Hemapher-c
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT HEMAFER-C (HEMAFER-S)
Composition:
Active substance: iron (III) hydroxide sucrose complex;
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: clear, slightly viscous brown solution.
Pharmacotherapeutic group.
Antianaemic agents. Iron preparations. ATC code B03AC.
Pharmacological Properties.
Pharmacodynamics.
The active component, iron sucrose, consists of polynuclear iron (III) hydroxide cores surrounded externally by a large number of non-covalently bound sucrose molecules. The average molecular weight of the complex is approximately 43 kDa. The polynuclear iron core has a structure similar to that of the ferritin core, 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 phase, iron is utilized for the synthesis of hemoglobin, myoglobin, and other iron-containing enzymes, or stored in the liver as ferritin.
Pharmacokinetics.
Distribution. Ferrokinetics of the sucrose-iron hydroxide complex labeled with 59Fe and 52Fe were evaluated 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 iron uptake occurs in the macrophages of the reticuloendothelial system of the spleen.
After a single intravenous dose of the medicinal product containing 100 mg of iron administered to healthy volunteers, maximum iron concentration was observed 10 minutes after administration, reaching a mean value of 538 mmol/L. The volume of distribution of the central compartment closely corresponded to plasma volume (approximately 3 liters).
Metabolism. After injection, sucrose is almost completely broken down, and the polynuclear iron core is predominantly taken up by the reticuloendothelial system of the liver, spleen, and bone marrow.
Erythrocyte iron uptake ranges from 68% to 97% within 4 weeks after administration.
Excretion. The average molecular weight 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 accounted for less than 5% of the dose. Within 24 hours, serum iron concentration decreased to baseline levels (pre-dose), and renal excretion of sucrose amounted 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 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 cannot be administered, 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-deficiency conditions resistant to therapy, when control of these conditions with oral iron preparations is inadequate.
The medicinal product should be used only when indications are based on appropriate investigations. Appropriate laboratory tests include assessment of parameters such as hemoglobin, serum ferritin, and transferrin saturation.
Contraindications.
- Known hypersensitivity to the active substance or to any of the 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 inherited disorders of iron metabolism (sideroachrestic anemia, thalassemia, cutaneous porphyria);
- first trimester of pregnancy.
Interaction with other medicinal products and other forms of interaction.
The medicinal product is indicated for patients who cannot be treated with oral iron preparations due to intolerance, inefficacy, or presence of gastrointestinal disorders. Like other parenteral iron preparations, this medicinal product should not be administered simultaneously with oral iron-containing agents, as absorption of orally administered iron is reduced. Therefore, treatment with oral iron preparations should not be initiated earlier than 5 days after the last injection of this medicinal product.
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. Hypersensitivity reactions have been reported that may progress to Kounis syndrome (acute allergic spasm of coronary arteries, which may cause myocardial infarction). Hemfer-S 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.
Hemfer-S should be prescribed by a physician only after a clear indication has been established. The drug must be administered only if medical personnel trained in the recognition and management of anaphylactic reactions are available and ready to act immediately, and if the facility is properly equipped with resuscitation equipment. Before each administration, the patient should be specifically questioned about any previous adverse reactions associated with intravenous iron preparations.
Typical symptoms of acute hypersensitivity reactions include: decreased blood pressure, tachycardia (including 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 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 existing allergies, including drug intolerance, severe bronchial asthma, eczema, or other forms of atopy, as well as patients with immunological and inflammatory disorders (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 may 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 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 the drug in patients with bacteremia. Extravasation should be avoided, as leakage of the drug into the injection site may cause pain, inflammation, tissue necrosis, and potentially long-lasting brown discoloration of the skin. In case of extravasation, administration should be stopped immediately. Tissue necrosis has not been observed in clinical studies with the drug so far.
Decreased blood pressure is commonly observed with intravenous iron preparations. Therefore, the drug should be used with caution. Particular caution is required when administering Hemfer-S to patients with hepatic insufficiency, decompensated liver cirrhosis, epidemic hepatitis, Osler-Rendu-Weber disease, acute-phase infectious kidney diseases, or uncontrolled hyperparathyroidism.
Important information on excipients
The medicinal product contains less than 1 mmol of sodium (23 mg) per ampoule, i.e., is essentially "sodium-free".
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 the drug in pregnant women during the second and third trimesters (303 pregnancy outcomes) showed no adverse effects on maternal or neonatal health.
It is currently unknown whether the iron (III) hydroxide sucrose complex of the drug crosses the placenta. Iron bound to transferrin crosses 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 drug 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 may pose a risk to both mother and child (see section "Special precautions for use"). Pre-pregnancy body weight data 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). An effect of iron in breast milk on the newborn/infant cannot be excluded; therefore, a risk/benefit assessment should be performed before administering the drug.
Ability to affect the speed of reaction when driving or operating machinery
Appropriate studies have not 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 drug administration, patients should refrain from driving or operating machinery until symptoms resolve.
Method of administration and dosage.
The medicinal product is administered intravenously only, slowly. It is not intended for subcutaneous or intramuscular administration.
The medicinal product should be used only when indications are based on appropriate investigations. Relevant 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 available (see section "Special 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 the medicinal product, 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 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 converts grams to milligrams) × 10.
| Total volume of the medicinal product to be administered (in ml) |
= Total iron deficit (mg) 20 mg iron/ml |
Table 1
Total dose of the medicinal product (ml) to be administered, based on patient's body weight and Hb level
| Body weight (kg) |
Total dose of medicinal product (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 divided into several doses. Standard dosing
Adults. 5–10 mL of the medicinal product (100–200 mg of iron) 1–3 times per week. See below for administration time and dilution factor.
Children aged 3 years and older. There is only limited data available on the use of the medicinal product in children. If clinically necessary, it is recommended to administer no more than 0.15 mL of the medicinal product (3 mg of elemental iron) per kg of body weight, 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 not more than 3 times per week is 10 mL of the medicinal product (200 mg of iron), with administration duration of no less than 10 minutes. For infusion, the maximum tolerated dose administered not more than once per week is 500 mg of iron (25 mL of the medicinal product) for patients with body weight above 70 kg, with administration duration of at least 3.5 hours; for patients with body weight of 70 kg or less, the dose is 7 mg of iron per kg of body weight, with 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 no improvement in hematological parameters is observed (an increase in hemoglobin level of approximately 0.1 g/dL per day or approximately 1.0–2.0 g/dL within 1–2 weeks after initiation of treatment), the initial diagnosis should be re-evaluated and the presence of persistent blood loss should be ruled out.
Administration
The medicinal product Hemaferr-S may be administered only intravenously, either by intravenous infusion, slow injection, or directly into the venous limb of a dialysis apparatus. The medicinal product 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, the 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 medicinal product (mg iron) |
Dose of medicinal product (ml) |
Maximum volume of sterile 0.9% sodium chloride solution for dilution (ml) |
Minimum administration 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 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 medicinal product (200 mg of iron) per single injection.
After injection, the patient's arm should be kept extended. Paravenous leakage must be avoided, as the presence of the medicinal product at the injection site may cause pain, inflammation, tissue necrosis, and brown discoloration of the skin (see section "Special precautions for use").
Injection into the venous limb of the dialysis system
The medicinal product may 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 for treatment in children under 3 years of age is not recommended.
Overdose
Overdose may lead to acute iron overload, which may manifest as hemochromatosis. Overdose should be treated, at the physician's discretion, with iron-binding agents (chelators), or according to standard medical practice.
Adverse Reactions.
The most common adverse reaction observed during clinical trials of iron sucrose was dysgeusia, occurring at a frequency of 4.5 cases per 100 individuals. Other common adverse reactions included nausea, arterial hypotension, arterial hypertension, and injection site pain, occurring at a frequency of 1 to 2 cases per 100 individuals.
Among the most significant serious adverse reactions associated with iron sucrose administration were hypersensitivity reactions, occurring at a frequency of 0.25 cases per 100 individuals in clinical studies.
Immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions) were rare. 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), gastrointestinal symptoms (abdominal pain, vomiting), and skin reactions (urticaria, erythema, pruritus).
The adverse reactions listed below were reported in 4064 participants of clinical trials in temporal association with iron sucrose administration, suggesting a possible causal relationship. Adverse reactions are classified by frequency as follows: common (from < 1/10 to ≥ 1/100), uncommon (from < 1/100 to ≥ 1/1000), and rare (from < 1/1000 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 frequently observed adverse reactions were: 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 unknown: confusion, bradycardia, thrombophlebitis.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after medicine authorization is important. It allows continuous monitoring of the benefit-risk balance of the medicine. Healthcare professionals and patients, or their legal representatives, should 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 saline: from a microbiological standpoint, the medicinal product should be used immediately.
Storage conditions.
Store in the original packaging at a temperature not exceeding 25 °C. Do not freeze. Keep out of the reach of children.
Incompatibilities.
The medicinal product 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 incompatibilities. Compatibility with polyethylene and polyvinyl chloride containers has not been studied.
Packaging.
5 mL in an ampoule. 5 ampoules in a blister; 1 blister in a cardboard box.
Prescription status. Prescription only.
Manufacturer.
UNI-PHARMA CLEON CETIS PHARMACEUTICAL LABORATORIES S.A.
Manufacturer's address and location of operations.
14th km National Road 1, Building A and Building B, Kato Kifisia Attica, 14564, Greece.