Sufar

INSTRUCTIONS for medical use of the medicinal product SUFER® (SUFER®)

Composition:

Active substance: iron (III) hydroxide sucrose complex;

1 ml of solution contains 20 mg of iron in the form of iron (III) hydroxide sucrose complex;

Excipient: water for injections.

Pharmaceutical form. Solution for intravenous injection.

Main physicochemical properties: brown aqueous solution.

Pharmacotherapeutic group. Parenteral anti-anemic agents. Iron preparations. ATC code B03A C.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

The active component of the medicinal product Sufer® is iron sucrose, which consists of polynuclear iron (III) hydroxide cores surrounded externally by a large number of non-covalently bound sucrose molecules. The size of the complex corresponds to an average molecular weight (Mr) of 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 is stored in the liver in the form of ferritin.

Clinical efficacy

Clinical studies have shown that hematological response after intravenous administration of iron (III) hydroxide sucrose complex occurs faster than with oral iron formulations.

Pharmacokinetics.

Distribution

Ferrokinetic assessment of iron (III) hydroxide sucrose complex labeled with 59Fe and 52Fe was performed in 6 patients with anemia and chronic kidney disease. Within the first 6–8 hours, 52Fe was taken up by the liver, spleen, and bone marrow. Uptake of the radioactive label by the spleen, which is rich in macrophages, is considered characteristic of iron uptake by the reticuloendothelial system.

After a single intravenous dose of Sufer® containing 100 mg of iron was administered to healthy volunteers, maximum 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 broken down, and the polynuclear iron core is predominantly taken up by the reticuloendothelial system of the liver, spleen, and bone marrow.

Within 4 weeks after administration, erythrocyte uptake of 59Fe ranged from 68% to 97%.

Excretion

The average molecular weight of the complex is approximately 43 kDa, which is sufficiently high and prevents its 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, total serum iron concentration returned 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 impairment affects the pharmacological properties of iron (III) hydroxide sucrose complex (see section "Special precautions for use").

Clinical characteristics.

Indications.

Iron deficiency in patients who cannot be administered oral iron preparations or in whom such preparations are ineffective, in the following cases:

• intolerance to oral iron preparations;
• presence of inflammatory gastrointestinal disorders (e.g., ulcerative colitis) that may be exacerbated by therapy with oral iron preparations;
• iron-deficiency conditions resistant to treatment, when control of these conditions with oral iron preparations is inadequate.

Sufer® should be used only when indications are based on appropriate laboratory tests. Appropriate laboratory analyses include determination of levels of the following parameters: hemoglobin, serum ferritin, transferrin saturation with iron.

Contraindications.

The use of Sufer® is contraindicated in the following conditions:

• 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 (hemosiderosis, hemochromatosis) or hereditary disorders of iron absorption (e.g., sideroblastic anemia, cutaneous porphyria, thalassemia);
• first trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Sufer® is indicated for patients who cannot be administered oral iron preparations due to intolerance, inefficacy, or presence of gastrointestinal disorders. Sufer® should not be used concomitantly with oral iron-containing preparations, as absorption of orally administered iron is reduced.

Special precautions for use.

Parenteral iron preparations may cause immediate-type hypersensitivity reactions, including serious anaphylactic/anaphylactoid reactions, which may potentially be fatal. Such reactions have been reported even in cases where previous administration of parenteral iron preparations was uneventful. Hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm that may lead to myocardial infarction) have been reported (see section "Adverse reactions"). Suferrin® should be administered to patients who previously experienced hypersensitivity reactions to other parenteral iron preparations (e.g., iron dextran) only if absolutely necessary and with all appropriate precautions.

Treatment with Suferrin® should be prescribed by a physician only after a clear indication has been established.

Suferrin® 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, the patient should be questioned about any previous adverse reactions associated with intravenous iron preparations.

Typical symptoms of immediate-type hypersensitivity reactions include: hypotension, tachycardia (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).

Each patient should be monitored for at least 30 minutes after administration of parenteral iron preparations to allow timely detection of hypersensitivity reactions. If allergic reactions or signs of intolerance occur during administration, treatment should be discontinued immediately.

For immediate management of acute anaphylactic/anaphylactoid reactions, epinephrine is recommended as first-line therapy (e.g., 0.3 mg intramuscularly), followed by antihistamines and/or corticosteroids (which have a slower 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 (e.g., systemic lupus erythematosus, rheumatoid arthritis), are at higher risk of hypersensitivity reactions.

Parenteral iron preparations should be administered to patients with hepatic impairment only after careful assessment of the benefit-risk ratio. Parenteral iron administration should be avoided in patients with liver dysfunction when iron overload is a triggering factor. Close monitoring of iron levels is recommended to prevent iron overload.

In patients with elevated ferritin levels, parenteral iron preparations may negatively affect the course of bacterial or viral infections.

Parenteral iron preparations should be used with caution in cases of acute or chronic infection. In patients with chronic infection, a benefit-risk assessment should be performed. Administration of Suferrin® should be discontinued in patients with bacteremia.

Care must be taken during administration to avoid paravenous leakage. Paravenous leakage of the drug may cause pain, inflammation, tissue necrosis, and prolonged brown skin discoloration at the site. If paravenous leakage occurs, administration should be stopped immediately.

Hypotension is commonly observed with intravenous iron preparations. The solution should be administered cautiously. 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 increased dose or infusion rate.

Particular caution should be exercised when administering Suferrin® to patients with hepatic insufficiency, decompensated liver cirrhosis, epidemic hepatitis, Rendu-Osler-Weber disease, acute-phase infectious kidney diseases, or uncontrolled hyperparathyroidism.

The ampoule should be inspected for precipitate and damage before use.

Only a brown-colored aqueous solution free of precipitate may be used.

Suferrin® should be administered immediately after opening the ampoule.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of iron sucrose complex in pregnant women during the first trimester are limited. Data on the use of parenteral iron preparations in pregnant women during the second and third trimesters (303 pregnancy outcome reports) 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 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 during the second and third trimesters of pregnancy is possible only strictly according to medical indications.

The benefit-risk ratio should be evaluated before administration during pregnancy, as hypersensitivity reactions may pose a risk to both mother and fetus (see section "Special precautions for use").

Bradycardia may occur in the fetus after parenteral iron administration to the pregnant woman. This condition is usually transient and occurs as a consequence of maternal hypersensitivity reaction. Fetal status should be closely monitored during intravenous iron administration in pregnant women.

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). An effect of iron from breast milk on the newborn/infant cannot be excluded; therefore, the benefit-risk ratio should be evaluated.

Ability to influence 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 somnolence occur after drug administration, patients should refrain from driving or operating machinery until symptoms resolve.

Method of Administration and Dosage

The medicinal product Sufer**®** should be administered slowly intravenously.

The preparation is not intended for intramuscular or subcutaneous administration.

Patients should be monitored during and after administration of Sufer**®** for signs and symptoms of hypersensitivity reactions. Appropriate emergency treatment 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 administration of the drug should be divided into multiple smaller doses.

Dose Calculation

The total cumulative dose of Sufer**®**, equivalent to the total iron deficit (mg), is determined based on the patient’s hemoglobin (Hb) level and body weight. The dose should be 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 is 130 g/L; stored iron is 15 mg/kg 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 Hb = 0.34%, blood volume = 7% of body weight, factor 1000 = conversion from grams to milligrams).

Total volume of Sufer**®** to be administered (in mL):

= total iron deficit (mg)
20 mg/mL

Table 1

Total cumulative dose of Sufer**®** (mL) to be administered based on patient's body weight and Hb level:

Table 2

Required Hb level depending on the patient's body weight:

To convert Hb (mmol) to Hb (g/L), multiply the first value by 16.

Standard dosage

Adults: 5–10 mL of Sufer® medicinal product (100–200 mg iron) 1–3 times per week. Duration of administration and dilution factor see below.

Children aged 3 years and older: there are only limited data on the use of the medicinal product in children. In case of clinical necessity, it is recommended to administer no more than 0.15 mL of Sufer® medicinal product (3 mg iron) per 1 kg of body weight, no more than 3 times per week. Duration 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 per week is 10 mL of Sufer® medicinal product (200 mg iron), with administration duration of at least 10 minutes.

For infusion, the maximum tolerated dose administered no more than once per week:

• for patients with body weight above 70 kg: 500 mg iron (25 mL of Sufer® medicinal product) over at least 3.5 hours;
• for patients with body weight 70 kg and below: 7 mg iron per kg of 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 (increase in hemoglobin level of approximately 1 g/L per day or approximately 10–20 g/L 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 excluded.

Administration

Sufer® may be administered only intravenously by slow injection, intravenous infusion, or directly into the venous limb of the dialysis system.

Sufer® 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, Sufer® medicinal product must be diluted only with sterile 0.9% sodium chloride solution according to the scheme specified in Table 3.

Table 3

Intravenous bolus administration

Suferrum® can also be administered intravenously slowly as an undiluted solution at a rate of 1 ml per minute (5 ml of Suferrum® medicinal product (100 mg iron) administered over 5 minutes), but the maximum volume should not exceed 10 ml of Suferrum® medicinal product (200 mg iron) per single injection.

After injection, the patient should straighten the arm. Paravenous leakage of the drug should be avoided, as it may lead to pain, inflammation, tissue necrosis, and prolonged brownish discoloration of the skin at the injection site (see section "Special precautions for use").

Injection into the venous limb of the dialysis system

Suferrum® can be administered directly into the venous limb of the dialysis system during a hemodialysis session, strictly following the instructions described for intravenous injection.

Children

Due to insufficient data, the use of Suferrum® medicinal product is not recommended for treatment of children under 3 years of age.

Overdose.

Overdose may lead to acute iron overload, which may manifest as hemosiderosis. In case of overdose, symptomatic treatment is recommended and, if necessary, administration of iron-binding agents (chelators).

Adverse Reactions

The most common adverse reaction during clinical trials was dysgeusia, occurring at a frequency of 4.5 events per 100 individuals. Other common adverse reactions included 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 adverse reactions associated with the use of the medicinal product are hypersensitivity reactions, which occurred at a frequency of 0.25 events per 100 individuals during 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, etc.), gastrointestinal symptoms (abdominal pain, vomiting, etc.), and skin symptoms (urticaria, erythema, pruritus, etc.).

Adverse effects are classified by frequency as follows: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (≤ 1/10000), and not known (frequency cannot be estimated from 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: transient taste disturbances, particularly metallic taste (dysgeusia), dizziness.

Uncommon: headache, paresthesia, hypoaesthesia.

Rare: loss of consciousness, somnolence.

Cardiac disorders

Uncommon: arterial hypotension and collapse, tachycardia.

Rare: palpitations.

Not known: Quincke's edema (angioedema).

Vascular disorders

Common: arterial hypotension, arterial hypertension.

Uncommon: hot flushes, phlebitis.

Not known: superficial thrombophlebitis at the injection site.

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnea.

Renal and urinary disorders

Uncommon: chromaturia.

Gastrointestinal disorders

Common: nausea.

Uncommon: vomiting, abdominal pain, diarrhea, constipation.

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: reactions at injection/infusion site¹.

Uncommon: chest pain, chills, asthenia, fatigue, peripheral edema, pain.

Rare: increased sweating (hyperhidrosis), fever.

¹ Most frequently reported: pain at injection/infusion site, extravasation, irritation, skin discoloration, bruising, pruritus.

The following adverse reactions were obtained from spontaneous post-marketing surveillance reports

Frequency not known: disturbance of consciousness, bradycardia, thrombophlebitis.

Reporting of suspected adverse reactions

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

Shelf life

3 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Shelf life after opening of the ampoule. From a microbiological standpoint, the product should be used immediately.

Shelf life after dilution with physiological saline. Chemical and physical stability after dilution at room temperature is 12 hours.

Storage conditions

Store in a place protected from light. Store at a temperature not exceeding 25 °C.
Do not freeze.

Incompatibilities

SUFER® may only be mixed with sterile 0.9% sodium chloride solution. No other intravenous solutions or therapeutic agents should be added due to the risk of precipitation and/or other pharmaceutical incompatibilities. Compatibility with polyethylene and polyvinyl chloride containers has not been studied.

Packaging

5 ml glass ampoules, pack of 5 in a blister pack; 1 blister pack per cardboard carton.

Prescription status

Prescription only.

Manufacturer

LLC "Yuria-Pharm"

Manufacturer's address and location of operations

108, Kozbirska Street, Cherkasy, Cherkasy Oblast, 18030, Ukraine. Tel.: (044) 281-01-01