only.

The medicinal product is not intended for subcutaneous or intramuscular administration. VISTA FERUM should be used only when the indication is based on appropriate laboratory tests, specifically parameters such as hemoglobin, serum ferritin, and transferrin saturation.

Patients should be monitored during and after administration of VISTA FERUM for signs and symptoms of hypersensitivity reactions. Appropriate emergency therapy must be readily available (see section "Special Warnings and Precautions for Use").

The total cumulative dose of the medicinal product should be individually calculated for each patient and must not be exceeded. The dose is determined based on the patient's body weight and hemoglobin level.

If the total required dose exceeds the maximum single dose allowed—200 mg (for injection) or 500 mg (for infusion)—the medicinal product should be administered in divided doses.

Dose Calculation

The total cumulative dose of VISTA FERUM, equivalent to the total iron deficit (mg), is determined based on the patient's hemoglobin (Hb) level and body weight. The dose is individually calculated according to the patient's total iron deficit using the Ganzoni formula:

Total iron deficit (mg) = body weight (kg) × (normal Hb level (g/L) – patient's Hb level (g/L)) × 0.24* + stored iron (mg)

For patients with body weight less than 35 kg:
Normal Hb level – 130 g/L, stored iron – 15 mg/kg body weight.

For patients with body weight greater than 35 kg:
Normal Hb level – 150 g/L, stored iron – 500 mg.

* The coefficient 0.24 = 0.0034 × 0.07 × 1000 (iron content in Hb = 0.34%, blood volume = 7% of body weight, coefficient 1000 = conversion from grams to milligrams).

Total volume of VISTA FERUM to be administered (in mL) = Total iron deficit (mg)
20 mg iron/mL

Table 1

Total cumulative dose of VISTA FERUM (mL) to be administered, based on patient's body weight and Hb level

Table 2

Required Hb level depending on patient's body weight

To convert Hb (mM) to Hb (g/dL), the first value should be multiplied by 1.6. If the required total dose exceeds the maximum allowable single dose of 200 mg (injection) or 500 mg (infusion), administration should be divided into several doses. Standard dosing.

Adults. 5–10 mL of VISTAFERUM medicinal product (100–200 mg iron) 1–3 times per week. Administration time and dilution factor are described below.

Children. The use of iron (III) hydroxide sucrose complex in children has not been sufficiently studied; therefore, the medicinal product is not recommended for use in pediatric patients. Maximum tolerated single or weekly dose.

Adults.

For injection, the maximum tolerated single dose administered no more than 3 times per week is 10 mL of VISTAFERUM medicinal product (200 mg iron), with administration duration of at least 10 minutes.

For infusion, the maximum tolerated single dose administered no more than once per week is 500 mg iron (25 mL of VISTAFERUM medicinal product) over at least 3.5 hours for patients with body weight above 70 kg; for patients with body weight of 70 kg or less, 7 mg iron per 1 kg body weight administered over at least 3.5 hours.

The infusion duration must be strictly observed, even if the patient does not receive the maximum tolerated single dose.

If there is no improvement in hematological parameters (increase in hemoglobin level by approximately 1 g/L blood per day or approximately 1.0–2.0 g/dL within 1–2 weeks after initiation of therapy), the patient’s initial diagnosis should be re-evaluated and the presence of persistent blood loss should be excluded.

Administration.

VISTAFERUM may be administered only intravenously, either by intravenous infusion, slow intravenous injection, or directly into the venous line of the hemodialysis apparatus. VISTAFERUM must not be administered intramuscularly or subcutaneously.

If the required total dose exceeds the maximum allowable single dose, the total dose should be divided into several administrations.

Intravenous infusion.

Immediately before administration, VISTAFERUM medicinal product must be diluted only in sterile 0.9% sodium chloride solution according to the scheme specified in Table 3.

Table 3

Intravenous administration.

VISTAFERUM can be administered intravenously by slow infusion at a rate of 1 mL of undiluted solution per minute; however, the maximum volume should not exceed 10 mL of VISTAFERUM (200 mg of iron) per single injection. Paravenous leakage must be avoided, as extravasation of VISTAFERUM at the injection site may cause pain, inflammation, tissue necrosis, and brownish skin discoloration (see section "Special precautions").

Injection into the venous compartment of the dialysis system.

VISTAFERUM can be administered directly into the venous limb of the dialysis circuit during hemodialysis sessions, strictly following intravenous injection procedures.

Children.

The use of iron (III) hydroxide sucrose complex in children has not been sufficiently studied; therefore, the medicinal product is not recommended for use in pediatric patients.

Overdose.

Symptoms: Overdose may lead to acute iron overload in the body, which may manifest as hemosiderosis.

Treatment. In case of overdose, symptomatic therapy is recommended and, if necessary, administration of iron-chelating agents.

Adverse Reactions

The most commonly observed adverse reactions include dysgeusia, occurring at a frequency of 4.5 cases per 100 individuals. Other common adverse reactions include nausea, arterial hypotension, arterial hypertension, and pain at the infusion site, occurring at a frequency of 1 to 2 cases per 100 individuals. Among the most significant serious adverse reactions associated with the administration of iron as iron (III) hydroxide sucrose complex are hypersensitivity reactions, occurring at a frequency of 0.25 cases per 100 individuals.

Immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions) occurred rarely. Overall, anaphylactoid/anaphylactic reactions are very serious adverse events that may lead to fatal outcomes (see section "Special Warnings and Precautions for Use"). Symptoms include circulatory collapse, arterial hypotension, tachycardia, respiratory symptoms (bronchospasm, laryngeal edema, pharyngeal edema, etc.), gastrointestinal symptoms (abdominal pain, vomiting, etc.), and skin symptoms (urticaria, erythema, pruritus, etc.).

All adverse reactions are listed by system organ class and frequency: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Immune system disorders

Rare: hypersensitivity reactions; frequency not known²: anaphylactoid/anaphylactic reactions, angioneurotic edema

Metabolism and nutrition disorders

Rare: iron overload

Nervous system disorders

Common: dysgeusia; rare: dizziness, headache, paresthesia, hypaesthesia; very rare: loss of consciousness, somnolence; frequency not known²: depressed level of consciousness, confusion, loss of consciousness, anxiety, tremor

Cardiac disorders

Rare: arterial hypotension and collapse, tachycardia; very rare: bradycardia, palpitations; frequency not known²: Kounis syndrome, bradycardia, tachycardia

Vascular disorders

Common: arterial hypotension, arterial hypertension; rare: thrombophlebitis, flushing, phlebitis; frequency not known²: superficial thrombophlebitis at injection site, circulatory collapse

Respiratory, thoracic and mediastinal disorders

Rare: dyspnea; frequency not known²: bronchospasm

Renal and urinary disorders

Very rare: chromaturia

Gastrointestinal disorders

Common: nausea; rare: vomiting, abdominal pain, diarrhea, constipation

Hepatobiliary disorders

Rare: increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyl transferase; very rare: increased blood lactate dehydrogenase

Skin and subcutaneous tissue disorders

Rare: pruritus, rash; frequency not known²: urticaria, erythema

Musculoskeletal and connective tissue disorders

Rare: muscle cramps, myalgia, arthralgia, limb pain, back pain

General disorders and administration site conditions

Common: pain at injection site¹; rare: chest pain, chills, asthenia, fatigue, peripheral edema, pain; very rare: increased sweating, pyrexia, chest pain; frequency not known²: cold sweat, malaise, pallor, influenza-like illness³

Adverse reactions reported from post-marketing experience

Frequency not known: clouding of consciousness, bradycardia, thrombophlebitis

¹ Most frequently observed adverse reactions: pain, extravasation, irritation, reactions at the site of administration, skin discoloration, hematoma, and pruritus at the injection/infusion site.

² Spontaneous reports from post-marketing experience; considered to be very rare.

³ May occur within several hours to several days.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after medicine authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are required to report any suspected adverse reactions through the national pharmacovigilance system.

Shelf life. 2 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 30 °C. Do not freeze. Keep out of reach of children.

Incompatibilities.

VISTAFERUM may only be mixed with sterile 0.9% sodium chloride solution. No other intravenous solutions or therapeutic agents should be added, as there is a risk of precipitation and/or other pharmaceutical interactions. Compatibility with polyethylene and polyvinyl chloride containers has not been studied.

Packaging. 5 ml in ampoules. 5 ampoules per cardboard box.

Prescription status. Prescription only.

Manufacturer. Nang Kuang Pharmaceutical Co., Ltd.

Manufacturer's name and address. No. 1001, 1001-1, Zhongshan Rd., Xinhua Dist, Tainan City, Taiwan (R.O.C.)