Instructions Venofer solution for injection 20 mg/ml ampoule 5 ml No. 5
Composition
active ingredient: 1 ml of solution contains 20 mg of iron (in the form of iron (III) hydroxide sucrose complex - 540 mg);
Excipients: sodium hydroxide, water for injections.
Dosage form
Solution for intravenous injection.
Main physicochemical properties: brown aqueous solution.
Pharmacotherapeutic group
Antianemic agents. Iron preparations. ATC code B0ZA C
Pharmacological properties
Pharmacodynamics.
The active component of the drug Venofer® iron sucrose consists of polynuclear iron (III) hydroxide centers, surrounded on the outside by a large number of non-covalently bound sucrose molecules. The average molecular weight of the complex is approximately 43 kDa. The polynuclear iron center has a structure similar to the structure of the ferritin center, which is a physiological iron-containing protein. The complex is designed in such a way that the absorbed iron is controlled to be delivered to the proteins that ensure its transport and storage in the body (transferrin and ferritin, respectively).
After intravenous administration, the multinuclear iron center from the complex is taken up mainly by the reticuloendothelial system of the liver, spleen, and bone marrow. In the second stage, the iron is used for the synthesis of hemoglobin, myoglobin, and other iron-containing enzymes or is stored in the liver as ferritin.
Distribution. The ferrokinetics of sucrose iron labeled with 52Fe and 59Fe were evaluated in 6 patients with anemia and chronic renal failure. During the first 6-8 hours, 52Fe is taken up by the liver, spleen, and bone marrow. Radioactive iron uptake occurs in macrophages of the reticuloendothelial system of the spleen.
After intravenous administration of a single dose of Venofer® containing 100 mg of iron to healthy volunteers, the maximum total serum iron concentration was observed 10 minutes after administration and reached a mean value of 538 mmol/L. The volume of distribution in the central compartment corresponded to the volume in blood plasma (approximately 3 liters).
Metabolism: After injection, sucrose is almost completely broken down, and the multinuclear iron center is taken up mainly by the reticuloendothelial system of the liver, spleen, and bone marrow.
Within 4 weeks after administration, iron uptake by erythrocytes ranges from 68% to 97%.
Elimination. The average molecular weight of the iron sucrose complex is approximately 43 kDa and is large enough to avoid renal excretion. Renal excretion of iron during the first 4 hours after injection of 100 mg iron is less than 5% of the administered dose. After 24 hours, total serum iron concentration has decreased to baseline (pre-administration) levels, and renal excretion of sucrose is approximately 75% of the administered dose.
Pharmacokinetics in specific patient groups. It is still unknown whether renal and hepatic insufficiency affect the pharmacological properties of iron (III) hydroxide sucrose complex (see section "Special instructions").
Indication
The use of the drug is indicated for patients with iron deficiency in case of ineffectiveness or impossibility of oral administration of iron-containing drugs, for example:
with intolerance to oral iron preparations;
in the presence of inflammatory diseases of the gastrointestinal tract (such as ulcerative colitis), when oral iron preparations can provoke an exacerbation of the disease;
in iron deficiency states resistant to therapy, when control of these states with oral iron preparations is insufficient.
Venofer® should only be used when the indications are based on appropriate studies. Appropriate laboratory tests include determination of hemoglobin, serum ferritin, and transferrin saturation.
Contraindication
Known hypersensitivity to the active substance or to other components of the medicinal product;
anemia not associated with iron deficiency (e.g., hemolytic anemia, megaloblastic anemia due to vitamin B12 deficiency, impaired erythropoiesis, bone marrow hypoplasia, anemia caused by lead poisoning);
iron overload (hemochromatosis, hemosiderosis) or hereditary disorders of iron absorption (sideroachretic anemia, thalassemia, porphyria cutanea);
First trimester of pregnancy.
Interaction with other medicinal products and other types of interactions
Venofer® is indicated only if oral iron preparations are not possible or if such therapy is ineffective. In the latter case, Venofer® should not be used simultaneously with oral iron preparations, as the absorption of iron administered orally is reduced.
Application features
Intravenous administration of parenteral iron preparations may lead to immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions), which may be fatal. Such reactions have been reported even in cases where previous use of parenteral iron preparations was without complications. Hypersensitivity reactions have been reported, which may progress to Kounis syndrome (acute allergic spasm of the coronary arteries, which can cause myocardial infarction). Venofer® should be used only in cases of extreme necessity and under strict precautions in patients who have experienced hypersensitivity reactions to iron dextran.
Treatment with Venofer® should be prescribed by the attending physician only after precise determination of the indication.
Venofer® should only be administered when medical personnel trained in the assessment and treatment of anaphylactic reactions are available for immediate response and in a facility equipped with resuscitation facilities. Before each administration of Venofer®, the patient should be specifically questioned about any previous adverse reactions associated with intravenous iron preparations.
Typical symptoms of acute hypersensitivity reactions are: decreased blood pressure, tachycardia (and even anaphylactic shock), respiratory symptoms (including bronchospasm, laryngeal edema and pharyngeal edema), gastrointestinal symptoms (including abdominal cramps, vomiting) or skin symptoms (including urticaria, erythema, pruritus).
Each patient should be observed for any symptoms of adverse reactions during and for at least 30 minutes after each intravenous administration of iron preparations. If any allergic reactions or signs of intolerance occur during administration of the drug, treatment should be discontinued immediately.
For emergency treatment of acute anaphylactic/anaphylactoid reactions, adrenaline, e.g. 0.3 mg intramuscularly, is recommended first, followed by antihistamines and/or corticosteroids (which have a later onset of action).
High risk of hypersensitivity reactions in patients with existing allergies, including drug intolerance, a history of severe bronchial asthma, eczema and other forms of atopy, as well as in patients with immunological and inflammatory diseases (such as systemic lupus erythematosus, rheumatoid arthritis).
Parenteral administration of iron preparations to patients with hepatic dysfunction should only be considered after careful risk/benefit analysis. Parenteral administration of iron preparations should be avoided in patients with hepatic dysfunction, where iron overload may be a precipitating factor. Careful monitoring of body iron levels is recommended to avoid iron overload.
In patients with elevated ferritin levels, parenteral iron administration may adversely affect the course of bacterial or viral infection.
Parenteral iron preparations should be used with caution in patients with acute or chronic infection.
In patients with chronic infection, a benefit/risk assessment should be performed. It is recommended that Venofer® be discontinued in patients with bacteremia.
Paravenous leakage should be avoided, as Venofer® injection site may cause pain, inflammation, tissue necrosis and potentially long-lasting brown discoloration of the skin. In case of paravenous leakage, the drug should be discontinued immediately. To date, no tissue necrosis has been observed in clinical studies with Venofer®.
A decrease in blood pressure is commonly observed with the use of intravenous iron preparations. Therefore, the drug should be used with caution.
Special caution should be exercised when using the drug Venofer® in patients with liver failure, decompensated cirrhosis of the liver, epidemic hepatitis, Osler-Randu-Weber disease, infectious kidney diseases in the acute phase, and uncontrolled hyperparathyroidism.
Venofer® contains up to 7 mg of sodium per 1 ml, equivalent to 0.4% of the WHO recommended maximum daily intake of sodium for an adult of 2 g.
Use during pregnancy or breastfeeding
There is insufficient data on the use of iron sucrose complex in pregnant women in the first trimester of pregnancy. Data on the use of the drug Venofer® in pregnant women in the second and third trimesters of pregnancy (303 reports of pregnancy outcomes) showed no adverse effects on the health of the mother and newborn child.
It is not yet known whether the iron (III) hydroxide sucrose complex of the drug Venofer® crosses the placenta. Iron bound to transferrin crosses the placental barrier. Iron bound to lactoferrin passes into breast milk.
The drug Venofer® is contraindicated for use in the first trimester of pregnancy (see the section "Contraindications"). The drug may be used in the second and third trimesters of pregnancy only strictly according to indications.
The risk/benefit ratio should be assessed before using the drug during pregnancy, as hypersensitivity reactions may carry a certain risk for the mother and child (see section "Special instructions"). Body weight before pregnancy should be taken into account to calculate the required amount of iron to avoid overdose.
Data on iron excretion in human breast milk after intravenous administration of iron sucrose are limited. In a clinical study, 10 healthy women with iron deficiency who were breastfeeding received 100 mg of iron in the form of a sucrose complex. After four days of treatment, the iron content in breast milk was not increased and did not differ from that in the control group (n = 5). An effect of iron in the mother's breast milk on the newborn/infant cannot be excluded, therefore the risk/benefit ratio of the drug should be assessed.
Ability to influence reaction speed when driving vehicles or other mechanisms
There are no relevant studies. The effect on the reaction rate when driving or using other mechanisms is unlikely. However, in the event of adverse reactions such as dizziness, confusion or fainting, after using the drug, you should refrain from driving or using other mechanisms until the symptoms disappear.
Method of administration and doses
Venofer® is administered only intravenously slowly.
The product is not intended for subcutaneous or intramuscular administration.
Venofer® should only be used when the indications are based on appropriate studies. Appropriate laboratory tests include determination of hemoglobin, serum ferritin, and transferrin saturation.
Patients should be observed for signs and symptoms of hypersensitivity reactions during and after administration of Venofer®. Appropriate emergency treatment should be provided (see section 4.4).
The total cumulative dose of the drug should be calculated for each patient individually and not exceeded. The dose is calculated taking into account the patient's body weight and hemoglobin level.
In cases where the total required dose exceeds the maximum permitted single dose of 200 mg (for injection) or 500 mg (for infusion), it is recommended to administer the drug in parts.
Dose calculation.
The total cumulative dose of Venofer®, equivalent to the total iron deficiency (mg), is determined taking into account the hemoglobin (Hb) level and body weight. The dose of the drug is calculated individually according to the total iron deficiency in the patient's body according to the Ganzoni formula:
Total iron deficiency (mg) = body weight (kg) ´ (normal Hb level (g/dl) ‒ patient's Hb level (g/dl)) ´ 2.4* + stored iron (mg).
For patients with a body weight of less than 35 kg: normal Hb level is 13 g/dl, the amount of deposited iron is 15 mg/kg of body weight.
For patients with a body weight of more than 35 kg: normal Hb level is 15 g/dl, the amount of deposited iron is 500 mg.
* Coefficient 2.4 = 0.0034 ´ 0.07 ´ 1000 (iron content in Hb = 0.34%, blood volume = 7% of body weight, coefficient 1000 = conversion of "g" to "mg") × 10.
The total volume of Venofer® that must be entered (in ml) | = Total iron deficiency (mg) 20 mg iron/ml |
Table 1
Total dose of Venofer® (ml) to be administered, taking into account the patient's body weight and Hb level
Body weight (kg) | Total dose of Venofer® (20 mg iron/ml) for administration |
| Hb 6.0 g/dl | Hb 7.5 g/dl | Hb 9.0 g/dl | Hb 10.5 g/dl |
| 10 | 15.0 ml | 15.0 ml | 12.5 ml | 10.0 ml |
| 15 | 25.0 ml | 22.5 ml | 17.5 ml | 15.0 ml |
| 20 | 32.5 ml | 27.5 ml | 25.0 ml | 20.0 ml |
| 25 | 40.0 ml | 35.0 ml | 30.0 ml | 27.5 ml |
| 30 | 47.5 ml | 42.5 ml | 37.5 ml | 32.5 ml |
| 35 | 62.5 ml | 57.5 ml | 50.0 ml | 45.0 ml |
| 40 | 67.5 ml | 60.0 ml | 55.0 ml | 47.5 ml |
| 45 | 75.0 ml | 65.0 ml | 57.5 ml | 50.0 ml |
| 50 | 80.0 ml | 70.0 ml | 60.0 ml | 52.5 ml |
| 55 | 85.0 ml | 75.0 ml | 65.0 ml | 55.0 ml |
| 60 | 90.0 ml | 80.0 ml | 67.5 ml | 57.5 ml |
| 65 | 95.0 ml | 82.5 ml | 72.5 ml | 60.0 ml |
| 70 | 100.0 ml | 87.5 ml | 75.0 ml | 62.5 ml |
| 75 | 105.0 ml | 92.5 ml | 80.0 ml | 65.0 ml |
| 80 | 112.5 ml | 97.5 ml | 82.5 ml | 67.5 ml |
| 85 | 117.5 ml | 102.5 ml | 85.0 ml | 70.0 ml |
| 90 | 122.5 ml | 107.5 ml | 90.0 ml | 72.5 ml |
Table 2
Required Hb level depending on patient's body weight
| Body weight | Required Hb |
| < 35 kg | 13 g/dl |
| ≥ 35 kg | 15 g/dl |
If the required total dose exceeds the maximum permissible single dose of 200 mg (injection) or 500 mg (infusion), then the administration should be carried out in several doses.
Standard dosage.
Adults: 5-10 ml of Venofer® (100-200 mg iron) 1-3 times a week. For time of administration and dilution factor, see below.
Children from 3 years: there are only limited data on the use of the drug in children. In case of clinical need, it is recommended to administer no more than 0.15 ml of the drug Venofer® (3 mg of elemental iron) per 1 kg of body weight no more than 3 times a week. For the time of administration and dilution factor, see below.
Maximum tolerated single or weekly dose.
Adults.
For injections, the maximum tolerated dose, administered no more than 3 times a week, is 10 ml of Venofer® (200 mg of iron), the duration of administration is at least 10 minutes.
For infusion, the maximum tolerated dose, administered no more than once a week, for patients with a body weight of more than 70 kg is 500 mg of iron (25 ml of Venofer®), the duration of administration is at least 3.5 hours;
for patients with a body weight of 70 kg and below - 7 mg of iron per 1 kg of body weight, duration of administration - at least 3.5 hours.
The infusion time should be strictly adhered to, even if the patient does not receive the maximum tolerated single dose.
If hematological improvement is not achieved (an increase in hemoglobin level of approximately 0.1 g/dL of blood per day or approximately 1.0–2.0 g/dL 1–2 weeks after the start of treatment), the patient's initial diagnosis should be reviewed and persistent blood loss should be excluded.
Application.
Venofer® can only be administered intravenously, by drip infusion, slow injection or directly into the venous section of the dialysis machine.
Venofer® should not be administered intramuscularly or subcutaneously.
If the required total dose exceeds the maximum permissible single dose, the total dose should be divided into several doses.
Intravenous drip.
Immediately before administration, Venofer® should be diluted only in sterile 0.9% sodium chloride solution according to the scheme specified in Table 3.
Table 3
Dosage of the drug Venofer® (mg iron) | Dosage of the drug Venofer® (ml) | Maximum volume of sterile 0.9% sodium chloride solution for dilution | Minimum input time |
| 50 mg | 2.5 ml | 50 ml | 8 minutes |
| 100 mg | 5 ml | 100 ml | 15 minutes |
| 200 mg | 10 ml | 200 ml | 30 minutes |
| 300 mg | 15 ml | 300 ml | 1.5 hours |
| 400 mg | 20 ml | 400 ml | 2.5 hours |
| 500 mg | 25 ml | 500 ml | 3.5 hours |
Intravenous administration.
Venofer® can be administered intravenously by slow infusion at a rate of 1 ml of undiluted solution per minute, but the maximum volume of the solution should not exceed 10 ml of Venofer® (200 mg of iron) per injection.
After injection, the patient's arm should be extended. Paravenous leaks should be avoided, as Venofer® entering the injection site may cause pain, inflammation, tissue necrosis, and brown discoloration of the skin (see section "Special instructions").
Injection into the venous section of the dialysis system.
Venofer® can be administered directly into the venous section of the dialysis system during a hemodialysis session, strictly following the rules for intravenous injection.
Children. Due to insufficient data, the use of Venofer® is not recommended for the treatment of children under 3 years of age.
Overdose
Overdose may lead to acute iron overload, which may manifest as hemosiderosis. Overdose should be treated, at the discretion of the physician, with iron binding agents (chelates) or according to standard medical practice.
Side effects
The most common adverse reactions observed during clinical trials of Venofer® are dysgeusia, which occurred with a frequency of 4.5 cases per 100 people. Other common adverse reactions include nausea, hypotension, hypertension, and infusion site pain, which occurred with a frequency of 1 to 2 cases per 100 people.
The following adverse reactions were reported in 4064 participants in clinical trials in temporal association with the administration of Venofer®, on the basis of which a causal relationship can be assumed. Adverse reactions are classified according to the following frequency categories: common (from ˂ 1/10 to ≥ 1/100), uncommon (from < 1/100 to ≥ 1/1000) and rare (from < 1/1000 to ≥ 1/10,000).
From the immune system.
Uncommon: hypersensitivity reactions.
From the side of metabolism and nutrition.
Uncommon: increased serum ferritin levels.
From the nervous system.
Common: dysgeusia, dizziness.
Uncommon: headache, paraesthesia, hypoesthesia.
Rare: loss of consciousness, drowsiness.
From the heart.
Uncommon: hypotension and collapse, tachycardia.
Rare: rapid heartbeat.
From the vascular system.
Common: hypotension, hypertension.
Uncommon: hot flushes, phlebitis.
On the part of the respiratory system, chest organs and mediastinum.
Uncommon: dyspnoea.
On the part of the kidneys and urinary system.
Uncommon: chromaturia.
From the digestive tract.
Common: nausea.
Uncommon: vomiting, abdominal pain, diarrhoea, constipation.
On the part of the liver and gallbladder.
Uncommon: increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyltransferase.
Rare: increased blood lactate dehydrogenase levels.
On the skin and subcutaneous tissue.
Uncommon: itching, rash.
On the part of the musculoskeletal system and connective tissue.
Uncommon: muscle spasms, myalgia, arthralgia, pain in extremity, back pain.
General disorders and administration site reactions.
Common: pain at the injection/infusion site1.
Uncommon: chest pain, chills, asthenia, fatigue, peripheral oedema, pain.
Rare: increased sweating, fever.
1 The most commonly observed adverse reactions are: pain, extravasation, irritation, injection site reactions, skin discoloration, hematoma, and pruritus at the injection/infusion site.
The following adverse reactions have been reported in voluntarily submitted post-marketing reports:
frequency unknown: clouding of consciousness, bradycardia, thrombophlebitis.
Reporting of suspected adverse reactions
Reporting adverse reactions after the registration of a medicinal product is important. This allows monitoring of the benefit/risk ratio of the medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the automated pharmacovigilance information system at the following link: https://aisf.dec.gov.ua.
Expiration date
3 years.
Do not use the medicine after the expiry date stated on the packaging.
After opening the ampoule, from a microbiological point of view, the drug should be used immediately.
After dilution with saline, the physical and chemical stability at room temperature is 12 hours.
Storage conditions
Store in the original packaging at a temperature not exceeding 25 °C.
Do not freeze. Keep out of reach of children!
Incompatibility
Venofer® can only be mixed with sterile 0.9% sodium chloride solution under aseptic conditions. 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 in a cardboard box.
Vacation category
According to the recipe.
Producer
Vifor (International) Inc., Switzerland.
Location of the manufacturer and its address of business. Rechenstrasse 37, 9014 St. Gallen, Switzerland.
