4.1. Therapeutic indications

Prevention of Rh(D) immunisation in Rh(D) negative women of childbearing age

• Antenatal prophylaxis

Planned antenatal prophylaxis

Antenatal prophylaxis following complications of pregnancy including:

Abortion/threatened abortion, ectopic pregnancy or hydatidiform mole, intrauterine foetal death (IUFD), transplacental haemorrhage (TPH) resulting from ante-partum haemorrhage (APH), amniocentesis, chorionic biopsy, obstetric manipulative procedures e.g. external version, invasive interventions, cordocentesis, blunt abdominal trauma or foetal therapeutic intervention

• Post-natal prophylaxis

Delivery of a Rh(D) positive (D, Dweak, Dpartial) baby

Treatment of Rh(D) negative persons after incompatible transfusions of Rh(D) positive blood or other products containing red blood cells e.g. platelet concentrate.

4.2. Posology and method of administration

Posology

The dose of anti-D immunoglobulin should be determined according to the level of exposure to Rh(D) positive red blood cells and based on the knowledge that 0.5 ml of packed Rh(D) positive red blood cells or 1 ml of Rh(D) positive blood is neutralised by approximately 10 micrograms (50 IU) of anti-D immunoglobulin.

The following doses are recommended based on the clinical studies performed with D-Gam.

Prevention of Rh(D) immunisation in Rh(D) negative women

• Antenatal prophylaxis.

According to general recommendations, currently administered doses range from 50 – 330 micrograms or 250 - 1650 IU

• Planned antenatal prophylaxis:

A single dose of 1,500 IU at 28 - 30 weeks of gestation or 500 IU given at both 28 and 34 weeks of gestation.

• Antenatal prophylaxis following complications of pregnancy:

A single dose should be administered as soon as possible and within 72 hours and if necessary repeated at 6 – 12 week intervals throughout the pregnancy:

- up to 20 weeks gestation –250 IU minimum

- after 20 weeks gestation – 500 IU per incident. A test for the size of the foetomaternal haemorrhage (FMH) should be performed when anti-D is given after 20 weeks and additional doses of anti-D should be administered as indicated.

• Postnatal prophylaxis. According to general recommendations, currently administered doses range from 100 – 300 micrograms or 500 – 1500 IU. If the lower dose (100 micrograms or 500 IU) is administered then testing of the amount of FMH should be performed.

The recommended dose is 500 IU.

For postnatal use, the product should be administered to the mother as soon as possible within 72 hours of delivery of a Rh positive (D, Dweak, Dpartial) infant. If more than 72 hours have elapsed, the product should not be withheld but administered as soon as possible.

The postnatal dose must still be given even when antenatal prophylaxis has been administered and even if residual activity from antenatal prophylaxis can be demonstrated in maternal serum.

If a large FMH (> 4 ml (0.7%-0.8% of women)) is suspected, e.g. in the event of foetal/neonatal anaemia or intrauterine foetal death, its extent should be determined by a suitable method e.g. Kleihauer-Betke acid elution test to detect foetal haemoglobin (HbF) or flow cytometry which specifically identifies RhD positive cells. Additional doses of anti-D immunoglobulin should be administered accordingly (10 micrograms or 50 IU) per 0.5 ml foetal red blood cells).

Incompatible transfusions of red blood cells (RBCs)

The recommended dose is 20 micrograms (100 IU) anti-D immunoglobulin per 2 ml of transfused Rh(D) positive blood or per 1 ml of RBC concentrate. It is recommended that there is a consultation with a specialist in transfusion medicine in order to evaluate the feasibility of a red cell exchange procedure to reduce the load of D positive red cells in circulation and to define the dose of anti-D immunoglobulin required to suppress immunisation. Follow-up tests for D positive red cells should be undertaken every 48 hours and further anti-D given until there are no detectable D positive red cells in circulation. In any case, due to possible risk of haemolysis it is suggested to not exceed a maximum dose of 3,000 micrograms (15,000 IU).

The use of an alternative intravenous product is recommended as it will achieve adequate plasma levels immediately. If no intravenous product is available, the very large volume should be administered intramuscularly over a period of several days (see section 4.4).

Paediatric population

The safety and efficacy of D-Gam in children aged 0-18 years has not been established. No data are available.

Method of administration

Intramuscular use.

The usual recommended site for intramuscular injection for adults is the deltoid.

If a large volume (> 2 ml for children or > 5 ml for adults) is required, it is recommended to administer this in divided doses at different sites.

If intramuscular administration is contra-indicated (bleeding disorders), an alternative intravenous product should be used.

Overweight/obese patients

In case of overweight/obese patients the use of an intravenous anti-D product should be considered (see section 4.4).

4.3. Contraindications

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

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1 (see section 4.4).

Hypersensitivity to human immunoglobulins especially in patients with antibodies against IgA.

4.4. Special warnings and precautions for use

Ensure that D-Gam is not administered into a blood vessel, because of the risk of shock.

In the case of post-natal use, the product is intended for maternal administration. It should not be given to the new-born infant.

Hypersensitivity

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

D-Gam contains a small quantity of IgA. Although anti-D immunoglobulin has been used successfully in selected IgA deficient individuals, individuals who are deficient in IgA have the potential for developing IgA antibodies and may have anaphylactic reactions after administration of plasma derived medicinal products containing IgA. The physician must therefore weigh the benefit of treatment with D-Gam against the potential risks of hypersensitivity reactions.

Rarely, human anti-D immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who have tolerated previous treatment with human immunoglobulin.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented.

Haemolytic reactions

Patients in receipt of incompatible transfusion, who receive very large doses of anti-D immunoglobulin, should be monitored clinically and by biological parameters, because of the risk of haemolytic reaction.

Thromboembolism

Arterial and venous thromboembolic events including myocardial infarction, stroke, deep venous thrombosis and pulmonary embolism have been associated with the use of immunoglobulins. Although thromboembolic events have not been observed for D-Gam, patients should be sufficiently hydrated before use of immunoglobulins. Caution should be exercised in patients with pre-existing risk factors for thrombotic events (such as hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic patients, patients with diseases which increase blood viscosity), especially when higher doses of D-Gam are prescribed.

Patients should be informed about first symptoms of thromboembolic events including shortness of breath, pain and swelling of a limb, focal neurological deficits and chest pain and should be advised to contact their physician immediately upon onset of symptoms.

Interference with serological testing

After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies, for example the antiglobulin test (Coombs' test) particularly in Rh(D) positive neonates whose mothers have received antenatal prophylaxis.

Overweight/obese patients

In overweight/obese patients, due to the possible lack of efficacy in case of intramuscular administration, an intravenous anti-D product is recommended.

Transmissible agents

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the non-enveloped hepatitis A and parvovirus B19 viruses.

There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.

It is strongly recommended that every time that D-Gam is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

4.5. Interaction with other medicinal products and other forms of interaction

Live attenuated virus vaccines

Active immunisation with live virus 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 virus vaccine may be impaired.

If anti-D immunoglobulin needs to be administered within 2-4 weeks of a live virus vaccination, then the efficacy of such a vaccination may be impaired.

No interaction studies have been performed.

4.6. Fertility, pregnancy and lactation

Pregnancy

This medicinal product is intended for use in pregnancy.

Breast-feeding

This medicinal product can be used during breast-feeding.

Immunoglobulins are excreted in human milk and may contribute to protecting the neonate from pathogens which have a mucosal port of entry.

Fertility

No animal fertility studies have been conducted with D-Gam. Clinical experience with human anti-D immunoglobulin suggests that no harmful effects are to be expected.

4.7. Effects on ability to drive and use machines

D-Gam has no influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.

Rarely human immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.

Local reactions at administration sites: swelling, soreness, redness, induration, local heat, itching, bruising and rash.

The following adverse reactions have been reported from post-marketing experience.

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).

Frequencies have been evaluated according to the following convention: Very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1,1000); very rare (<1/10,000), not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

MedDRA Standard System Organ Class

Adverse reaction

Frequency

Immune system disorders

Hypersensitivity, anaphylactic shock

Rare

Nervous system disorders

Headache

Not known

Cardiac disorders

Tachycardia

Not known

Vascular disorders

Hypotension

Rare

Gastrointestinal disorders

Nausea, vomiting

Not known

Skin and subcutaneous tissue disorders

Skin reaction, erythema, pruritus

Not known

Musculoskeletal and connective tissue disorders

Arthralgia, back pain

Not known

General disorders and administration site conditions

Pyrexia, malaise, chills

At the injection site: swelling, pain, erythema, induration, warmth, pruritus, rash

Not known

For safety information with respect to transmissible agents, see section 4.4.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Consequences of an overdose are not known.