Haemopur (Solution) Instructions for Use

Marketing Authorization Holder

OPK Biotech LLC (Russia)

ATC Code

B05AA10 (Hemoglobin glutamer (bovine))

Active Substance

Hemoglobin glutamer (Rec.INN registered by WHO)

Dosage Form

Haemopur

Solution for infusion: 250 ml

Dosage Form, Packaging, and Composition

Solution for infusion of dark red color, without sediment or suspension.

Excipients: sodium 154 mmol/l, acetylcysteine 0.2 g/dl (antioxidant), water for injection up to 250 ml.

Chloride 111 mmol/l, potassium 4.1 mmol/l, calcium 1.1 mmol/l, lactate 27 mmol/l (buffer solution),

250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene.
250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene (5) – cardboard boxes.
250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene (10) – cardboard boxes.
250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene (15) – cardboard boxes.
250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene (25) – cardboard boxes.
250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene (30) – cardboard boxes.
250 ml – infusion bags (1) – gas-impermeable protective packaging made of aluminum foil coated with polyethylene (55) – cardboard boxes.

Clinical-Pharmacological Group

Plasma substitute

Pharmacotherapeutic Group

Plasma substitute and gas transport agent

Pharmacological Action

HAEMOPUR^® is an oxygen-transporting fluid (hemoglobin-based oxygen carrier) that increases the concentration of both total and plasma hemoglobin and ensures oxygen delivery to tissues and organs.

The action of HAEMOPUR^® is associated with its most important pharmacological property, namely, the ability to increase oxygen delivery to tissues. HAEMOPUR^® binds oxygen in the lungs and releases it to tissues more effectively than red blood cell hemoglobin, due to the high value of the P50 indicator (the partial pressure of oxygen at which the level of hemoglobin oxygen saturation is 50%). The relationship between the partial pressure of oxygen and blood oxygen saturation is graphically expressed as an oxyhemoglobin dissociation curve (ODC), which has an S-shape; this shape of the ODC corresponds to optimal conditions for blood oxygen saturation in the lungs and oxygen release from the blood in the tissues. The normal P50 for blood is 27 mm Hg, it determines the affinity of hemoglobin for oxygen: the higher the P50 (i.e., there are fewer sites on hemoglobin molecules for oxygen binding), the lower the affinity of hemoglobin for oxygen, but the greater the ability to release oxygen in the tissues. Under physiological conditions, when pH decreases (tissue hypoxia), P50 increases, the affinity of hemoglobin for oxygen decreases (Bohr effect), which improves oxygen delivery at the tissue level. For the drug HAEMOPUR^®, P50 is 40 mm Hg, which ensures a shift of the oxygen dissociation curve to the right (indicates a decrease in the interaction between hemoglobin and oxygen), thereby making oxygen delivery at the tissue level more effective. Provided that all hemoglobin molecules of the HAEMOPUR^® drug are fully saturated with oxygen, binding of approximately 1.36 ml of oxygen per 1 g of hemoglobin is achieved (the same as for human hemoglobin).

An oxygen content in arterial blood of 200 ml/l is sufficient to meet the oxygen needs of tissues.

When a free hemoglobin concentration in plasma of ≥ 0.6 g of hemoglobin per kg of body weight is reached (total plasma hemoglobin concentration ≥ 45 g), an increase in oxygen content in the arterial bed by more than 20% and an increase in the volume of oxygen diffusion through the alveolar-capillary membrane of the lungs by 10-15% compared to the norm are noted.

The drug HAEMOPUR^® provides a gas transport function instead of red blood cells in patients with anemia, ensuring sufficient blood oxygenation, which allows to delay or completely eliminate the need for red blood cell transfusion. In clinical studies, it has been proven that transfusion of the drug HAEMOPUR^® stimulates the formation of the body’s own erythrocytes within 7-14 days, resulting in no need for the use of red blood cell mass.

The drug HAEMOPUR^® is able to penetrate into narrowed or partially blocked vessels, improving oxygenation of ischemic tissues. HAEMOPUR^® has a viscosity of 1.3 centipoise, about 1/3 the viscosity of blood, thus, adding HAEMOPUR^® to blood reduces the overall blood viscosity. This also contributes to improved blood flow and rheology.

Pharmacokinetics

The T_1/2 of the drug ranges from 18 to 24 hours. The drug is eliminated by the reticuloendothelial system (RES). Clearance is 0.12 l/h. C_max of hemoglobin in plasma is proportional to the dose of the drug. HAEMOPUR^® is characterized by linear pharmacokinetics (within 0.6 and 2.5 g/kg). V_d corresponds to the plasma volume.

Indications

The drug HAEMOPUR is used for the following indications

• Treatment of acute anemia of any etiology, including during planned and emergency surgical operations;
• The need to reduce, delay, or completely eliminate the need for red blood cell transfusion;
• Treatment of tissue hypoxia of various etiologies (ischemia of organs and tissues, acute blood loss);
• Use in conditions where red blood cell transfusion is not possible;
• Use in complex therapy for the treatment of anemia during chemotherapy.

Indications for initiating the transfusion of the drug are the presence of one or more signs of anemia

• Heart rate ≥ 100 beats per minute;
• Systolic BP < 90 mm Hg or < 70% of the preoperative value;
• Hemoglobin less than 100 g/l;
• Acute blood loss of more than 7 ml/kg within 2 hours or less;
• Oliguria, diuresis less than 5 ml/kg/h for at least 2 hours.

ICD codes

Dosage Regimen

Administer the drug intravenously. One dose of the drug is 250 ml (1 infusion bag).

Constant oxygenation is established with the initial transfusion of a saturation dose – 500 ml of the drug (2 doses), followed by periodic administration of 250-500 ml (1-2 doses) per day. After the first transfusion, if the patient retains clinical symptoms and signs of anemia, additional doses of the drug may be administered to the patient, up to a maximum of 7 doses within 6 days. During clinical trials, most patients required less than 6 doses of the drug to resolve clinical symptoms of anemia. The decision to transfuse repeated doses of the drug should be based not on the hemoglobin level, but on the clinical symptoms of anemia.

Table 1. Dosing principle

The hemoglobin level must be monitored every 24 hours after the start of transfusion of the 1st dose and 1 hour after the end of transfusion of each dose. Before starting the transfusion of HAEMOPUR^®, once during the procedure, and every 3 hours after it, it is necessary to monitor the blood gas composition (oxygen saturation of arterial blood). After 72 hours, the effect of activating the body’s own erythrocytes begins to appear (maximum at 7-14 days), and the use of the drug HAEMOPUR^® can be discontinued.

Monitoring principles

• Blood pressure (BP) (continuously)
• Pulse oximetry saturation (continuously)
• Hemoglobin (1 hour after transfusion of each dose, every 24 hours after the start of transfusion of the 1st dose)
• Oxygen saturation in arterial blood before the procedure, during it, and every 3 hours after it.

The drug is usually administered at a rate of 1-2 ml/min. If necessary, depending on the patient’s condition, the administration rate can be increased. During the initial administration of HAEMOPUR^® in patients with a clinically significant increase in blood pressure, it is recommended to initiate an infusion of nitroglycerin in minimal doses. Subsequently, to regulate blood pressure in case of a clinically significant increase, it is recommended to use calcium channel blockers, beta-blockers.

Table 2. Dosing principle

A clinical response – a decrease in heart rate, an increase in blood pressure – should appear during the transfusion of the first 50-100 ml of the drug.

Transfusion technique

• The solution before use must have a clean, saturated ruby color; if the solution is brown, methemoglobin has formed and it cannot be used;
• The outer packaging should be removed before use; once opened, the drug must be used within 24 hours;
• HAEMOPUR^® does not require a cross-match test for compatibility with the patient’s blood before administration;
• HAEMOPUR^® is administered in compliance with all conditions of asepsis and antisepsis, using a standard set for intravenous access;
• Routes of drug administration – central or peripheral venous access;
• It should be administered through a separate infusion catheter to avoid mixing with other infusion solutions;
• Other medicinal products should not be added to the drug solution;
• The contents of two packages of the drug should not be mixed;
• There is no need to use infusion filters.

Table 3. What to expect during transfusion

Blood transfusion is not contraindicated in patients receiving the drug HAEMOPUR^®.

Adverse Reactions

• Short-term reversible gastrointestinal disorders (dysphagia, nausea, vomiting, dyspepsia, diarrhea, intestinal spasm);
• Increase in BP by 15-20 mm Hg, headache;
• Dermatitis;
• Allergic reactions;
• Yellowing of the skin, sclera;
• Short-term increase in “hepatic” transaminases and pancreatic enzymes: AST, ALT, lipase.

The manifestation of yellowness of the skin and eye sclera is a consequence of the natural utilization of hemoglobin during the conversion of hemoglobin to bilirubin and is not associated with clinical liver dysfunction.

Transient increase in the level of enzymes in the blood is not associated with clinical damage to the liver or pancreas.

If an allergic reaction develops during the transfusion of the drug, the infusion should be stopped immediately and symptomatic treatment should be carried out.

Contraindications

HAEMOPUR^® is contraindicated in patients over 80 years of age, patients with hypersensitivity to bovine hemoglobin, and patients with systemic mastocytosis.

Uncontrolled arterial hypertension is a contraindication to transfusion.

With caution. The safety of using the drug in children (under 18 years of age), pregnant and breastfeeding women has not been confirmed. Due to the lack of precise clinical data, the drug should be used with caution in these groups of patients, after a careful benefit-risk assessment.

Use in Pregnancy and Lactation

The safety of using the drug in pregnant and breastfeeding women has not been confirmed. Due to the lack of precise clinical data, the drug should be used with caution, after a careful benefit-risk assessment.

Pediatric Use

The safety of using the drug in children (under 18 years of age) has not been confirmed. Due to the lack of precise clinical data, the drug should be taken with caution, after a careful benefit-risk assessment.

Geriatric Use

Contraindicated in patients over 80 years of age.

Special Precautions

When transfusing the drug, it should be taken into account that it is an iso-oncotic colloidal solution. It should be used with caution together with other colloids to avoid circulatory overload.

Serum and plasma samples from patients who have received an infusion of the drug HAEMOPUR^® have a red color due to hemoglobin, which may incorrectly reflect the results of clinical laboratory tests, depending on the type of analyzer or reagent used. Accurate determination of bilirubin or albumin concentration is impossible in the presence of the drug HAEMOPUR^® in plasma or serum.

Overdose

No cases of overdose were identified during clinical studies of the drug.

In patients with concomitant heart failure, administration of the drug HAEMOPUR^® may cause hypervolemia, especially with simultaneous administration of other solutions in large volumes. Treatment is symptomatic.

Drug Interactions

Compatible with donor blood, dextrose solutions, antibiotics, 0.9% sodium chloride (NaCl) solution, solutions containing electrolytes and not supporting colloid osmotic pressure.

Concomitant administration of other colloidal solutions (such as plasma, hydroxyethyl starch, etc.) should be carried out with caution to avoid circulatory overload.

Storage Conditions

Store at a temperature from 2 to 30°C (86°F). Do not freeze. Use within 24 hours after opening the package. Keep out of reach of children!

Shelf Life

Shelf life. 3 years. Do not use after the expiration date indicated on the package.

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.