00 micrograms (1500 IU) solution for intramuscular injection

International Nonproprietary Name: Human anti-D immunoglobulin

Composition

Active substance:
Each pre-filled syringe containing 2 ml of solution contains 300 micrograms (1500 IU) of human anti-D immunoglobulin. It is prepared from the blood plasma of human donors.

Excipients: glycine, sodium chloride, water for injections.

Description

A clear, colourless, pale yellow or light brown solution. During storage, slight cloudiness or a small amount of sediment may appear.

Pharmacotherapeutic group

Anti-D (Rh) immunoglobulin

ATC code: J06BB01.

Pharmacological properties

IMMUNORHO is a solution of human anti-D immunoglobulin containing antibodies that act against the D-type Rhesus factor.

The D-type Rhesus factor is a specific characteristic of human blood cells. People who carry the D-type Rhesus factor are Rh(D)-positive, while those who do not carry it are Rh(D)-negative.

When an Rh(D)-negative person receives Rh(D)-positive blood—for example, when the blood of an Rh(D)-negative pregnant woman comes into contact with the blood of an Rh(D)-positive fetus—the mother’s immune system recognizes the Rh(D)-positive fetal erythrocytes as foreign blood cells and produces specific antibodies against the D-type Rhesus factor.

This process, known as immunization, usually takes 2–3 weeks. Therefore, Rh(D)-positive blood cells are not destroyed during the first exposure and no signs or symptoms usually occur. Upon subsequent exposure to Rh(D)-positive blood, the antibodies previously produced are ready to destroy the Rh(D)-positive fetal erythrocytes. This may cause hemolytic disease of the newborn.

When human anti-D (Rh) immunoglobulin is administered to an Rh(D)-negative person, it prevents the formation of antibodies against Rh(D)-positive erythrocytes. Immunization against the D-type Rhesus factor can be prevented in more than 99% of cases. To achieve this, treatment with IMMUNORHO should be started with an adequate dose before the first exposure to Rh(D)-positive erythrocytes or as soon as possible after exposure.

The mechanism by which anti-D immunoglobulin prevents immunization against Rh(D)-positive erythrocytes is not known. It may be related to the removal of erythrocytes from the circulation before they reach the relevant sites. Other, more complex mechanisms involving antigen recognition and antigen presentation by appropriate cells, with or without the participation of antibodies, may also be involved.

Pharmacokinetic properties

After intramuscular administration, anti-D immunoglobulin is slowly absorbed and reaches the circulation after a delay of approximately 2–3 days.

The half-life of human anti-D immunoglobulin is approximately 3–4 weeks, although this may vary from patient to patient. IgG and IgG complexes are broken down in cells of the reticuloendothelial system.

Indications for use

IMMUNORHO is used to prevent Rh(D) immunization in Rh(D)-negative women of reproductive age in the following situations:

Antenatal prophylaxis

• Routine antenatal prophylaxis.
• Antenatal prophylaxis following pregnancy complications, including:
  • abortion/threatened abortion;
  • ectopic pregnancy;
  • hydatidiform mole;
  • antepartum hemorrhage resulting from transplacental bleeding;
  • amniocentesis;
  • chorionic biopsy;
  • obstetric procedures, such as external version;
  • invasive procedures;
  • fetal blood sampling from the umbilical cord (cordocentesis);
  • acute abdominal trauma;
  • therapeutic procedures involving the fetus in utero.

Postnatal prophylaxis

Following delivery of an Rh(D)-positive infant (D, weak D, partial D).

IMMUNORHO is also indicated in Rh(D)-negative women of reproductive age following inappropriate transfusion of Rh(D)-positive blood or other products containing erythrocytes, such as platelet concentrates.

Contraindications

• Hypersensitivity to human immunoglobulin or to any of the other components of this medicinal product.
• Hypersensitivity to human immunoglobulins, particularly in patients with antibodies against IgA.

Special warnings and precautions for use

Consult your doctor or nurse before using IMMUNORHO.

Due to the risk of shock, care must be taken to ensure that IMMUNORHO is not administered intravenously.

For postnatal use, the product is intended for administration to the mother. It must not be administered to the newborn infant.

The product is not intended for use in Rh(D)-positive individuals.

Hypersensitivity

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

IMMUNORHO contains a small amount of IgA. Although human anti-D immunoglobulin has been successfully used in some individuals with IgA deficiency, individuals with IgA deficiency may develop anti-IgA antibodies and may experience anaphylactic reactions following administration of medicinal products derived from plasma containing IgA.

Therefore, the physician should carefully assess the benefits of treatment with IMMUNORHO against the potential risk of hypersensitivity reactions.

In rare cases, human anti-D immunoglobulin may cause an anaphylactic reaction accompanied by a decrease in blood pressure, even in patients who have previously tolerated treatment with human immunoglobulin.

If an allergic or anaphylactic reaction is suspected, the injection must be stopped immediately. The physician will discontinue administration and treat the reaction according to its nature and severity.

Hemolytic reactions

If very high doses of anti-D immunoglobulin are administered following an inappropriate blood transfusion, a hemolytic reaction may occur.

For this reason, your doctor will monitor you closely and determine whether specific blood tests are necessary.

Thromboembolism

Arterial and venous thromboembolic events, including myocardial infarction, stroke, deep vein thrombosis and pulmonary embolism, have been associated with the use of immunoglobulins.

Although thromboembolic events have not been observed in patients receiving IMMUNORHO, patients should receive adequate fluids before administration of immunoglobulins.

Particular attention should be paid to patients with pre-existing risk factors for thrombotic events, including:

• hypertension;
• diabetes mellitus;
• vascular disease or a history of thrombotic events;
• hereditary or acquired thrombophilia;
• prolonged immobilization;
• severe hypovolemia;
• diseases associated with increased blood viscosity;

particularly patients receiving high doses of IMMUNORHO.

Patients should be informed about the initial symptoms of thromboembolic events, including shortness of breath, swelling and pain in the limbs, focal neurological deficits and chest pain, and should be advised to contact their doctor immediately if these symptoms occur.

The appropriate dose should be calculated in consultation with a specialist in transfusion medicine.

Viral safety

Standard measures should be taken to prevent infections resulting from the use of medicinal products prepared from human blood or plasma. These include:

• careful selection of blood and plasma donors to exclude donors at risk of carrying infections;
• screening of each donor and additional donors for signs of viral/infectious diseases;
• inclusion of virus inactivation/removal steps during the processing of blood or plasma.

Despite these measures, the possibility of transmission of infection cannot be completely excluded when medicinal products prepared from human blood or plasma are administered. This also applies to unknown or newly identified 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 the non-enveloped hepatitis A virus (HAV).

The measures may have limited effectiveness against non-enveloped viruses such as parvovirus B19. Immunoglobulins are unlikely to be associated with hepatitis A or parvovirus B19 infections because the product contains antibodies that provide protection against these infections.

Whenever IMMUNORHO is administered to a patient, it is recommended that the product name and batch number be recorded to maintain a link between the patient and the product batch.

Blood tests

If you or your newborn require blood tests (serological tests), tell your doctor that you have received IMMUNORHO.

After administration of this product, some blood test results may be falsely positive due to passive transfer of antibodies against certain erythrocyte antigens, such as A, B and D.

If you are a mother who received this product before delivery, some blood tests performed on your newborn, such as the antiglobulin test (Coombs test), may be affected.

Warnings concerning excipients

Each vial of this medicinal product contains up to 7.8 mg of sodium, which corresponds to 0.38% of the recommended maximum daily dietary sodium intake for adults.

IMMUNORHO must not be mixed with other medicinal products.

If you experience any adverse effects not mentioned in this leaflet, contact your doctor or pharmacist.

Interaction with other medicinal products

Tell your doctor or pharmacist if you are taking, or have recently taken, any other medicinal products.

Vaccines

IMMUNORHO may interfere with the effectiveness of live attenuated viral vaccines such as measles, rubella and mumps vaccines.

These vaccines should be postponed for 3 months after administration of IMMUNORHO.

If you have received a vaccination during the previous 2–4 weeks, inform your doctor before treatment.

Anti-D immunoglobulin should be administered 2–4 weeks after vaccination with live viral vaccines. If anti-D immunoglobulin must be administered within 2–4 weeks after a live viral vaccination, the effectiveness of the vaccine may be reduced; therefore, your doctor should plan appropriate monitoring of vaccine effectiveness.

Children

Although no specific interaction studies have been conducted in the pediatric population, no differences are expected between adults and children.

Pregnancy and lactation

IMMUNORHO is intended for use during pregnancy and may also be used during lactation.

Immunoglobulins are excreted in human milk.

No animal reproductive studies have been conducted with IMMUNORHO. Clinical experience has shown no harmful effects of human anti-D immunoglobulin on reproductive function.

Effects on ability to drive and use machines

IMMUNORHO has no effect on the ability to drive vehicles or operate other potentially hazardous machinery.

Method of administration and dosage

The dose of anti-D immunoglobulin should be determined according to the extent of exposure to Rh(D)-positive erythrocytes, taking into account that approximately 10 micrograms (50 IU) of anti-D immunoglobulin neutralizes 0.5 ml of Rh(D)-positive erythrocytes or 1 ml of Rh(D)-positive blood.

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

Antenatal prophylaxis

According to general recommendations, the currently accepted dose ranges from 50–330 micrograms (250–1650 IU).

Routine antenatal prophylaxis:

• One dose at 28–30 weeks of pregnancy, or
• Two doses at 28 and 34 weeks of pregnancy.

Antenatal prophylaxis following pregnancy complications

One dose should be administered as soon as possible and within 72 hours and, if necessary, repeated during pregnancy at intervals of 6–12 weeks.

Postnatal prophylaxis

According to general recommendations, the currently accepted dose ranges from 100–300 micrograms (500–1500 IU).

If the lower dose of 100 micrograms (500 IU) is administered, testing should be performed to determine the volume of fetomaternal hemorrhage.

For postnatal use, the product should be administered to the mother as soon as possible and within 72 hours after delivery of an Rh-positive (D, weak D or partial D) infant.

If more than 72 hours have elapsed, administration should not be withheld; the product should be administered as soon as possible.

The postnatal dose should still be administered even if antenatal prophylaxis was given and residual activity of the antenatal prophylaxis is detectable in the mother’s serum.

If significant fetomaternal hemorrhage >4 ml is suspected, for example in cases of fetal/neonatal anemia or intrauterine fetal death, its volume should be determined using an appropriate method, such as the Kleihauer-Betke acid elution test or flow cytometry capable of detecting fetal HbF or Rh(D)-positive cells.

Additional doses of anti-D immunoglobulin should then be administered accordingly: 10 micrograms (50 IU) per 0.5 ml of fetal erythrocytes.

Inappropriate transfusion of Rh(D)-positive erythrocytes

The recommended dose is 20 micrograms (100 IU) of anti-D immunoglobulin per 2 ml of transfused Rh(D)-positive blood or per 1 ml of RBC concentrate.

Consultation with a transfusion medicine specialist is recommended to determine the appropriate anti-D immunoglobulin dose and assess whether an erythrocyte exchange procedure is appropriate for reducing the circulating load of D-positive erythrocytes and preventing immunization.

Follow-up testing for D-positive erythrocytes should be performed every 48 hours, and additional anti-D should be administered until no D-positive erythrocytes are detected in the circulation.

In any case, due to the potential risk of hemolysis, it is recommended not to exceed a maximum dose of 3000 micrograms (15,000 IU).

An intravenous formulation is recommended because it allows the appropriate plasma levels to be reached immediately.

If no intravenous product is available, a very high dose should be administered intramuscularly over several days.

Method of administration

IMMUNORHO is administered intramuscularly.

If a large volume is required (>2 ml in children or >5 ml in adults), administration in divided doses at different injection sites is recommended.

If intramuscular administration is contraindicated, for example in patients with bleeding disorders, an alternative intravenous product should be used.

Patients with high body mass

For patients with high body mass (BMI ≥30), use of an intravenous anti-D product should be considered.

Children

No specific precautions or monitoring are required.

The safety and efficacy of IMMUNORHO in children have not been established. The appropriate dose should be calculated in consultation with a transfusion medicine specialist.

Injection solution

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

The prepared solution is clear and colourless or pale yellow/light brown. During storage, slight cloudiness or a small amount of particulate matter may appear.

Do not use the solution if it is cloudy or contains sediment.

The protective cap of the pre-filled syringe should be removed and the injection administered.

Adverse effects

Like all medicinal products, this medicine may cause side effects, although not everybody experiences them.

The following adverse effects may occur rarely with human anti-D immunoglobulin products intended for intramuscular administration:

• allergic reaction (hypersensitivity);
• headache;
• dizziness;
• increased heart rate (tachycardia);
• low blood pressure (hypotension);
• nausea;
• vomiting;
• skin reactions;
• skin redness (erythema);
• itching/pruritus;
• joint pain (arthralgia);
• back pain;
• fever;
• malaise;
• chills.

Injection-site reactions: swelling, pain, skin redness (erythema), induration, warmth, pruritus, redness, itching and rash.

In isolated cases, anaphylactic shock may occur.

These reactions may occur even in patients who have not previously experienced hypersensitivity to the product.

Reporting suspected adverse reactions is important because it allows continuous monitoring of the benefit-risk balance of the medicinal product.

Adverse effects in children

No specific data are available for the pediatric population.

If you experience any side effect, contact your doctor or healthcare professional, including any possible side effects not listed in this leaflet.

Overdose

No cases of overdose are known.

Pharmaceutical form

Solution for intramuscular injection.

2 ml of solution in a pre-filled syringe with a rubber (halobutyl) stopper and a pre-sealed needle.

One pre-filled syringe is packaged in a cardboard box together with the package leaflet.

Storage conditions

Keep out of the reach of children.

Do not use this medicinal product after the expiry date stated on the package. The expiry date refers to the last day of the specified month.

Store the injection solution in its original packaging, in a refrigerator at 2–8°C, protected from light by keeping it in the inner carton.

Do not freeze.

Do not use the medicinal product if the solution is cloudy or contains sediment.

Do not dispose of medicinal products via wastewater or household waste. Ask your pharmacist how to dispose of medicines that you no longer use. These measures will help protect the environment.

Shelf life

3 years.

Do not use after the expiry date.

Conditions of dispensing

Prescription-only medicine.

Manufacturer

Kedrion S.p.A.
S.S. 7 bis Km 19.5, 80029 S. Antimo (Naples), Italy.

Marketing Authorisation Holder

Kedrion S.p.A.
Loc. Ai Conti, 55051 Castelvecchio Pascoli, Barga (Lucca), Italy.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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