Ferviven
UkraineTable of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT FERVIVEN (FERVIVEN)
Composition:
Active substance: iron (in the form of iron (III) hydroxide sucrose complex);
1 ampoule (5 ml) of solution contains iron (in the form of iron (III) hydroxide sucrose complex) 100 mg;
Excipients: sodium hydroxide, water for injections.
Pharmaceutical form. Solution for intravenous injection.
Main physicochemical properties: dark red or brown solution.
Pharmacotherapeutic group.
Antianaemic agents. Iron preparations. ATC code B03AC.
Pharmacological Properties
Pharmacodynamics
The active component of the medicinal product, 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 predominantly taken up 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 stored in the liver as ferritin.
Pharmacokinetics
Distribution
Ferrokinetics of iron sucrose labeled with 52Fe and 59Fe were evaluated in 6 patients with anemia and chronic kidney disease. Within 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 a single intravenous dose of the medicinal product FERVIVEN containing 100 mg of iron administered to healthy volunteers, the maximum total serum iron concentration was observed 10 minutes after administration, reaching a mean value of 538 mmol/L. The volume of distribution in the central compartment corresponds to the plasma volume (approximately 3 liters).
Metabolism
After intravenous administration, 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 within 4 weeks after 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 excretion 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, the total plasma iron concentration decreases to the baseline level (pre-dose), and renal excretion of sucrose amounts to approximately 75% of the administered dose.
Special Patient Populations
It is currently unknown whether renal or hepatic impairment affects the pharmacological properties of the iron (III) hydroxide sucrose complex (see section "Special Warnings and Precautions for Use").
Clinical characteristics.
Indications.
The medicinal product is indicated for patients with iron deficiency when oral iron therapy is ineffective or not possible, for example:
- in case of intolerance to oral iron preparations;
- in the presence of inflammatory gastrointestinal diseases (such as ulcerative colitis), where oral iron preparations may provoke disease exacerbation;
- in iron-deficient states resistant to therapy, when control of these conditions with oral iron preparations is insufficient.
The medicinal product should be used only when indications are based on appropriate laboratory tests. Appropriate laboratory tests include assessment of levels of hemoglobin, serum ferritin, and transferrin saturation.
Contraindications.
- Hypersensitivity to the active substance and/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 (hemochromatosis, hemosiderosis) or inherited disorders of iron metabolism (sideroblastic anemia, thalassemia, cutaneous porphyria).
- First trimester of pregnancy.
Interaction with other medicinal products and other forms of interaction.
The medicinal product is indicated only when oral iron therapy cannot be used or has insufficient efficacy. In the latter case, concomitant use of this medicinal product with oral iron-containing preparations is not recommended, as absorption of orally administered iron is reduced.
Special precautions for use.
Risk of hypersensitivity reactions
Intravenous administration of iron-containing preparations may lead to immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions), which can be fatal. Such reactions have been reported even when previous parenteral administration of iron preparations was uneventful. Hypersensitivity reactions have been reported to progress to Kounis syndrome (acute allergic coronary artery spasm, which may cause myocardial infarction) (see section "Adverse reactions"). The medicinal product may be administered to patients who have experienced hypersensitivity reactions to iron dextran only if absolutely necessary and with strict precautionary measures.
The medicinal product should be prescribed only by a physician after precise determination of the indication.
The medicinal product may be administered only if medical personnel experienced in the assessment and management of anaphylactic reactions are available and fully equipped with resuscitation equipment. Before each administration, patients should be questioned about any previous adverse reactions associated with intravenous iron preparations.
Typical symptoms of acute hypersensitivity reactions include: decreased blood pressure, tachycardia (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).
Each patient should be monitored for adverse reactions during and for at least 30 minutes after each intravenous administration of the medicinal product. 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, epinephrine (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 a history of allergies, including drug intolerance, severe bronchial asthma, eczema, or other forms of atopy, as well as patients with immunological and inflammatory disorders (such as systemic lupus erythematosus, rheumatoid arthritis), are at higher risk of hypersensitivity reactions.
Use in patients with hepatic impairment
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.
Use in patients with acute or chronic infection
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. For patients with chronic infections, a benefit-risk assessment should be performed. It is recommended to discontinue the medicinal product in patients with bacteremia.
Risk of injection site reactions
Extravasation should be avoided, as leakage of the medicinal product into perivenous tissues may cause pain, inflammation, tissue necrosis, and brown discoloration of the skin. In case of perivenous leakage, administration should be stopped immediately. To date, no tissue necrosis has been reported in clinical trials using FERIVVEN.
Risk of arterial hypotension
Decreased blood pressure is commonly observed with intravenous iron preparations. Therefore, the medicinal product should be used with caution.
The medicinal product should be used with particular caution in patients with hepatic insufficiency, decompensated liver cirrhosis, epidemic hepatitis, Osler-Weber-Rendu disease, acute-phase infectious kidney diseases, and uncontrolled hyperparathyroidism.
Precautions regarding excipients
The medicinal product contains less than 1 mmol (23 mg)/dose of sodium, i.e., it is practically sodium-free.
Use during pregnancy or breastfeeding
Pregnancy
There is insufficient data on the use of iron sucrose complex in pregnant women during the first trimester of pregnancy. Data from use during the second and third trimesters (303 pregnancy outcomes) 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 is excreted into breast milk.
Studies on the effect on iron levels in newborns have not been conducted.
The medicinal product is contraindicated during the first trimester of pregnancy (see section "Contraindications"). Use during the second and third trimesters is permitted only strictly according to medical indications.
A risk-benefit assessment should be performed before administering the medicinal product during pregnancy, as hypersensitivity reactions may pose risks to both mother and fetus (see section "Special precautions for use"). Pre-pregnancy body weight should be considered when calculating the required iron dose to avoid overdose.
Breastfeeding period
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). Since the potential impact of iron passed through breast milk on the newborn/infant cannot be excluded, the medicinal product should be used during breastfeeding only after careful risk-benefit assessment.
Ability to influence the speed of reaction 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.
Dosage and Administration
The medicinal product is intended for slow intravenous administration only. The product is not intended for subcutaneous or intramuscular administration.
The medicinal product should be administered only when the indication is based on appropriate diagnostic tests. Appropriate laboratory tests include assessment of parameters such as hemoglobin, serum ferritin, and transferrin saturation.
Patients should be monitored during and after administration of the medicinal product for signs and symptoms of hypersensitivity reactions. Appropriate emergency treatment must be readily available (see section "Special Warnings and Precautions for Use").
Dosage
The total cumulative dose of the medicinal product should be individually calculated for each patient and must not be exceeded. The dose should be calculated 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 the medicinal product, equivalent to the total iron deficit (mg), should be determined based on the patient's hemoglobin (Hb) level and body weight. The dose should be individually calculated according to the patient's total body 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 is 130 g/L, stored iron is 15 mg per kg of body weight.
For patients with body weight 35 kg or more: normal Hb level is 150 g/L, stored iron is 500 mg.
* The factor 0.24 = 0.0034 × 0.07 × 1000 (iron content in hemoglobin = 0.34%, blood volume = 7% of body weight, factor 1000 = conversion from grams to milligrams).
| Total volume of the medicinal product to be administered (ml) |
= Total iron deficit (mg) 20 mg iron/ml |
Table 1
Total cumulative dose of the medicinal product (ml) to be administered, based on the patient's body weight and Hb level
| Body weight |
Total dose of medicinal product (20 mg iron/ml) to be administered |
|||
| (kg) |
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 divided into several doses.
Standard dosing
Adults: administer the medicinal product at a dose of 5–10 mL (100–200 mg iron) 1–3 times per week. See below for administration duration and dilution factor.
Children aged 3 years and older: data on the use of iron sucrose in children are limited. If clinically necessary, it is recommended to administer the medicinal product at a dose not exceeding 0.15 mL (3 mg elemental iron) per 1 kg body weight, 1–3 times per week. See below for administration duration and dilution factor.
Maximum tolerated single or weekly dose of the medicinal product
Adults: for injection, the maximum tolerated dose administered no more than 3 times per week is 10 mL (200 mg iron), with 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) 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 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 (an increase in hemoglobin level of approximately 1 g/L blood per day or approximately 1.0–2.0 g/dL within 1–2 weeks after initiation of treatment), the patient’s initial diagnosis should be re-evaluated and the presence of persistent blood loss should be ruled out.
Method of administration
The medicinal product must be administered only intravenously, either by intravenous infusion, slow injection, or directly into the venous line of the hemodialysis apparatus.
It 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 multiple administrations.
The injectable solution should be used immediately after opening the ampoule.
Intravenous infusion
Immediately before administration, the medicinal product must be diluted only in sterile 0.9% sodium chloride solution according to the scheme specified in Table 3.
To maintain stability, the medicinal product should not be diluted to lower concentrations.
Table 3
| Dose of medicinal product (mg of iron) |
Dose of medicinal product (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
The medicinal product can 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 (200 mg of iron) per single injection.
After injection, the patient's arm should be extended. Paravenous leakage must be avoided, as extravasation of the medicinal product 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
The medicinal product can be administered directly into the venous limb of the dialysis system during a hemodialysis session, strictly following the guidelines for intravenous injection.
Children.
Due to insufficient data, the use of the medicinal product is not recommended in 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-binding agents (chelators), or according to standard medical practice.
Side effects
The most common side effect observed during clinical trials of iron sucrose is dysgeusia, occurring at a rate of 4.5 events per 100 individuals. Other common side effects include nausea, arterial hypotension, arterial hypertension, and infusion site pain, occurring at a frequency of 1 to 2 events per 100 individuals.
Among the most significant serious side effects associated with the use of iron sucrose are hypersensitivity reactions, which occurred at a rate of 0.25 events per 100 individuals during clinical studies.
Immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions) are rare. Overall, anaphylactoid/anaphylactic reactions are very serious adverse reactions that may lead to fatal outcomes (see section "Special precautions"). Symptoms include circulatory collapse, arterial hypotension, tachycardia, respiratory symptoms (bronchospasm, laryngeal edema, pharyngeal edema), gastrointestinal symptoms (abdominal pain, vomiting), and skin symptoms (urticaria, erythema, pruritus).
The adverse reactions listed below were reported in 4064 participants of clinical trials in temporal association with administration of the medicinal product, suggesting a possible causal relationship.
Adverse reactions are classified by frequency of occurrence as follows: common (≥ 1/100 to < 1/10), rare (< 1/100 to ≥ 1/1000), very rare (< 1/1000 to ≥ 1/10000), and not known (frequency cannot be estimated from the available data, as these events were reported exclusively during post-marketing surveillance rather than clinical trials).
Immune system disorders:
Uncommon: hypersensitivity reactions.
Metabolism and nutrition disorders:
Uncommon: increased serum ferritin levels.
Nervous system disorders:
Common: dysgeusia, dizziness;
Uncommon: headache, paresthesia, hypoaesthesia;
Rare: loss of consciousness, somnolence.
Cardiac disorders:
Uncommon: arterial hypotension and collapse, tachycardia;
Rare: palpitations;
Not known: Koilonychia syndrome.
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 levels, increased aspartate aminotransferase levels, increased gamma-glutamyl transferase levels;
Rare: increased blood lactate dehydrogenase levels.
Skin and subcutaneous tissue disorders:
Uncommon: pruritus, rash.
Musculoskeletal and connective tissue disorders:
Uncommon: muscle spasms, myalgia, arthralgia, limb pain, back pain;
Not known: hypophosphatemic osteomalacia.
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 Most frequently observed adverse reactions: 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: confusion, 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, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.
Shelf life
3 years.
Storage conditions
Store protected from light at temperatures not exceeding 25 °C, in the original packaging and out of reach of children. Do not freeze.
Incompatibilities
The medicinal product may be mixed only 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 a glass ampoule; 5 ampoules in a blister pack; 1 blister pack in a cardboard box.
Prescription status
Prescription only.
Manufacturer
WORLD MEDICINE ILAC SAN. VE TIC. A.S.
Manufacturer's address and place of business
COSB G.O.Pasa Mah. 6. Cad. No:30, Cerkezkoy/Tekirdag, Turkey.