Venofer
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT VENOFER® (VENOFER®)
Composition:
Active substance: 1 ml of solution contains 20 mg of iron (as iron (III) hydroxide sucrose complex — 540 mg);
Excipients: sodium hydroxide, water for injections.
Pharmaceutical form. Solution for intravenous injection.
Main physicochemical properties: brown aqueous solution.
Pharmacotherapeutic group. Antianemic agents. Iron preparations. ATC code B03AC.
Pharmacological properties.
Pharmacodynamics.
The active component of the medicinal product Venofer® 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 allow controlled delivery of iron 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 predominantly taken up by the reticuloendothelial system of the liver, spleen, and bone marrow. In the second stage, iron is used for the synthesis of hemoglobin, myoglobin, and other iron-containing enzymes, or is stored in the liver as 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 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 plasma volume (approximately 3 liters).
Metabolism. After injection, sucrose is almost completely degraded, and the polynuclear iron core is predominantly taken up by the reticuloendothelial system of the liver, spleen, and bone marrow.
Iron uptake by erythrocytes during 4 weeks after administration ranges from 68% to 97%.
Excretion. The average molecular mass of the iron sucrose complex is approximately 43 kDa, which is sufficiently large to prevent renal excretion. Renal excretion of iron within the first 4 hours after injection of 100 mg of iron is less than 5% of the administered dose. Within 24 hours, the 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 insufficiency affects the pharmacological properties of iron (III) hydroxide sucrose complex (see section "Special precautions for use").
Clinical characteristics.
Indications.
The use of the medicinal product is indicated for patients with iron deficiency when oral iron-containing preparations are ineffective or cannot be administered, for example:
- in case of intolerance to oral iron preparations;
- in the presence of inflammatory gastrointestinal diseases (such as ulcerative colitis), when oral iron preparations may provoke disease exacerbation;
- in iron-deficient conditions resistant to therapy, when control of these conditions with oral iron preparations is insufficient.
Venofer® should be used only when the indication is based on appropriate investigations. Appropriate laboratory tests include determination of levels of such parameters as hemoglobin, serum ferritin, and transferrin saturation.
Contraindications.
- 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, disorders of erythropoiesis, bone marrow hypoplasia, anemia caused by lead poisoning);
- iron overload (hemochromatosis, hemosiderosis) or hereditary disorders of iron absorption (sideroblastic anemia, thalassemia, cutaneous porphyria);
- first trimester of pregnancy.
Interaction with other medicinal products and other types of interactions.
Venofer® is indicated only when oral iron preparations cannot be used or when such therapy is insufficiently effective. In the latter case, Venofer® should not be used concomitantly with oral iron-containing products, as absorption of orally administered iron is reduced.
Special precautions for use.
Intravenous administration of parenteral iron preparations 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. Cases of hypersensitivity reactions have been reported that could progress to Kounis syndrome (acute allergic spasm of the coronary arteries, which may cause myocardial infarction). Venofer® may be administered to patients who previously experienced hypersensitivity reactions to iron dextran only if absolutely necessary and under strict precautionary measures.
Treatment with Venofer® should be initiated only by a physician after precise determination of the indication.
Venofer® may be administered only if medical personnel trained in the assessment and management of anaphylactic reactions are available and prepared to act immediately, and if the facility is properly equipped with resuscitation equipment. Prior to each administration of Venofer®, the patient should be specifically questioned about prior adverse reactions associated with intravenous iron preparations.
Typical symptoms of acute hypersensitivity reactions include: 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 monitored for any signs of adverse reactions during and for at least 30 minutes after each intravenous administration of iron-containing preparations. If any allergic reactions or signs of intolerance occur during administration, treatment should be discontinued immediately.
For emergency treatment of acute anaphylactic/anaphylactoid reactions, epinephrine is recommended first (e.g., 0.3 mg intramuscularly), 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 disorders (such as systemic lupus erythematosus, rheumatoid arthritis) are at high risk of hypersensitivity reactions.
Parenteral administration of iron preparations to patients with liver dysfunction should only be considered after careful risk/benefit assessment. Parenteral iron administration 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.
In patients with elevated ferritin levels, parenteral iron administration may negatively affect the course of bacterial or viral infections.
Parenteral iron-containing preparations 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 Venofer® in patients with bacteremia.
Paravenous leakage should be avoided, as extravasation of Venofer® at the injection site may cause pain, inflammation, tissue necrosis, and potentially long-lasting brown skin discoloration. In case of paravenous leakage, administration should be stopped immediately. To date, tissue necrosis has not been observed in clinical studies with Venofer®.
Hypotension is commonly observed with intravenous iron preparations. Therefore, caution should be exercised when administering the drug.
Special caution is required when administering Venofer® to patients with hepatic insufficiency, decompensated liver cirrhosis, epidemic hepatitis, Osler-Rendu-Weber disease, acute-phase infectious kidney diseases, and uncontrolled hyperparathyroidism.
Venofer® contains up to 7 mg of sodium per 1 mL, equivalent to 0.4% of the WHO recommended maximum daily sodium intake of 2 g for adults.
Use during pregnancy or breastfeeding.
There is insufficient data on the use of iron sucrose complex in pregnant women during the first trimester of pregnancy. Data on the use of Venofer® in pregnant women during the second and third trimesters (303 pregnancy outcomes reported) showed no adverse effects on maternal or neonatal health.
It is currently unknown whether the iron (III) hydroxide sucrose complex in Venofer® crosses the placenta. Iron bound to transferrin crosses the placental barrier. Iron bound to lactoferrin is excreted into breast milk.
Studies on the impact on iron levels in newborns have not been conducted.
Venofer® is contraindicated during the first trimester of pregnancy (see section "Contraindications"). Use during the second and third trimesters of pregnancy is possible only strictly according to indications.
A risk/benefit assessment should be performed before using the drug during pregnancy, as hypersensitivity reactions may pose a risk 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 following intravenous administration of iron sucrose are limited. In a clinical study, 10 healthy breastfeeding women with iron deficiency received 100 mg of iron as 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 in breast milk on the newborn/infant cannot be ruled out; therefore, a risk/benefit assessment should be performed before administering the drug.
Ability to affect reaction speed when driving or operating machinery.
No specific studies have been conducted. The effect on reaction speed when driving or operating machinery is unlikely. However, if adverse reactions such as dizziness, confusion, or pre-syncope occur after administration, patients should refrain from driving or operating machinery until symptoms resolve.
Method of Administration and Dosage
Venofer® is administered only by slow intravenous injection.
The product is not intended for subcutaneous or intramuscular administration.
Venofer® should be used only when the indication is based on appropriate laboratory tests. Relevant laboratory parameters include measurements of hemoglobin, serum ferritin, and transferrin saturation.
Patients should be monitored during and after administration of Venofer® for signs and symptoms of hypersensitivity reactions. Appropriate emergency treatment must be available (see section "Special Warnings and Precautions for Use").
The total cumulative dose of the drug 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 recommended single dose of 200 mg (for injection) or 500 mg (for infusion), the administration of the drug should be divided into fractions.
Dose Calculation
The total cumulative dose of Venofer®, 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/dL) − patient's Hb level (g/dL)) × 2.4* + stored iron (mg).
For patients with body weight less than 35 kg: normal Hb level is 13 g/dL; stored iron is 15 mg/kg body weight.
For patients with body weight greater than or equal to 35 kg: normal Hb level is 15 g/dL; stored iron is 500 mg.
* The factor 2.4 = 0.0034 × 0.07 × 1000 (iron content in Hb = 0.34%, blood volume = 7% of body weight, factor 1000 = conversion from grams to milligrams) × 10.
| Total volume of Venofer® to be administered (in ml)
|
= Total iron deficit (mg) 20 mg iron/ml |
Table 1
Total dose of the medicinal product Venofer® (ml) to be administered, based on patient's body weight and Hb level
| Body weight (kg) |
Total dose of medicinal product Venofer® (20 mg iron/ml) to be administered |
|||
| 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 |
To convert Hb (mM) to Hb (g/dL), multiply the first value 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 performed in several divided doses.
Standard dosing.
Adults: 5–10 mL of Venofer® medicinal product (100–200 mg iron) 1–3 times per week. See below for administration time and dilution factor.
Children from 3 years of age: there are only limited data on the use of the medicinal product in children. If clinically necessary, a dose of no more than 0.15 mL of Venofer® medicinal product (3 mg elemental iron) per 1 kg body weight is recommended, administered no more than 3 times per week. See below for administration time and dilution factor.
Maximum tolerated single or weekly dose.
Adults.
For injection, the maximum tolerated dose administered no more than 3 times per week is 10 mL of Venofer® medicinal product (200 mg iron), with an administration duration of at least 10 minutes.
For infusion, the maximum tolerated dose administered no more than once per week is 500 mg iron (25 mL of Venofer® medicinal product) for patients weighing more than 70 kg, with an administration duration of at least 3.5 hours;
for patients weighing 70 kg or less, the dose is 7 mg iron per 1 kg body weight, with an administration duration of at least 3.5 hours.
The infusion time must be strictly observed, even if the patient does not receive the maximum tolerated single dose.
If hematological parameters do not improve (an increase in hemoglobin level of approximately 0.1 g/dL of 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.
Venofer® may only be administered intravenously, either by intravenous infusion, slow injection, or directly into the venous line of a dialysis apparatus.
Venofer® 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, Venofer® medicinal product must be diluted only in sterile 0.9% sodium chloride solution according to the scheme specified in Table 3.
Table 3
| Dose of the medicinal product Venofer® (mg of iron) |
Dose of the medicinal product Venofer® (ml) |
Maximum volume of sterile 0.9% sodium chloride solution for dilution |
Minimum infusion 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® may be administered intravenously by slow infusion at a rate of 1 ml of undiluted solution per minute; however, the maximum volume of solution should not exceed 10 ml of Venofer® (200 mg of iron) per single injection.
After injection, the patient’s arm should be extended. Paravenous leakage should be avoided, as extravasation of Venofer® at the injection site may cause pain, inflammation, tissue necrosis, and brown discoloration of the skin (see section "Special precautions").
Injection into the venous limb of the dialysis system.
Venofer® may be administered directly into the venous limb 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 physician’s discretion, with iron-chelating agents or according to standard medical practice.
Adverse Reactions
The most frequently observed adverse reactions during clinical trials of the medicinal product Venofer® were dysgeusia, occurring at a frequency of 4.5 cases per 100 patients. Other common adverse reactions included nausea, arterial hypotension, arterial hypertension, and infusion site pain, occurring at frequencies of 1 to 2 cases per 100 patients.
Among the most significant serious adverse reactions associated with the use of Venofer®, hypersensitivity reactions occurred at a frequency of 0.25 cases per 100 patients during clinical studies. 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.).
The adverse reactions listed below were observed in 4064 participants of clinical trials in temporal association with administration of Venofer®, suggesting a possible causal relationship. Adverse effects are classified by frequency of occurrence into the following categories: common (from < 1/10 to ≥ 1/100), uncommon (from < 1/100 to ≥ 1/1000), and rare (from < 1/10,000 to ≥ 1/10,000).
Immune system disorders
Uncommon: hypersensitivity reactions.
Metabolism and nutrition disorders
Uncommon: increased serum ferritin levels.
Nervous system disorders
Common: dysgeusia, dizziness.
Uncommon: headache, paresthesia, hypoesthesia.
Rare: loss of consciousness, somnolence.
Cardiac disorders
Uncommon: arterial hypotension and collapse, tachycardia.
Rare: palpitations.
Vascular disorders
Common: arterial hypotension, arterial hypertension.
Uncommon: flushing, phlebitis.
Respiratory, thoracic and mediastinal disorders
Uncommon: dyspnea.
Renal and urinary disorders
Uncommon: chromaturia.
Gastrointestinal disorders
Common: nausea.
Uncommon: vomiting, abdominal pain, diarrhea, constipation.
Hepatobiliary disorders
Uncommon: increased alanine aminotransferase, increased aspartate aminotransferase, increased gamma-glutamyl transferase.
Rare: increased blood lactate dehydrogenase.
Skin and subcutaneous tissue disorders
Uncommon: pruritus, rash.
Musculoskeletal and connective tissue disorders
Uncommon: muscle spasms, myalgia, arthralgia, limb pain, back pain.
General disorders and administration site conditions
Common: pain at injection/infusion site1.
Uncommon: chest pain, chills, asthenia, fatigue, peripheral edema, pain.
Rare: increased sweating, pyrexia.
1 The most commonly observed adverse reactions at the injection/infusion site are pain, extravasation, irritation, reactions at the site of administration, skin discoloration, hematoma, and pruritus at the injection/infusion site.
In spontaneously reported post-marketing surveillance data, the following adverse reactions have been reported:
Frequency not known: altered consciousness, bradycardia, thrombophlebitis.
Reporting suspected adverse reactions
Reporting of suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, are encouraged to report any suspected adverse reactions and lack of efficacy via the automated pharmacovigilance information system at: https://aisf.dec.gov.ua.
Shelf life. 3 years.
Do not use the medicinal product after the expiry date stated on the packaging.
After opening the ampoule — from a microbiological standpoint, the product should be used immediately.
After dilution with physiological saline — physicochemical 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!
Incompatibilities. Venofer® may 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 per cardboard box.
Prescription status. Prescription only.
Manufacturer. Vifor (International) Inc., Switzerland.
Manufacturer's address and place of business. Rechenstrasse 37, 9014 St. Gallen, Switzerland.