No data are available on overdosage. Consequences of an overdose are not known.
Hypersensitivity to human immunoglobulins.
The intramuscular route is contraindicated in persons with severe thrombocytopenia or other disorders of haemostasis.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Summary of the safety profile
The most serious adverse reactions observed during the treatment are hypersensitivity or allergic reactions which may in rare cases progress to a sudden fall in blood pressure and anaphylactic shock even when the patient has shown no hypersensitivity to previous administration. When anti-D immunoglobulins are administered by the intramuscular route, local pain and tenderness may be observed at the injection site.
Tabulated list of adverse reactions
The following adverse reactions have been reported from 592 patients in clinical studies and from post-marketing experience. The summary table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level).
Frequency has been evaluated using the following criteria: 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).
| System Organ Class (SOC, MedDRA) | Adverse Reaction (MedDRA Preferred Term (PT) | Frequency of ADR |
| Immune system disorders | Hypersensitivity, anaphylactic shock | rare |
| Nervous system disorders | Headache | uncommon |
| Cardiac disorders | Tachycardia | rare |
| Vascular disorders | Hypotension | rare |
| Respiratory, thoracic and mediastinal disorders | Dyspnoea | rare |
| Gastrointestinal disorders | Nausea, vomiting | rare |
| Skin and subcutaneous tissue disorders | Skin reaction, erythema, pruritus | uncommon |
| Musculoskeletal and connective tissue disorders | Arthralgia | rare |
| General disorders and administration site conditions | Fever, malaise, chills | uncommon |
| At injection site: swelling, pain, erythema, induration, warmth, pruritus, rash | rare |
There have been spontaneous reports of severe intravascular haemolysis when anti-D has been administered intravenously to Rh(D) positive patients with primary immune thrombocytopenia (ITP).
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:
UK: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard
Ireland: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517; website: www.hpra.ie; Email: [email protected]
Due to induction of and interference with antibodies, there are limited preclinical data of relevance for anti-D immunoglobulin.
Repeated dose testing and embryo-foetal toxicity studies have not been conducted and are impracticable to conduct.
The potential for mutagenic effects of immunoglobulins have not been studied.
Prevention of Rh(D) isoimmunisation in Rh(D) negative women
- Antepartum prophylaxis
- Planned antepartum prophylaxis
- Antepartum prophylaxis following complications of pregnancy including:
Abortion/threatened abortion, ectopic pregnancy or hydatidiform mole, intrauterine foetal death, transplacental haemorrhage resulting from antepartum haemorrhage, amniocentesis, chorionic biopsy, obstetric manipulative procedures e.g. external version, invasive interventions, cordocentesis, blunt abdominal trauma or foetal therapeutic intervention.
- Postpartum prophylaxis
- Delivery of a Rh(D) positive (D, Dweak, Dpartial) baby
An Rh(D) incompatible pregnancy is assumed if the foetus/baby is either Rh(D) positive or Rh(D) unknown or if the father is either Rh(D) positive or Rh(D) unknown.
Treatment of Rh(D) negative adults, children and adolescents (0 - 18 years) after incompatible transfusions of Rh(D) positive blood or other products containing red blood cells e.g. platelet concentrate.
Pharmacotherapeutic group: immune sera and immunoglobulins: Anti-D (Rh) immunoglobulin. ATC Code: J06BB01.
Mechanism of action
Rhophylac contains specific antibodies (IgG) against the Rh(D) antigen of human erythrocytes. It can also contain antibodies to other Rh antigens, e.g. anti-Rh C antibodies.
During pregnancy, and especially at the time of childbirth, foetal RBCs may enter the maternal circulation. When the woman is Rh(D) negative and the foetus Rh(D) positive, the woman may become immunised to the Rh(D) antigen and produce anti-Rh(D) antibodies which cross the placenta and may cause haemolytic disease of the new-born.
Passive immunisation with anti-D immunoglobulin prevents Rh(D) immunisation in more than 99% of cases provided that a sufficient dose of anti-D immunoglobulin is administered soon enough after exposure to Rh(D) positive foetal RBCs.
The mechanism by which anti-D immunoglobulin suppresses immunisation to Rh(D) positive red cells is not known. Suppression may be related to the clearance of the red cells from the circulation before they reach immunocompetent sites or, it may be due to more complex mechanisms involving recognition of foreign antigen and antigen presentation by the appropriate cells at the appropriate sites in the presence or absence of antibody.
Pharmacodynamic effects
Prevention of Rh(D) isoimmunisation
In Rh(D) negative healthy male volunteers, both the intravenous and intramuscular administration of 200 micrograms (1000 IU) of Rhophylac at 48 hours after injection of 5 ml of Rh(D) positive RBCs resulted in an almost complete clearance of Rh(D) positive RBCs within 24 hours.
While the intravenous administration of Rhophylac caused an instant onset of RBC disappearance, the onset of elimination of RBCs following intramuscular administration was delayed as anti-D IgG had to be first absorbed from the injection site.
On an average, 70% of injected red cells were cleared 2 hours after intravenous administration of Rhophylac.
After intramuscular administration, a similar degree of red cell clearance was measured after 12 hours.
Furthermore, the efficacy, safety and pharmacokinetics of Rhophylac are supported by the results of three clinical studies in patients. In one clinical study, Rhophylac 200 micrograms (1000 IU) was administered postpartum in 139 per protocol patients.
In the other two clinical studies, Igantid micrograms (1500 IU) was administered antepartum in 446 per protocol patients and in addition postpartum in 256 who gave birth to an Rh(D) positive baby.
None of the patients included in these studies developed antibodies against the Rh(D) antigen.
In the clinical studies with Igantid, 222 women were given the antepartum dose of Igantid intravenously, and 224 women were given it intramuscularly. In more than 99 % of cases, the method of post- and antepartum administration was the same.
Clinical studies with Rhophylac at doses below 200 micrograms (1000 IU) have not been conducted.
Paediatric population
The safety and effectiveness of Rhophylac have not been established in paediatric subjects after incompatible transfusion of Rh(D) positive blood or other products containing RBCs.
Absorption and Distribution
The bioavailability of human anti-D immunoglobulin for intravenous use is complete and immediate. IgG is quickly distributed between plasma and extravascular fluid.
Human anti-D immunoglobulin for intramuscular administration is slowly absorbed into the recipient's circulation and reaches a maximum after a delay of 2 to 3 days.
Elimination
Human anti-D immunoglobulin has a half-life of about 3 to 4 weeks. This half-life may vary individually from patient to patient.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
In the case of postpartum use, anti-D immunoglobulin is intended for maternal administration. It should not be given to the new-born infant.
The product is neither intended for use in Rh(D) positive individuals, nor for individuals already immunised to Rh(D) antigen.
Hypersensitivity
Allergic reactions to anti-D immunoglobulin may occur even in patients who have tolerated previous administrations. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalised urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. The treatment required depends on the nature and severity of the side effect.
In case of shock, the current medical standards for treatment of shock should be observed. If symptoms of allergic or anaphylactic type reactions occur, immediate discontinuation of the administration is required.
The concentration of IgA in Rhophylac was found to be below the detection limit of 5 micrograms/ml. Nevertheless, the product may contain trace amounts of IgA. Although anti-D immunoglobulin has been used successfully to treat selected IgA-deficient patients, individuals who are deficient in IgA have the potential for developing IgA antibodies and may have anaphylactic reactions after administration of blood components containing IgA. The physician must therefore weigh the benefit of treatment with Rhophylac against the potential risks of hypersensitivity reactions.
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.
Obesity
There have been reports that the intramuscular administration of Rhophylac in patients with a body mass index (BMI) > 30 is associated with an increased risk of lack of effect. Therefore, in patients with a BMI >30, intravenous administration should be considered.
Rhophylac contains up to 11.5 mg (0.5 mmol) sodium per syringe. That should be taken into consideration for patients on a controlled sodium diet.
Information on safety with respect to 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). They may be of limited value against non-enveloped viruses such as hepatitis A (HAV) and parvovirus B19.
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 Rhophylac 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.
Rhophylac has no influence on the ability to drive and use machines.
Posology
The dose of anti-D immunoglobulin should be determined according to the level of exposure to Rh(D) positive red blood cells (RBCs) and based on the knowledge that 0.5 ml of packed Rh(D) positive RBCs 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 Rhophylac.
Consideration should also be given to dose and dose schedules for human anti-D immunoglobulin for intramuscular and intravenous use recommended in other official guidance.
Prevention of Rh(D) isoimmunisation in Rh(D) negative women
- Antepartum prophylaxis: The recommended dose is a single dose of 300 micrograms (1500 IU) administered by intravenous or intramuscular injection.
- Planned antepartum prophylaxis:
A single dose of 300 micrograms at 28 - 30 weeks of gestation.
- Antepartum prophylaxis following complications of pregnancy:
A single dose of 300 micrograms should be administered as soon as possible and within 72 hours. If necessary, the dose may be repeated at 6 - 12 week intervals throughout the pregnancy.
- Postpartum prophylaxis: The recommended dose is a single dose of 300 micrograms (1500 IU), administered by intravenous or intramuscular injection. When administered intravenously, a minimum dose of 200 micrograms may be sufficient provided large foeto-maternal haemorrhage can be excluded.
For postpartum use, the product should be administered to the mother as soon as possible within 72 hours of delivery of an Rh(D) 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 postpartum dose must still be given even when antepartum prophylaxis has been administered and even if residual activity from antepartum prophylaxis can be demonstrated in maternal serum.
If a large foeto-maternal haemorrhage (>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 HbF or flow cytometry which specifically identifies Rh(D) positive cells.
Additional doses of anti-D immunoglobulin should be administered accordingly (10 micrograms or 50 IU) per 0.5 ml foetal RBCs.
Incompatible transfusions of RBCs in Rh(D) negative patients
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. The appropriate dose should be determined in consultation with a specialist in blood transfusion. Follow-up tests for Rh(D) positive RBCs should be done every 48 hours and further anti-D administered until all Rh(D) positive RBCs have cleared from the circulation.
A maximum dose of 3000 micrograms (15,000 IU) is sufficient even if more than 300 ml of Rh(D) positive blood or 150 ml of erythrocyte concentrate was transfused.
Intravenous use is recommended as it will achieve adequate plasma levels immediately.
If given by intramuscular injection the large volume should be administered over a period of several days.
Paediatric population
As the posology in case of incompatible transfusion depends on the volume of Rh(D) positive blood or RBC concentrate transfused, the recommended dose in children and adolescents (0-18 years) is not considered to be different to that of adults. However, the appropriate dose should be determined in consultation with a specialist in blood transfusion.
Use in the elderly
As the posology in case incompatible transfusion depends on the volume of Rh(D)-positive blood or RBC concentrate transfused, the recommended dose in elderly patients (> 65 years of age) is not considered to be different to that of adults. The appropriate dose should be determined in consultation with a specialist in blood transfusion.
Method of administration
As with all blood products, patients should be observed for at least 20 minutes following administration of Rhophylac.
For intravenous or intramuscular use, to be administered by slow injection.
If a large volume (>2 ml for children or >5 ml for adults) is required and intramuscular injection is chosen, it is recommended to administer this in divided doses at different sites.
If intramuscular administration is contraindicated (bleeding disorders), Rhophylac should be administered intravenously.
Overweight patients
In patients with a body mass index (BMI) >30 intravenous administration should be considered.
Rhophylac should be brought to room or body temperature before use.
Rhophylac should be inspected visually for particulate matter and discolouration prior to administration.
Do not use solutions which are cloudy or have deposits.
Rhophylac is for single use only (one syringe - one patient).
Any unused product or waste material should be disposed of in accordance with local requirements.
