Rezonativ

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT REZONATIV

Composition:

International Nonproprietary Name: Human anti-D immunoglobulin;

Active substance: 1 ml of solution contains 625 IU (125 μg) of human anti-D immunoglobulin. (total protein content 165 mg, with human immunoglobulin G content not less than 95%);

Excipients: glycine, sodium chloride, sodium acetate, polysorbate 80, water for injections.

The content of immunoglobulin A (IgA) does not exceed 0.05% of the total protein content.

One 1 ml ampoule contains 625 IU (125 μg) of human anti-Rhesus (anti-D) immunoglobulin.

One 2 ml ampoule contains 1250 IU (250 μg) of human anti-Rhesus (anti-D) immunoglobulin.

Activity is determined by quantitative analysis according to the European Pharmacopoeia. Equivalence in International Units is referenced to the international standard preparation as defined by the World Health Organization.

Distribution of IgG subclasses (approximate values): IgG1 – 70.5%, IgG2 – 26.0%, IgG3 – 2.8%, IgG4 – 0.8%. Maximum IgA content: 82.5 μg/ml. Produced from human blood plasma.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear or slightly opalescent solution, colorless to pale yellow or light brown. Slight cloudiness or a small amount of mechanical particles may form during storage.

Pharmacotherapeutic group.
Immune sera and 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 mother is Rh(D)-negative and the fetus is Rh(D)-positive, the mother may become immunized against the Rh(D) antigen and produce anti-Rh(D) antibodies, which cross the placenta and may cause hemolytic disease of 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 related to the clearance of red blood cells from the circulation before they reach immunocompetent sites, or possibly due to more complex mechanisms involving the recognition of foreign antigen and antigen presentation by appropriate cells at relevant sites, in the presence or absence of antibody.

Postnatal prophylaxis studies (studies 1–6) and antenatal prophylaxis (study 7) in patients.

Clinical trials of Resonativ were initiated to evaluate the efficacy and safety of the product. The table below provides an overview of the most important efficacy data:

PMP – postpartum prophylaxis; IUP – in utero prophylaxis; n.p. – not reported.

* 6-8 weeks before the expected date of delivery.

Based on data from these studies, it can be concluded that treatment with Rhogenate provides reliable anti-D prophylaxis.

Study of transfusion of Rh-incompatible blood components.

In study No. 8, the efficacy of Rhogenate was evaluated in 21 Rh-negative volunteers who received Rh-positive, ABO-compatible fetal red blood cells in volumes corresponding to 10 mL (1 case), 25 mL (10 cases), and 50 mL (10 cases) of cord blood. Two to three days later, 260 mcg of Rhogenate was administered intramuscularly. Six months (in one case, 9 months) after the start of the experiment, no serological signs of Rh immunization were detected in any of the subjects. During the period from 6 months to 2.5 years, 8 individuals from the 25 mL group and all 10 individuals from the 50 mL group received 5 mL of Rh-positive, ABO-compatible cord blood. Two to three days later, 260 mcg and 333 mcg of Rhogenate were administered, respectively. Six months later (in one case, 8 months later), no Rh antibodies were detected in any of the individuals.

The results of this study demonstrate that Rh prophylaxis is achieved with administration of anti-D immunoglobulin at a dose of 10 mcg per 1 mL of fetal blood. It was concluded that, since fetoplacental hemorrhage at the end of pregnancy poses a risk of Rh immunization, Rhogenate at a dose of 260 mcg prevents serologically detectable Rh immunization in at least 998 out of 1,000 Rh-negative mothers.

Pharmacokinetic study of Rhogenate.

The main pharmacokinetic parameters and metabolism of Rhogenate were studied in 15 Rh-negative pregnant women who received Rhogenate intramuscularly at week 28 of pregnancy. Eight women received a dose of 125 mcg, and seven women received 250 mcg. Additionally, three non-pregnant Rh-negative women received lower doses.

The biological half-life of anti-D IgG after intramuscular injection of Rhogenate at a dose of 125 mcg in these women was consistent with values described in the literature (see section "Pharmacokinetics").

Pharmacokinetics.

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

The half-life in the circulation in individuals with normal IgG levels is 3–4 weeks. The half-life may vary among different patients.

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

Clinical characteristics.

Indications.

Prevention of Rh(D) immunization in Rh(D)-negative women of childbearing age

• Antenatal prophylaxis.
  • Planned antenatal prophylaxis.
  • Antenatal prophylaxis following complications of previous pregnancy, including miscarriage/threatened miscarriage, ectopic pregnancy or hydatidiform mole, intrauterine fetal death, transplacental hemorrhage due to antepartum bleeding, amniocentesis, chorionic biopsy or obstetric manipulative procedures such as external cephalic version, invasive interventions, cordocentesis, blunt abdominal trauma, or fetal therapeutic interventions.
• Postnatal prophylaxis.
  • Birth of an Rh(D)-positive (D, weak D, partial D) infant.

Treatment of Rh(D)-negative women of childbearing age following transfusion of Rh(D)-incompatible blood or other blood products containing red blood cells, e.g., platelet concentrate/platelet mass.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients.

Hypersensitivity to human immunoglobulin, particularly in patients with antibodies to IgA.

Special precautions.

Resonativ must not be administered intravenously (risk of shock). The product should be administered intramuscularly, and prior to injection, the syringe plunger should be carefully withdrawn to ensure that the needle has not entered a blood vessel.

After postnatal administration, Resonativ is intended for administration to the mother. It should not be administered to the newborn.

The product is not intended for administration to Rh(D)-positive individuals or to individuals previously immunized against Rh(D) antigen.

Patients should be observed for at least 20 minutes after administration and for 1 hour following accidental intravenous injection.

Human anti-D immunoglobulin may exceptionally cause a drop in blood pressure with anaphylactic reaction, even in patients who previously tolerated treatment with human immunoglobulin.

In case of symptoms of allergic or anaphylactic reaction, administration must be stopped immediately.

Hypersensitivity

True hypersensitivity reactions are rare, but allergic reactions to anti-D immunoglobulin may occur. Patients should be informed about early signs of hypersensitivity reactions such as urticaria, generalized urticaria, chest tightness, dyspnea, hypotension, and anaphylaxis. Treatment depends on the nature and severity of the adverse reaction. In case of shock, modern medical treatment for shock should be administered.

Resonativ contains a small amount of IgA. Although anti-D immunoglobulin has been successfully used in the treatment of individual patients with IgA deficiency, patients with IgA deficiency may develop antibodies against IgA and may experience anaphylactic reactions after administration of medicinal products containing IgA derived from human plasma. The physician must weigh the benefits against the risks of potential hypersensitivity reactions.

Rarely, human anti-D immunoglobulin may cause a drop in blood pressure with anaphylactic reaction even in patients who have previously tolerated treatment with human immunoglobulin.

Suspicion of allergic or anaphylactoid reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment should be initiated.

Hemolytic reactions

Patients who have undergone transfusion of incompatible blood and received a high dose of anti-D immunoglobulin should be continuously monitored for clinical and biological parameters due to the risk of hemolytic reactions.

Thromboembolic events

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 with the use of Resonativ, patients should be adequately hydrated prior to immunoglobulin administration. Caution is required when treating patients with pre-existing risk factors for thrombotic events (such as hypertension, diabetes, history of vascular disease or thrombotic complications, patients with acquired or inherited thrombophilic disorders, patients with prolonged immobility, patients with severe hypovolemia, or patients with conditions increasing blood viscosity), especially when higher doses of Resonativ are administered.

Patients should be informed about early symptoms of thromboembolic complications such as dyspnea (shortness of breath), pain and swelling of a limb, focal neurological symptoms, and chest pain; they should seek immediate medical consultation if such symptoms occur.

Effect on serological testing

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

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

Patients with overweight/obesity

For patients with overweight/obesity, intravenous administration of anti-Rh(D) product is recommended due to the potential for reduced efficacy of intramuscular administration.

Standard measures to prevent infections transmitted by medicinal products derived from human blood or plasma include donor selection, testing of individual blood donations and plasma pools for specific infection markers, and implementation of effective manufacturing processes for virus inactivation or removal. Nevertheless, when using medicinal products derived from human blood or plasma, the possibility of transmission of infectious agents cannot be completely excluded. This also applies to unknown or newly emerging viruses and other pathogens.

The measures used are considered effective against enveloped viruses such as HIV, hepatitis B virus, and hepatitis C virus, as well as against the non-enveloped hepatitis A virus.

For certain non-enveloped viruses, such as parvovirus B19, the effectiveness of the measures is limited.

There is reassuring clinical experience regarding the absence of transmission of hepatitis A virus or parvovirus B19 with immunoglobulins, and it is assumed that the presence of antibodies is an important factor in antiviral protection.

It is strongly recommended that the name and batch number of Resonativ be recorded each time the product is administered to a patient.

Important information about certain excipients of Resonativ

This medicinal product contains less than 1 mmol sodium (23 mg) per 1 ml (625 IU), in other words, it is considered "sodium-free."

In case of shock, standard medical treatment must be initiated.

Interaction with other medicinal products and other forms of interaction.

Live attenuated viral vaccines.

Active immunization with live viral vaccines (e.g., measles, mumps, or rubella) should be postponed for 3 months after the last administration of anti-D immunoglobulin, as the efficacy of the live viral vaccine may be reduced.

If anti-D immunoglobulin needs to be administered within 2–4 weeks after vaccination with live viral vaccines, the efficacy of the viral vaccine may be reduced.

Interference with serological assays.

After immunoglobulin injection, transient increase in various passively transferred antibodies into the patient's blood may lead to false-positive results in serological tests.

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

Special precautions for use

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

The solution should be clear or slightly opalescent, ranging from colorless to pale yellow or light brown.

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

Any unused product or waste material should be disposed of in accordance with local regulations.

Use during pregnancy or breastfeeding

Resonativ is intended for use during pregnancy.

Fertility

No studies on the effect of Resonativ on animal fertility have been conducted. Nevertheless, based on clinical experience with human anti-Rhesus immunoglobulin, it is expected that Resonativ does not affect fertility.

Breastfeeding

Resonativ can be used during breastfeeding.

Immunoglobulins are excreted in breast milk. No adverse reactions in infants born to over 450 women who received standard doses of Resonativ in the postpartum period have been reported.

Ability to conceive

No reproductive toxicity studies in animals have been conducted with Resonativ. Clinical experience with anti-Rhesus immunoglobulin indicates that its administration is not expected to have a harmful effect on fertility.

Ability to affect reaction speed when driving vehicles or operating machinery

Resonativ does not affect the ability to drive vehicles or operate machinery.

Method of Administration and Dosage

Resonativ should be administered intramuscularly.

If large total doses (>5 mL for adults) are required, it is recommended to divide them into smaller doses and administer at different injection sites.

In cases of hemorrhagic disorders where intramuscular injections are contraindicated, Resonativ may be administered subcutaneously if intravenous preparations are unavailable. After injection, a soft compressive dressing should be carefully applied to the injection site.

The dose of anti-D immunoglobulin should be determined according to the extent of exposure to Rh(D)-positive red blood cells, considering that approximately 10 mcg (50 International Units, 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.

Based on clinical trial data for Resonativ, the following dosing recommendations are advised.

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

• Antenatal prophylaxis:

According to general recommendations, doses of 50–330 mcg or 250–1650 IU (or 0.4–2.64 mL) are currently prescribed.

• Planned antenatal prophylaxis:

A single dose (e.g., 250 mcg or 1250 IU (or 2 mL)) is administered at 28–30 weeks of gestation, or two doses at 28 and 34 weeks of gestation.

• Antenatal prophylaxis following complications of previous pregnancy:

A single dose (e.g., 125 mcg or 625 IU (or 1 mL)) should be administered before 12 weeks of gestation; and 250 mcg or 1250 IU (or 2 mL) after 12 weeks of gestation. The dose should be given as soon as possible within 72 hours and, if necessary, repeated every 6–12 weeks throughout pregnancy.

After amniocentesis or chorionic villus sampling, a single dose (e.g., 250 mcg or 1250 IU (or 2 mL)) should be administered.

• Postnatal prophylaxis: according to general recommendations, doses of 100–300 mcg or 500–1500 IU (or 0.8–2.4 mL) are currently prescribed. If a lower dose (100 mcg or 500 IU) is prescribed, the volume of fetal-maternal hemorrhage should be determined.

Standard dose: 1250 IU (250 mcg or 2 mL).

After delivery, the product should be administered to the mother as soon as possible within 72 hours after 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 early as possible.

The product should be administered postnatally even if antenatal prophylaxis has been performed, and also when residual activity from antenatal prophylaxis is present in maternal serum.

If a significant fetoplacental hemorrhage (>4 mL (0.7%–0.8% of women)) is suspected, e.g., in cases of fetal/neonatal anemia or intrauterine fetal death, the 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 (10 mcg or 50 IU per 0.5 mL of fetal red blood cells) should be administered accordingly.

Transfusion of Incompatible Red Blood Cells (RBCs)

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

Consultation with a transfusion medicine specialist is recommended to assess the need for red blood cell exchange transfusion to reduce the burden of Rh-positive red cells in circulation and to determine the required dose of anti-D immunoglobulin to suppress immunization. Additional testing for Rh D-positive red blood cells should be performed every 48 hours, and administration of anti-D immunoglobulin should be continued until all Rh D-positive red cells are cleared from circulation. In any case, due to the potential risk of hemolysis, exceeding the maximum recommended dose of 3000 mcg (15,000 IU) should be avoided. Use of an alternative intravenous preparation is recommended, as it achieves adequate plasma levels immediately. If an intravenous preparation is unavailable, large volumes may be administered intramuscularly over several days.

Children

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

Patients with High Body Weight

For patients with high body weight, consideration should be given to using intravenous anti-D immunoglobulin.

Overdose

Data on overdose are lacking. Patients who have received transfusion of incompatible blood and a high dose of anti-D immunoglobulin should be continuously monitored for clinical and biological parameters due to the risk of hemolytic reactions.

In other Rh(D)-negative individuals, overdose does not result in more frequent or severe adverse effects than those observed with standard doses.

Adverse reactions.

Short description of the safety profile

Adverse reactions that may occasionally occur include chills, headache, dizziness, fever, allergic reactions, nausea, arthralgia (joint pain), low blood pressure, and mild lower back pain.

Rarely, human immunoglobulins may cause a sudden drop in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has not demonstrated hypersensitivity upon previous administration.

Local reactions at the injection site: swelling, painful sensation, redness, induration (hardening), feeling of warmth, itching, hematoma, local pain, tenderness, and rash. Some of these reactions may be prevented by dividing larger doses into smaller doses administered at multiple sites.

For information on safety regarding transmission of infections, see section "Special precautions for use".

Reliable data on the frequency of adverse reactions from clinical trials have not been obtained. The following adverse reactions have been reported:

The table below follows the Medical Dictionary for Regulatory Activities (MedDRA) system organ classification (SOC) and preferred terms.

Frequency is categorized according to the following conventional notation: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from available data).

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after authorization of the medicinal product is important. It allows for continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions.

Shelf life.

2.5 years.

An opened ampoule must be used immediately.

Storage conditions.

Store at 2 to 8 °C (in the refrigerator).

Keep ampoules in the original packaging to protect from light. Do not freeze.

Keep out of reach and sight of children.

Within the shelf life, the medicinal product may be stored at temperatures up to 25 °C (outside the refrigerator) for up to 1 month. If the medicinal product has not been used within 1 month, it must be disposed of.

Incompatibilities.

Rezonyat must not be mixed with other medicinal products.

Packaging.

1 ml or 2 ml solution for injection in Type I glass ampoules, Ph. Eur., with a red snap ring, 1 ampoule per plastic blister pack.

1 plastic blister pack per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Octapharma AB, Sweden.

Manufacturer's name and address.

Lars Forssells gata 23, Stockholm, 11275, Sweden.