Venofer^® (Solution) Instructions for Use

Marketing Authorization Holder

Vifor (International), Inc. (Switzerland)

Manufactured By

IDT Biologika, GmbH (Germany)

Quality Control Release

VIFOR (International), Inc. (Switzerland)

ATC Code

B03AC (Parenteral preparations of trivalent iron)

Active Substance

Iron sucrose (BAN)

Dosage Forms

	Venofer®	Solution for intravenous administration 20 mg/1 ml: fl. 5 ml 5 pcs.
		Solution for intravenous administration 20 mg/1 ml: amp. 5 ml 5 pcs.

Dosage Form, Packaging, and Composition

Solution for intravenous administration aqueous, brown in color.

Excipients : sodium hydroxide – 0-5 mg (as a 10% sodium hydroxide solution – q.s. to adjust pH to 10.5-11.0), water for injection – 580-640 mg.

5 ml – ampoules of colorless glass (5) – contour cell packs (1) – cardboard boxes.
5 ml – vials of colorless glass (5) – contour cell packs (1) – cardboard boxes.

Clinical-Pharmacological Group

Antianemic drug for parenteral administration

Pharmacotherapeutic Group

Antianemic agent, iron preparation for parenteral administration

Pharmacological Action

Iron preparation. The polynuclear iron (III) hydroxide centers are surrounded on the outside by numerous non-covalently bound sucrose molecules. As a result, a complex is formed with a molecular weight of approximately 43 kDa, which makes its excretion by the kidneys in unchanged form impossible. This complex is stable and does not release iron ions under physiological conditions. The iron in this complex is bound to structures similar to natural ferritin.

Pharmacokinetics

Distribution

After a single intravenous administration of Venofer^® containing 100 mg of iron, the C_max of iron, averaging 538 µmol, is reached 10 minutes after the injection.

The V_d of the central compartment almost completely corresponds to the volume of serum – about 3 L.

The V_d at steady state is approximately 8 L (indicating low distribution of iron in body fluids). Due to the low stability of iron sucrose compared to transferrin, a competitive exchange of iron in favor of transferrin is observed. As a result, about 31 mg of iron (III) is transferred within 24 hours.

Elimination

T_1/2 is about 6 hours. Less than 5% of the iron from the total clearance is excreted by the kidneys in the first 4 hours. After 24 hours, the serum iron level returns to the initial (pre-administration) value, and approximately 75% of the sucrose leaves the vascular bed.

Indications

Iron deficiency conditions

• When rapid iron replenishment is necessary;
• In case of intolerance to oral iron preparations or non-compliance with the treatment regimen;
• In the presence of active inflammatory bowel diseases when oral iron preparations are ineffective.

ICD codes

Dosage Regimen

Venofer^® is administered only intravenously (by slow drip or bolus) or into the venous limb of the dialysis system. It is not intended for intramuscular administration. Simultaneous administration of the full therapeutic dose of the drug is not allowed.

Before administering the first therapeutic dose, a test dose must be prescribed. If intolerance phenomena occur during the observation period, the drug administration should be stopped immediately. Before opening the ampoule, it should be inspected for possible sediment and damage. Only a brown solution without sediment can be used.

Drip infusion It is preferable to administer Venofer^® by drip infusion to reduce the risk of a pronounced decrease in blood pressure and the danger of the solution entering the perivenous space. Immediately before infusion, Venofer^® should be diluted with 0.9% sodium chloride solution in a ratio of 1:20, for example, 1 ml (20 mg of iron) in 20 ml of 0.9% sodium chloride solution. The resulting solution should be administered at the following rate: 100 mg of iron — in no less than 15 minutes; 200 mg of iron — over 30 minutes; 300 mg of iron — over 1.5 hours; 400 mg of iron — over 2.5 hours; 500 mg of iron — over 3.5 hours. Administration of the maximum tolerable single dose, which is 7 mg of iron/kg, should be carried out over at least 3.5 hours, regardless of the total dose of the drug.

Before the first drip infusion of the therapeutic dose of Venofer^®, a test dose must be administered: 20 mg of iron for adults and children with a body weight over 14 kg, and half the daily dose (1.5 mg of iron/kg) for children with a body weight less than 14 kg, over 15 minutes. In the absence of adverse events, the remaining part of the solution should be administered at the recommended rate.

Bolus injection Venofer^® can also be administered as an undiluted solution intravenously slowly, at a rate of 1 ml of Venofer^® (20 mg of iron) per minute; 5 ml of Venofer^® (100 mg of iron) should be administered over at least 5 minutes. The maximum volume of the drug should not exceed 10 ml of Venofer^® (200 mg of iron) per injection.

Before the first bolus injection of the therapeutic dose of Venofer^®, a test dose should be prescribed: 1 ml of Venofer^® (20 mg of iron) for adults and children with a body weight over 14 kg and half the daily dose (1.5 mg of iron/kg) for children with a body weight less than 14 kg over 1-2 minutes. In the absence of adverse events during the subsequent 15 minutes of observation, the remaining part of the solution should be administered at the recommended rate. After the injection, the patient is advised to keep the arm in an extended position for some time.

Administration into the dialysis system

Venofer^® can be administered directly into the venous limb of the dialysis system, strictly following the rules described for intravenous injection.

Dose calculation: the dose is calculated individually according to the total iron deficiency in the body using the formula

Total iron deficiency (mg) = body weight (kg) × [target Hb level – patient’s Hb level] (g/L) × 0.24* + deposited iron (mg).

For patients with a body weight less than 35 kg: target Hb level = 130 g/L, amount of deposited iron = 15 mg/kg body weight.

For patients with a body weight more than 35 kg: target Hb level = 150 g/L, amount of deposited iron = 500 mg.

*Factor 0.24 = 0.0034 × 0.07 × 1000 (iron content in Hb = 0.34%; blood volume = 7% of body weight; factor 1000 = conversion from “g” to “mg”).

Total volume (ml) of Venofer^® to be administered = total iron deficiency (mg) / 20 mg/ml (Tables 1 and 2).

Table 1

If the total therapeutic dose exceeds the maximum allowable single dose, fractional administration of the drug is recommended. If no improvement in hematological parameters occurs 1-2 weeks after starting treatment with Venofer^®, the initial diagnosis should be reconsidered.

Dose calculation for iron replenishment after blood loss or autologous blood donation

The dose of Venofer^® is calculated using the following formula

If the amount of blood lost is known intravenous administration of 200 mg of iron (10 ml of Venofer^®) leads to the same increase in Hb concentration as transfusion of 1 unit of blood (=400 ml with Hb concentration=150 g/L).

Amount of iron to be replenished (mg) = number of units of blood lost × 200 or Required volume of Venofer^® (ml) = number of units of blood lost × 10.

If the Hb level is decreased the previous formula should be used provided that iron stores do not need to be replenished.

Amount of iron (mg) to be replenished = body weight (kg) × 0.24 × [target Hb level – patient’s Hb level] (g/L).

For example: body weight 60 kg, Hb deficit = 10 g/L: the required amount of iron is approximately 150 mg, and the required volume of Venofer^® = 7.5 ml.

Standard dose

Adults and elderly patients are prescribed 5-10 ml of Venofer^® (100-200 mg of iron) 1-3 times a week depending on the hemoglobin level.

There is only limited data on the use of the drug in children under 3 years of age. If necessary, it is recommended to administer no more than 0.15 ml of Venofer^® (3 mg of iron) per kg of body weight 1-3 times a week depending on the hemoglobin level.

Maximum tolerable single dose

Adults and elderly patients for bolus injection – 10 ml of Venofer^® (200 mg of iron), duration of administration not less than 10 minutes; for drip infusion, depending on the indications, the single dose can reach 500 mg of iron. The maximum allowable single dose is 7 mg/kg and is administered once a week, but it should not exceed 500 mg of iron. The administration time and dilution method are as indicated above.

Adverse Reactions

Side effects probably associated with the administration of Venofer^® were observed very rarely (< 0.01% and ≥ 0.001%).

Nervous system disorders dizziness, headache, loss of consciousness, paresthesia.

Cardiovascular system disorders palpitations, tachycardia, decreased blood pressure, collapse-like states, feeling of heat, flushing.

Respiratory system disorders bronchospasm, dyspnea.

Digestive system disorders diffuse abdominal pain, epigastric pain, diarrhea, taste perversion, nausea, vomiting.

Skin and subcutaneous tissue disorders erythema, pruritus, rash, pigmentation disorder, increased sweating.

Musculoskeletal and connective tissue disorders arthralgia, back pain, joint swelling, myalgia, limb pain.

Allergic reactions anaphylactoid reactions, facial edema, laryngeal edema.

Local reactions pain and swelling at the injection site (especially in case of extravasal administration of the drug).

General disorders and administration site conditions asthenia, chest pain, feeling of heaviness in the chest, weakness, peripheral edema, malaise, pallor, fever, chills.

Contraindications

• Anemia not associated with iron deficiency;
• Signs of iron overload (hemosiderosis, hemochromatosis);
• Impaired iron utilization;
• First trimester of pregnancy;
• Hypersensitivity to the components of the drug.

With caution the drug should be prescribed to patients with bronchial asthma, eczema, polyvalent allergy, allergic reactions to other parenteral iron preparations; patients with low iron-binding capacity of serum and/or folic acid deficiency; patients with hepatic insufficiency, with acute or chronic infectious diseases, with elevated serum ferritin levels because parenterally administered iron may have an adverse effect in the presence of bacterial or viral infection.

Use in Pregnancy and Lactation

Contraindicated in the first trimester of pregnancy.

Limited experience with the use of Venofer^® in pregnant patients has shown no adverse effects of iron sucrose on the course of pregnancy and the health of the fetus/newborn. To date, no well-controlled studies have been conducted in pregnant women. In experimental studies on reproductive effects in animals, no direct or indirect harmful effects on embryonic/fetal development, childbirth, or postnatal development were identified. Nevertheless, further investigation of the ratio of the expected therapeutic benefit for the mother and the possible risk to the fetus is required.

The entry of non-metabolized iron sucrose into breast milk is unlikely. Thus, Venofer^® does not pose a danger to breastfed infants.

Use in Hepatic Impairment

With caution should be prescribed to patients with hepatic insufficiency.

Geriatric Use

Use is possible according to the dosing regimen.

Special Precautions

Venofer^® should be prescribed only to those patients in whom the diagnosis of anemia is confirmed by appropriate laboratory data (e.g., results of serum ferritin determination or hemoglobin and hematocrit levels, red blood cell count and their parameters – mean corpuscular volume, mean corpuscular hemoglobin).

Intravenous iron preparations can cause allergic or anaphylactoid reactions, which can be potentially life-threatening.

The administration rate of Venofer^® must be strictly observed (rapid administration of the drug may cause a decrease in blood pressure). A higher frequency of adverse reactions (especially – decreased blood pressure), which can also be severe, is associated with an increase in dose. Thus, the recommended administration time must be strictly observed, even if the patient is not receiving the maximum tolerable single dose.

Studies conducted in patients with hypersensitivity reactions to iron dextran showed no complications during treatment with Venofer^®.

Penetration of the drug into the perivenous space should be avoided, as the entry of Venofer^® outside the vessel leads to tissue necrosis and brown discoloration of the skin. In case of this complication, to accelerate the elimination of iron and prevent its further penetration into surrounding tissues, the application of heparin-containing preparations to the injection site is recommended (gel or ointment is applied with light movements, without rubbing).

From a microbiological point of view, the drug should be used immediately.

Shelf life after dilution with saline chemical and physical stability after dilution at room temperature is 12 hours. From a microbiological point of view, the drug should be used immediately. If the drug is not used immediately after dilution, the user is responsible for the conditions and storage time, which in any case should not exceed 3 hours at room temperature if the dilution was performed under controlled and guaranteed aseptic conditions.

Effect on ability to drive vehicles and operate machinery

It is unlikely that Venofer^® would have an undesirable effect on the ability to drive vehicles and operate machinery.

Overdose

Symptoms hemosiderosis due to acute overload.

Treatment symptomatic therapy is recommended and, if necessary, the use of iron-binding drugs (chelates), for example, deferoxamine intravenously.

Drug Interactions

The drug should not be administered simultaneously with oral iron formulations, as the absorption of iron from the gastrointestinal tract is reduced. Treatment with oral iron preparations can be started no earlier than 5 days after the last injection.

Pharmaceutical interactions

Venofer^® can be mixed in the same syringe only with physiological saline. No other solutions for intravenous administration and therapeutic drugs should be added, as there is a risk of precipitation and/or other pharmaceutical interaction. Compatibility with containers made of materials other than glass, polyethylene and polyvinyl chloride has not been studied.

Storage Conditions

The drug should be stored out of the reach of children, in the original packaging, at a temperature from 4°C (39.2°F) to 25°C (77°F); do not freeze.

Shelf Life

Shelf life – 3 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.