Feroxid

INSTRUCTIONS for medical use of the medicinal product FEROXYD (FEROXYD)

Composition:

Active substance: iron (III) hydroxide sucrose complex;

1 ml of solution contains iron (III) hydroxide sucrose complex equivalent to iron (III) 20 mg;

Excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: colloidal solution ranging from brown to reddish-brown in color.

Pharmacotherapeutic group.
Antianemic 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 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 stage, 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.

Pharmacokinetics

Distribution. Ferrokinetics of the iron hydroxide sucrose 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 macrophages of the reticuloendothelial system of the spleen.

After a single intravenous dose containing 100 mg of iron was administered to healthy volunteers, the maximum iron concentration was observed 10 minutes after administration and reached 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 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 ranged from 68% to 97%.

Excretion. The average molecular weight of the complex is approximately 43 kDa, which is sufficiently large to avoid 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, the total serum iron concentration decreased to the baseline level (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 Warnings and Precautions for Use").

Clinical characteristics.

Indications.

Iron deficiency in patients who cannot be treated with oral iron preparations or in whom such preparations are ineffective or oral administration of iron-containing agents is not feasible due to:

• intolerance to oral iron preparations;
• presence of inflammatory gastrointestinal disorders (e.g., ulcerative colitis) which 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.

The drug should be used only when indications are based on appropriate diagnostic investigations. Relevant laboratory tests include assessment of hemoglobin, serum ferritin, and transferrin saturation levels.

Contraindications.

• Known hypersensitivity to the active substance or to any of the excipients;
• anemia not related to iron deficiency (e.g., hemolytic anemia, vitamin B12 deficiency-related megaloblastic anemia, disorders of erythropoiesis, bone marrow hypoplasia, anemia caused by lead poisoning);
• conditions associated with iron overload (hemidosiderosis, hemochromatosis) or hereditary disorders of iron metabolism (e.g., sideroblastic anemia, cutaneous porphyria, thalassemia);
• first trimester of pregnancy.

Interaction with other medicinal products and other forms of interaction.

Feroxid is indicated for patients who cannot receive oral iron preparations due to intolerance, ineffectiveness, or presence of gastrointestinal disorders. Like other parenterally administered iron preparations, Feroxid should not be used concomitantly with oral iron-containing agents, as the 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 Feroxid.

Special precautions for use.

Intravenous administration of parenteral iron preparations may lead to immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions), which can be fatal. Therefore, antiallergic therapy must be conducted in a facility equipped appropriately for cardiopulmonary resuscitation. Cases of such reactions have been reported even when previous administration of parenteral iron preparations was uncomplicated. Ferrocid should be administered to patients who have experienced hypersensitivity reactions to other parenteral iron preparations (e.g., iron dextran) only in urgent cases and with strict adherence to all precautionary measures.

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

Ferrocid may be administered only if medical personnel experienced in assessing and managing anaphylactic reactions are available for immediate intervention, and the facility is adequately equipped with resuscitation equipment. Before each administration, patients should be questioned about prior adverse reactions associated with intravenous iron preparations. Cases of hypersensitivity reactions progressing to Kounis syndrome (acute allergic coronary artery spasm, which may lead to myocardial infarction) have been reported.

Typical symptoms of immediate-type hypersensitivity reactions include: decreased arterial 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 adverse reactions for at least 30 minutes after each intravenous administration of iron-containing preparations. 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 primarily recommended (e.g., 0.3 mg intramuscularly), followed by antihistamines and/or corticosteroids (which have a later 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 diseases (such as systemic lupus erythematosus, rheumatoid arthritis) are at high risk of hypersensitivity reactions.

Parenteral iron preparations should be administered to patients with impaired liver function only after careful assessment of benefit/risk ratio. Parenteral iron administration should be avoided in patients with impaired liver function when iron overload is a triggering factor. To prevent iron overload, careful monitoring of body iron levels is recommended.

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, the benefit/risk ratio should be evaluated. Administration of Ferrocid should be discontinued in patients with bacteremia.

Caution is also required when administering the drug to individuals with low serum iron-binding capacity and/or folic acid deficiency.

During administration, particular attention must be paid to avoiding paravenous leakage. Paravenous leakage may lead to pain, inflammation, tissue necrosis, and prolonged brownish discoloration of the skin at the site. If paravenous leakage occurs, administration of the drug should be stopped immediately.

Decreased arterial pressure is commonly observed with intravenous iron preparations. Therefore, the drug should be used cautiously. The recommended infusion rate must be strictly followed to avoid the development of arterial hypotension. Higher incidence of adverse reactions (particularly hypotension) is associated with increased dose or infusion rate.

Special caution is required when administering Ferrocid to patients with hepatic insufficiency, decompensated liver cirrhosis, epidemic hepatitis, Rendu-Osler disease, acute-phase infectious kidney diseases, and uncontrolled hyperparathyroidism.

Before administration, ampoules should be inspected for sediment or damage. Only a clear, homogeneous aqueous solution ranging from brown to reddish-brown, free from sediment, should be used. Ferrocid should be administered immediately after opening the ampoule.

In post-marketing use, symptomatic hypophosphatemia has been reported, leading to osteomalacia and fractures requiring clinical intervention, including surgical treatment.

Patients should inform their physician if they experience worsening symptoms, fatigue with myalgia, or bone pain. Serum phosphate levels should be monitored in patients receiving repeated high-dose infusions or long-term treatment, as well as in patients with existing risk factors for hypophosphatemia. If persistent hypophosphatemia occurs, the treatment regimen should be re-evaluated.

The preparation contains less than 1 mmol of sodium (23 mg) per ampoule and is therefore essentially "sodium-free."

Use during pregnancy or breastfeeding.

There are no data on the use of iron (III) hydroxide sucrose complex in pregnant women during the first trimester of pregnancy. Data on the use of iron (III) hydroxide sucrose complex in the second and third trimesters of pregnancy indicate 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 impact on iron levels in newborns have not been conducted.

Ferrocid 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.

The risk/benefit ratio should be evaluated before administration during pregnancy, as hypersensitivity reactions may pose risks to both mother and fetus (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 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 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 from breast milk on the newborn/infant cannot be excluded; therefore, the risk/benefit ratio should be evaluated.

Ability to influence the speed of reaction while driving or operating machinery.

Appropriate studies have not been conducted. The effect on reaction speed while driving or operating machinery is unlikely. However, if adverse reactions such as dizziness or confusion occur after drug administration, patients should refrain from driving or operating machinery until symptoms resolve.

Method of Administration and Dosage

Feroxid is administered intravenously only. Administration may be performed either as a slow intravenous injection, intravenous infusion, or directly into the venous limb of a dialysis circuit.

The product is not intended for intramuscular or subcutaneous administration.

The drug should be used only when the indication is based on appropriate laboratory tests. Relevant laboratory tests include measurements of hemoglobin, serum ferritin, and transferrin saturation.

Patients should be monitored during and after administration of Feroxid 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 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 administration of the drug is recommended in divided doses.

Dose Calculation

The total cumulative dose of Feroxid, equivalent to the patient’s total iron deficit (mg), should be determined based on the 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/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 Ferofide to be administered (in ml)

= Total iron deficit (mg) 20 mg/ml

Total cumulative dose of Feroxide drug (ml) to be administered, based on patient's body weight and Hb level

Table 1

Body weight (kg)	Cumulative therapeutic dose of Feroxidum for administration
	Hb 60 g/L		Hb 75 g/L		Hb 90 g/L		Hb 105 g/L
	mL	mg Fe	mL	mg Fe	mL	mg Fe	mL	mg Fe
10	16	320	14	280	12	240	11	220
15	24	480	21	420	19	380	16	320
20	32	640	28	560	25	500	21	420
25	40	800	35	700	31	620	26	520
30	48	960	42	840	37	740	32	640
35	63	1260	57	1140	50	1000	44	880
40	68	1360	61	1220	54	1080	47	940
45	74	1480	66	1320	57	1140	49	980
50	79	1580	70	1400	61	1220	52	1040
55	84	1680	75	1500	65	1300	55	1100
60	90	1800	79	1580	68	1360	57	1140
65	95	1900	84	1680	72	1440	60	1200
70	101	2020	88	1760	75	1500	63	1260
75	106	2120	93	1860	79	1580	66	1320
80	111	2220	97	1940	83	1660	68	1360
85	117	2340	102	2040	86	1720	71	1420
90	122	2440	106	2120	90	1800	74	1480

Required Hb level depending on patient's body weight

Table 2

Body weight	Required Hb
< 35 kg	130 g/L
≥ 35 kg	150 g/L

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 and elderly patients: 5–10 ml of Ferogradumet (100–200 mg iron) 1–3 times per week depending on the Hb level. See below for administration time and dilution factor.

Children aged 3 years and older: there are only limited data on the use of the drug in children. If clinically necessary, it is recommended to administer no more than 0.15 ml of Ferogradumet (3 mg iron) per kg body weight, not more than 3 times per week. See below for administration time and dilution factor.

Maximum tolerated single or weekly dose.

Adults and elderly patients

For injections: maximum tolerated dose is 10 ml of Ferogradumet (200 mg iron), no more than 3 times per week, with administration lasting at least 10 minutes.

For infusion: maximum tolerated dose — no more than once per week:

• for patients weighing more than 70 kg: 500 mg iron (25 ml of Ferogradumet) over at least 3.5 hours;

• for patients weighing up to 70 kg: 7 mg iron per kg body weight over 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 there is no improvement in hematological parameters (increase in hemoglobin level by approximately 1 g/l of blood per day or approximately 10–20 g/l within 1–2 weeks after initiation of therapy), the initial diagnosis should be re-evaluated and the presence of persistent blood loss should be ruled out.

Administration

Ferogradumet must be administered only intravenously, either by intravenous infusion, slow injection, or directly into the venous limb of the hemodialysis apparatus.

Ferogradumet 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.

Ferogradumet should be administered by intravenous infusion to reduce the risk of arterial hypotension and the risk of extravasation.

Immediately before administration, Ferogradumet must be diluted in sterile 0.9% sodium chloride solution according to the scheme specified in Table 3, at a 1:20 ratio, for example:

• 1 ml of Ferogradumet (20 mg iron) in a maximum of 20 ml of sterile 0.9% sodium chloride solution.

Table 3

Dose of Feroxidum drug (mg of iron)	Dose of Feroxidum drug (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

Dilution of Ferogradumet in volumes of physiological solution larger than recommended is not permitted in order to ensure solution stability.

Intravenous bolus administration.

Ferogradumet may also be administered intravenously as a slow infusion of the undiluted solution at a rate of 1 mL per minute (5 mL of Ferogradumet (100 mg iron) administered over 5 minutes), but the maximum volume of solution should not exceed 10 mL of Ferogradumet (200 mg iron) per single injection.

After injection, the patient should keep the injected arm straight. Paravenous leakage of the drug should be avoided, as it may cause pain, inflammation, tissue necrosis, and prolonged brownish skin discoloration at the injection site (see section "Special precautions").

Injection into the venous port of the dialysis system.

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

Dosage calculation for iron replenishment after blood loss or blood donation.

The dose of Ferogradumet required to compensate for iron deficiency should be calculated using the following formula:

• if the amount of blood loss is known: intravenous administration of 200 mg iron (10 mL of Ferogradumet) increases Hb concentration to the same extent as transfusion of 1 unit of blood (400 mL with Hb concentration of 150 g/L);

amount of iron to be replaced (mg) = number of units of lost blood × 200, or

required volume of Ferogradumet (mL) = number of units of lost blood × 10;

• in case of decreased Hb level, use the previous formula, but note that iron stores do not need to be replenished.

Amount of iron to be replaced (mg) = body weight (kg) × 0.24 × (normal Hb level (g/L) – patient's Hb level) (g/L).
For example: body weight = 60 kg, Hb deficit = 10 g/L ⇒ required iron amount = 150 mg ⇒ required volume of Ferogradumet = 7.5 mL.

Children.

Due to insufficient data, the use of Ferogradumet is not recommended for the treatment of children under 3 years of age.

Overdose.

Overdose may lead to acute iron overload, potentially manifesting as hemosiderosis. In case of overdose, symptomatic treatment is recommended and, if necessary, administration of iron-chelating agents.

Side effects.

The most commonly reported adverse reaction to the medicine is dysgeusia. Common adverse reactions include nausea, arterial hypotension, arterial hypertension, and pain at the infusion site, occurring at a frequency of 1 to 2 events per 100 individuals.

Among the most important serious adverse reactions associated with the use of the medicine are hypersensitivity reactions, which occurred at a frequency of 0.25 events per 100 individuals during clinical trials. Immediate-type hypersensitivity reactions (anaphylactoid/anaphylactic reactions) occurred rarely. Overall, anaphylactoid/anaphylactic reactions are very serious adverse reactions that may lead to fatal outcomes (see section "Special 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.).

Serious adverse reactions

You should inform your doctor if you experience fatigue or pain in your muscles or bones (pain in arms or legs, joints, or back). This may be a sign of low phosphate levels in the blood, which can lead to bone softening (osteomalacia). This condition may sometimes result in bone fractures. Your doctor may also monitor your blood phosphate levels, especially if you will require multiple iron-containing medication procedures over time.

Adverse effects are classified by frequency of occurrence 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 only during post-marketing surveillance, not in clinical trials).

Infections and parasitic diseases.

Rare: pneumonia.

Blood and lymphatic system disorders.

Uncommon: polycythemia¹.

Immune system disorders.

Uncommon: hypersensitivity reactions.

Not known: anaphylactoid reactions, angioedema.

Metabolism and nutrition disorders.

Rare: iron overload.

Nervous system disorders.

Common: transient taste disturbances, particularly metallic taste (dysgeusia).

Uncommon: headache, dizziness, burning sensation, paresthesia, hypaesthesia.

Rare: syncope, migraine, somnolence.

Not known: loss of consciousness, altered consciousness, confusion, anxiety, tremor.

Cardiac disorders.

Common: arterial hypotension and collapse, tachycardia.

Rare: palpitations.

Not known: bradycardia, Kounis syndrome.

Vascular disorders.

Common: arterial hypotension, arterial hypertension.

Uncommon: thrombophlebitis, phlebitis.

Rare: flushing.

Not known: circulatory collapse, superficial venous thrombosis.

Respiratory, thoracic and mediastinal disorders.

Uncommon: dyspnea.

Not known: bronchospasm.

Renal and urinary disorders.

Uncommon: chromaturia.

Gastrointestinal disorders.

Common: nausea.

Uncommon: vomiting, abdominal pain, diarrhea, constipation.

Rare: dry mouth.

Skin and subcutaneous tissue disorders.

Uncommon: pruritus, rash.

Not known: urticaria, erythema.

Musculoskeletal and connective tissue disorders.

Uncommon: muscle cramps, myalgia, arthralgia, limb pain, back pain.

Rare: discomfort in limbs, muscle spasms.

Not known: hypotonia, hypophosphatemic osteomalacia.

General disorders and administration site conditions.

Common: pain at injection site.

Uncommon: chills; asthenia; fatigue; pain; reactions, irritation, transudation, skin discoloration to brown, burning sensation, swelling, and inflammation at injection site; peripheral edema.

Rare: feeling of warmth, chest pain, fever, pruritus at injection site, hematoma at injection site.

Very rare: increased sweating, pallor, malaise, edema.

Investigations.

Uncommon: increased gamma-glutamyl transferase, increased alanine aminotransferase levels, increased aspartate aminotransferase levels, liver function test abnormalities.

Rare: increased serum ferritin¹, increased blood creatinine levels, increased blood lactate dehydrogenase levels.

¹ May occur due to overdose or iron overload.

Shelf life. 3 years.

Do not use the medicine after the expiry date stated on the packaging.

After opening the ampoule, from a microbiological standpoint, the medicine should be used immediately.

After dilution with physiological saline, physico-chemical stability at room temperature lasts for 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.

Ferofid can only be mixed with sterile 0.9% sodium chloride solution. 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 an ampoule, 5 ampoules per cardboard pack.

Prescription category. Prescription only.

Manufacturer.

HELP S.A.

HELP S.A.

Manufacturer's address and place of business.

Pedini, Ioannina, 45500, Greece

Pedini Ioanninon, Ioannina, 45500, Greece

Marketing authorization holder.

M.BIOTECH LIMITED

M.BIOTECH LIMITED

Address of marketing authorization holder.

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom

Gladstone House, 77-79 High Street, Egham TW20 9HY, Surrey, United Kingdom