IMUNORO

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT IMUNORO

Composition:

active substance: human anti-D immunoglobulin;

1 ml of injection solution contains:

distribution of IgG subclasses (approximate values):

IgG1 66.0 %

IgG2 30.0 %

IgG3 2.5 %

IgG4 1.5 %

maximum immunoglobulin A (IgA) content — 300 μg/ml;

Excipients: glycine, sodium chloride, water for injections.

Produced from human blood plasma.

The pre-filled syringe (2 ml) contains 1500 IU (300 μg) of human anti-D immunoglobulin.

100 μg of human anti-D immunoglobulin corresponds to 500 international units (IU).

Potency is determined by the quantitative assay of the European Pharmacopoeia. The international unit equivalence of the international reference preparation is specified by the World Health Organization.

Excipients with known effect

This medicinal product contains no more than 7.8 mg of sodium in the pre-filled syringe.

Pharmaceutical form. Solution for injection for intramuscular administration.

Main physicochemical properties: clear, colourless or pale yellow or light brown liquid.

Pharmacotherapeutic group. Immune sera and immunoglobulins. Specific immunoglobulins. Anti-D (Rh) immunoglobulin. ATC code J06B B01.

Pharmacological Properties.

Pharmacodynamics.

Anti-D immunoglobulin contains specific antibodies (IgG) against the D rhesus (Rh) antigen of human red blood cells.

During pregnancy, and particularly during childbirth, fetal red blood cells may enter the maternal circulation. If the woman is Rh(D)-negative and the fetus is Rh(D)-positive, the woman may become immunized against the Rh(D) antigen and produce anti-Rh(D) antibodies, which can cross the placenta and may cause hemolytic disease in the newborn. Passive immunization with anti-D immunoglobulin prevents Rh(D) immunization in more than 99% of cases, provided an adequate dose of anti-D immunoglobulin is administered promptly after exposure to Rh(D)-positive fetal red blood cells.

The mechanism by which anti-D immunoglobulin suppresses immunization to Rh(D)-positive red blood cells is not fully understood. This suppression may be due to the rapid clearance of red blood cells from the circulation before they reach immunocompetent sites, or it may involve more complex mechanisms related to the recognition of foreign antigen and antigen presentation by appropriate cells in specific sites, in the presence or absence of antibody.

Children

Specific studies on efficacy and safety in children are lacking.

Pharmacokinetics.

Human anti-D immunoglobulin for intramuscular administration is slowly absorbed into the recipient's bloodstream and reaches peak levels within 2–3 days after administration.

The half-life of human anti-D immunoglobulin is approximately 3–4 weeks. The half-life may vary between individual patients.

IgG and IgG complexes are degraded by cells of the reticuloendothelial system.

Children

Specific studies on efficacy and safety in children are lacking.

Preclinical Safety Data

Immunoglobulins are natural components of the human body.

Toxicity studies following single high-dose administration in animals are not considered relevant, as high doses cause hypervolemia. Repeated-dose (multiple-dose) toxicity studies and embryotoxic/fetotoxic studies are not feasible due to the induction and synthesis of antibodies. The effect of the medicinal product on the immune system of newborns has not been studied.

Given that clinical experience with immunoglobulins has not demonstrated carcinogenic or mutagenic effects, experimental studies, including those involving heterologous species, are not considered necessary.

Clinical characteristics.

Indications.

For prevention of rhesus immunization [Rh(D)] in women of childbearing age with Rh(D)-negative blood group:

• Antenatal prophylaxis
  • Planned antenatal prophylaxis
  • Antenatal prophylaxis after complications of previous pregnancy, including:

spontaneous abortion/threatened abortion, ectopic pregnancy or hydatidiform mole, intrauterine fetal death, transplacental hemorrhage due to antepartum bleeding, amniocentesis, chorionic biopsy, obstetric manipulative procedures, e.g. external cephalic version, invasive interventions, cordocentesis, blunt abdominal trauma or fetal therapeutic interventions.

• Postnatal prophylaxis
  • Birth of an Rh(D)-positive (D, Dweak, Dpartial) infant

For treatment of Rh(D)-negative women of childbearing age after transfusion of incompatible Rh(D)-positive blood or other blood products containing red blood cells, e.g. platelet concentrate.

Contraindications.

Hypersensitivity to the active substance or to any of the excipients listed in the section "Composition".

Hypersensitivity to human immunoglobulins, especially in patients with antibodies against immunoglobulin A (IgA).

Special precautions.

Before administration, the medicinal product should be brought to room temperature or body temperature.

The solution should be clear and colorless or pale yellow to light brown. During storage, the solution may become slightly opalescent or a small amount of visible solid particles may form.

Do not use the solution if it is markedly cloudy or if a precipitate is present.

Before injecting the preparation, gently rotate the plunger rod of the syringe.

Any unused medicinal product and/or waste material resulting from its use should be destroyed in accordance with local requirements.

Interaction with other medicinal products and other forms of interaction.

Live attenuated viral vaccines

Vaccination with live attenuated viral vaccines, particularly against measles, mumps and rubella viruses, should not be performed earlier than 3 months after the last administration of anti-D immunoglobulin, since administration of immunoglobulin may interfere with the development of an adequate immune response to live attenuated viral vaccines.

If anti-D immunoglobulin must be administered within 2–4 weeks after vaccination with live viral vaccines, the effectiveness of such vaccination may be reduced.

Children

Although specific interaction studies in children have not been conducted, no differences between adults and children are expected.

Special precautions for use.

To avoid the risk of shock when using the medicinal product IMUNORO, ensure that the product is not administered intravascularly.

Postnatally, the medicinal product is intended for administration to the mother. The medicinal product must not be administered to the newborn infant.

Traceability

To improve traceability of biological medicinal products, the name and batch number of the product should be recorded whenever the product is administered to a patient.

Hypersensitivity

True hypersensitivity reactions are rare, but allergic reactions to anti-D immunoglobulin may occur.

The medicinal product IMUNORO contains a small amount of immunoglobulin A (IgA). Although anti-D immunoglobulin has been successfully used in individual patients with immunoglobulin A (IgA) deficiency, anti-IgA antibodies may develop in IgA-deficient patients, and anaphylactic reactions may occur after administration of medicinal products derived from human plasma containing immunoglobulin A (IgA). Therefore, the physician must weigh the benefits of treatment with IMUNORO against the potential risk of hypersensitivity reactions.

Rarely, human anti-D immunoglobulin may cause a drop in blood pressure leading to an anaphylactic reaction, even in patients who previously tolerated human immunoglobulin treatment well.

If an allergic or anaphylactic reaction is suspected, administration of the medicinal product should be stopped immediately. In case of shock, standard medical anti-shock measures should be implemented.

Hemolytic reactions

Patients who have received large doses of anti-D immunoglobulin due to transfusion of incompatible blood should be under clinical surveillance and require monitoring of biological parameters due to the risk of hemolytic reactions.

Thromboembolism

Arterial and venous thromboembolic complications, such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism, have been associated with the use of immunoglobulins. Although thromboembolic complications have not been observed in patients receiving IMUNORO, patients should be adequately hydrated prior to immunoglobulin administration.

Caution should be exercised when treating patients with pre-existing risk factors for thrombotic events (such as hypertension, diabetes, history of vascular disease or thrombotic complications, acquired or congenital thrombophilic disorders, prolonged immobilization, severe hypovolemia, or conditions increasing blood viscosity), especially when high doses of IMUNORO are prescribed.

Patients should be informed about the early symptoms of thromboembolic complications, such as difficulty breathing (dyspnea), pain and swelling of a limb, focal neurological symptoms, and chest pain, and should be advised to seek immediate medical attention if such symptoms occur.

Effect on serological test results

After administration of immunoglobulin, transient increases in levels of various antibodies passively transferred into the patient's bloodstream may lead to false-positive results in serological testing.

Passive transfer of antibodies against erythrocyte antigens, such as A, B, D, may interfere with the results of certain serological tests for erythrocyte antibodies (e.g., Coombs test), particularly in Rh(D)-positive infants whose mothers received antenatal prophylaxis.

Patients with overweight / obesity

Due to potentially reduced efficacy of intramuscular administration, patients with overweight or obesity are recommended to receive anti-D immunoglobulin for intravenous administration.

Safety information regarding transmissible agents

Standard precautions to prevent infections from medicinal products derived from human blood or plasma include donor selection, screening of individual donations and plasma pools for specific infectious markers, and the use of effective viral inactivation/removal steps during manufacturing.

Nevertheless, it is not possible to completely exclude the risk of transmitting infectious agents when administering medicinal products derived from human blood or plasma. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective against enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV), as well as against non-enveloped viruses such as hepatitis A virus (HAV).

The measures taken may have limited effectiveness against non-enveloped viruses such as parvovirus B19.

There is reassuring clinical experience regarding the absence of transmission of hepatitis A virus or parvovirus B19 with immunoglobulins. It is also expected that the presence of antibodies provides an important factor in antiviral protection.

It is strongly recommended to record the name and batch number of the IMUNORO product each time it is administered to a patient to ensure traceability between the patient's condition and the specific product batch.

Important information on excipients

This medicinal product contains up to 7.8 mg of sodium in the pre-filled syringe, which corresponds to 0.38% of the WHO recommended maximum daily sodium intake of 2 g for adults.

Children

No specific pediatric precautions or monitoring are required.

Use during pregnancy or breastfeeding.

Pregnancy

This medicinal product is intended for use during pregnancy.

Breastfeeding

This medicinal product may be used during breastfeeding. Immunoglobulins are excreted in breast milk.

Fertility

The effect of IMUNORO on fertility has not been studied. Clinical experience with anti-D immunoglobulin indicates that a harmful effect on fertility is not expected.

Ability to affect reaction speed when driving or operating machinery.

IMUNORO does not affect the ability to drive or operate machinery.

Administration and Dosage

Dosage

The dose of anti-D immunoglobulin should be determined according to the level of exposure to Rh(D)-positive red blood cells, based on the calculation that approximately 10 mcg (50 IU) of anti-D immunoglobulin is required to neutralize 0.5 mL of Rh(D)-positive red cell mass or 1 mL of Rh(D)-positive whole blood.

Additionally, recommended doses and dosing schedules for human anti-D immunoglobulin for intramuscular administration according to other official guidelines should also be considered.

Prevention of Rh(D) Immunization in Rh(D)-Negative Women

• Antenatal prophylaxis. According to current general recommendations, doses of 50–330 mcg or 250–1650 IU are administered.
  • Planned antenatal prophylaxis:

single dose at 28–30 weeks of gestation, or two doses at 28 and 34 weeks of gestation.

• Antenatal prophylaxis following pregnancy complications:

a single dose should be administered as soon as possible within the next 72 hours; if necessary, repeated administration at 6–12 week intervals during pregnancy.

• Postnatal prophylaxis. According to current general recommendations, doses of 100–300 mcg or 500–1500 IU are administered. If a lower dose (100 mcg or 500 IU) is prescribed, a test to determine the extent of fetal-maternal hemorrhage should be performed.

After delivery, the medicinal product should be administered to the mother as soon as possible within 72 hours after the birth of an Rh-positive (D, weak D, partial D) infant. Even if more than 72 hours have passed, the product should still be administered as soon as possible.

The postnatal dose should be administered even if antenatal prophylaxis has been performed, and even if residual activity of anti-D is detected in maternal serum following antenatal prophylaxis.

If a significant fetomaternal hemorrhage is suspected [> 4 mL (0.7–0.8% of women)], for example in cases of fetal/neonatal anemia or intrauterine fetal death, its extent should be determined by appropriate methods, such as the acid elution test of Kleihauer-Betke for detection of fetal hemoglobin (HbF), or flow cytometry for specific detection of Rh(D)-positive cells. Additional doses of anti-D immunoglobulin should be administered accordingly (10 mcg or 50 IU per 0.5 mL of fetal red blood cells).

Transfusion of Incompatible Red Blood Cells

The recommended dose is 20 mcg (100 IU) of anti-D immunoglobulin per 2 mL of transfused Rh(D)-positive blood or 1 mL of packed red blood cells.

Consultation with a specialist in transfusion medicine is recommended to assess the need for red blood cell exchange transfusion to reduce the D-positive red cell load in circulation and to determine the required dose of anti-D immunoglobulin to suppress immunization. Additional tests for D-positive red blood cells should be performed every 48 hours, and additional anti-D immunoglobulin administered until Rh(D)-positive red blood cells are no longer detectable in circulation. In each case, due to the potential risk of hemolysis, it is recommended not to exceed the maximum dose of 3000 mcg (15,000 IU).

The use of an alternative intravenous medicinal product is recommended as a means of achieving adequate plasma levels immediately. In the absence of an intravenous product, very high doses administered intramuscularly should be given over several days (see section "Special Warnings and Precautions for Use").

Children

The safety and efficacy of the medicinal product IMMUNORO in children have not been established. Appropriate dosing should be determined under the supervision of a specialist in transfusion medicine.

Route of Administration

IMMUNORO should be administered intramuscularly.

If a large volume (> 2 mL in children or > 5 mL in adults) needs to be administered, it is recommended to divide the dose into smaller volumes and inject at different sites.

If intramuscular administration is contraindicated (e.g., bleeding disorders), an alternative intravenous medicinal product should be used.

Patients with High Body Weight

For patients with high body weight / obesity, the use of intravenous anti-D immunoglobulin should be considered (see section "Special Warnings and Precautions for Use").

Children

The safety and efficacy of the medicinal product IMMUNORO in children have not been established.

Overdose

The consequences of overdose are unknown.

Adverse reactions.

Short description of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia (joint pain), hypotension (low blood pressure), and mild back pain may occasionally occur.

Rarely, human immunoglobulins may cause a sudden drop in blood pressure and, in individual cases, anaphylactic shock, even in patients who previously tolerated treatment with human immunoglobulin well.

Local reactions at the injection site may include swelling, pain, erythema (redness), induration (hardening), warmth, itching, hematoma, and rash.

Adverse reactions in tabular form

The table below presents adverse reactions that may occur with medicinal products containing anti-D human immunoglobulin for intramuscular administration, classified according to MedDRA (Medical Dictionary for Regulatory Activities) system organ classes and preferred terms.

Confirmed data on the frequency of adverse reactions from clinical trials are lacking.

Frequency was estimated using the following conventional categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000), frequency not known (cannot be estimated from available data).

Children

Specific data in children are not available.

For safety information regarding transmissible agents, see section "Special precautions for use".

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after registration of the medicinal product is important. It allows ongoing monitoring of the benefit/risk balance of this medicinal product. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life.

3 years.

Storage conditions.

Store in a refrigerator (at a temperature of 2 to 8 °C).

Do not freeze.

Keep the pre-filled syringe in the original cardboard packaging to protect from light.

Incompatibilities.

Due to the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Packaging.

2 ml of solution in a pre-filled syringe with an injection needle; 1 syringe in a cardboard box labelled in Ukrainian.

Prescription status.

Prescription only.

Manufacturer.

KEDRION S.P.A.

Manufacturer's address and location of manufacturing activities.

S.S.7 BIS KM. 19.5 – 80029 SANT'ANTIMO (NA), Italy.

Marketing Authorisation Holder.

KEDRION S.P.A.

Address of the Marketing Authorisation Holder.

LOCALITA' AI CONTI, CASTELVECCHIO PASCOLI, 55051 BARGA, LUCCA (LU), Italy.