Human anti-D immunoglobulin.
Each 2 ml solution in pre-filled syringe contains: Human anti-D immunoglobulin G (IgG) 1,500 IU (300 micrograms) corresponding to a concentration of 750 IU (150 micrograms) per ml.
The product contains a maximum of 30 mg/ml of human plasma proteins of which 10 mg/ml is human albumin as stabiliser. At least 95% of the other plasma proteins are IgG. Rhophylac contains not more than 5 micrograms/ml IgA.
Rhophylac is a clear, colourless to pale yellow immunoglobulin solution. The solution is slightly hypertonic.
Excipients/Inactive Ingredients: Human albumin 10 mg/ml, Glycine 20.6 mg/ml, Sodium chloride ≤250 mmol/l.
Pharmacotherapeutic group: immune sera and immunoglobulins: Anti-D (Rh) immunoglobulin. ATC Code: J06BB01.
Pharmacology: Pharmacodynamics: Rhophylac contains specific IgG antibodies against the Rh(D) antigen of human erythrocytes.
Mechanism of action: During pregnancy, and especially at the time of childbirth, foetal red blood cells may enter the maternal circulation. When the woman is Rh(D)-negative and the foetus Rh(D)-positive, the women might become immunised to the Rh(D) antigen and may produce anti-Rh(D) antibodies which cross the placenta and may cause haemolytic disease of the newborn. 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 early enough after exposure to Rh(D)-positive foetal red blood cells.
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.
In clinical studies in Rh(D)-negative healthy male volunteers, both the intravenous and intramuscular administration of Rhophylac resulted in an efficient clearance of Rh(D)-positive erythrocytes from the circulation. While the intravenous administration of Rhophylac caused an instant onset of red blood cell disappearance, the onset of elimination of red blood cells 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.
Clinical Efficacy: Clinical studies have shown that ante- and postpartum administration of Rhophylac effectively prevents Rh(D) immunization of Rh(D)-negative women.
In two clinical studies in Rh(D)-negative women, Rhophylac was administered in 28th week of pregnancy and within 72 hours of the birth of a Rh(D)-positive child. 222 women were given the antepartum dose of Rhophylac 300 intravenously, and 224 women were given it intramuscularly. In more than 99% of cases, the method of post- and antepartum administration was the same.
6 to 11 months after the birth, 256 of the 278 women who had given birth to a Rh(D)-positive child were available for a follow-up examination. Anti-D antibodies were not detected in any of the women, indicating that rhesus immunization had not occurred.
Pharmacokinetics: Distribution: Measurable levels of antibodies are obtained approximately 4 hours after intramuscular injection. Peak serum levels are usually achieved 5 days later. Measurable levels of antibodies are obtained immediately after intravenous injection. Two to 3 weeks post injection, serum levels are aligned and a difference between the two routes of administration can no longer be detected.
Elimination: The mean half-life in the circulation of pregnant women with normal IgG levels was 17 days.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
Toxicology: Preclinical Data: There are no preclinical data of relevance for anti-D immunoglobulin. Repeated dose testing and embryofoetal toxicity studies have not been conducted and are impracticable due to induction of, and interference with antibodies. The potential for mutagenic effects of immunoglobulins have not been studied.
Prevention of Rh(D) immunisation in Rh(D)-negative women: Pregnancy/delivery of a Rh(D)-positive baby.
Abortion/threatened abortion, ectopic pregnancy or hydatidiform mole.
Transplacental haemorrhage resulting from antepartum haemorrhage, amniocentesis, chorionic biopsy or obstetric manipulative procedures e.g. external version, or abdominal trauma.
Treatment of Rh(D)-negative persons after incompatible transfusions of Rh(D)-positive blood or other products containing red blood cells.
The following dose schedules are recommended based on the clinical studies performed with Rhophylac, however consideration must be given to professional guidelines for the use of anti-D IgG in the individual country of application.
Dosage: Prevention of Rh(D) immunisation in Rh(D)-negative women: Antepartum prophylaxis: The recommended dose is a single dose of 300 micrograms (1,500 IU) administered by intravenous or intramuscular injection.
Planned antepartum prophylaxis: A single dose of 300 micrograms at 28 to 30 weeks of gestation.
Antenatal prophylaxis following complications of pregnancy: 300 micrograms should be administered by intravenous or intramuscular injection as soon as possible and not later than 72 hours after the at-risk event. If the 72-hour limit is exceeded, Rhophylac should be administered anyway. If necessary, administration of anti-D IgG should be repeated every 6 to 12 weeks until the time of delivery.
Postpartum prophylaxis: 300 μg should be administered as soon as possible after delivery and no later than 72 hours thereafter, by the intravenous or intramuscular route. If the 72-hour limit is exceeded, Rhophylac should be administered anyway. The postpartum dose must be given even when antepartum prophylaxis has been administered.
If a large foeto-maternal haemorrhage (greater than 4 ml (0.7% to 0.8% of women)) is suspected, e.g., in the event of foetal anaemia or intrauterine foetal death, its extent should be determined by a suitable method, e.g. Kleihauer-Betke test, and additional doses of anti-D should be administered as indicated (20 micrograms/100 IU for each 1 ml of foetal red blood cells).
Incompatible transfusions: 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 erythrocyte concentrate. The intravenous route of administration is recommended. If given by intramuscular administration the large doses should be administered over a period of several days. A maximum dose of 3,000 micrograms is sufficient in the case of larger incompatible transfusions independent of whether the transfusion volume is greater than 300 ml of Rh(D)-positive blood.
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.
Method of administration: Rhophylac can be administered by intravenous or intramuscular injection.
In case of haemorrhagic disorders where intramuscular injections are contraindicated, Rhophylac should be administered intravenously. If large doses (>5 ml) are required and intramuscular injection is chosen, it is advisable to administer them in divided doses at different sites.
Overweight patients: In patients with a body mass index (BMI) ≥30 intravenous administration should be considered (see Precautions).
No data are available on overdosage. Patients in receipt of an 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. In other Rh-negative individuals overdosage should not lead to more frequent or more severe undesirable effects than the normal dose.
Hypersensitivity to the active substance or to any of the components (see Description).
The intramuscular route is contraindicated in persons with severe thrombocytopenia or other disorders of haemostasis.
In the case of postpartum use, anti-D immunoglobulin is intended for maternal administration. It should not be given to the newborn infant.
The product is not intended for use in Rh(D)-positive individuals.
Patients should be observed for at least 20 minutes after administration.
If symptoms of allergic or anaphylactic type reactions occur, immediate discontinuation of the administration is required.
Allergic responses to anti-D immunoglobulin may occur. 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.
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.
There have been reports that the intramuscular administration of Rhophylac in patients with a body mass index (BMI) ≥30 is associated with a risk of lack of efficacy. Therefore, in patients with a BMI ≥30 intravenous administration should be considered.
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 HIV, HBV and HCV. They may be of limited value against non-enveloped viruses such as HAV or 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.
Effects on Ability to Drive and Use Machines: No effects on ability to drive and use machines have been observed.
This medicinal product is used in pregnancy and postpartum.
No study drug-related adverse events were reported for the children delivered of 432 women who received antepartum administration of Rhophylac.
This medicinal product can be used during breastfeeding.
The following adverse reactions have been reported from 592 patients in clinical studies and from postmarketing 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 and <1/10), uncommon (≥1/1,000 and <1/100), rare (≥1/10,000 and <1/1,000), very rare (<1/10,000). (See table.)
Click on icon to see table/diagram/image
For safety information with respect to transmissible agents, see Precautions.
Interactions of Rhophylac with other treatments have not been investigated. The information given in this section is derived from the literature and current guidelines.
Active immunisation with live virus vaccines (e.g. measles, mumps, rubella or varicella) should be postponed until 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 to 4 weeks of a live virus vaccination, then the efficacy of such a vaccination may be impaired.
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 for red blood cell antibodies e.g. Coomb's test in the neonate.
Rhophylac can contain antibodies to other Rh antigens, e.g. anti-Rh(C) antibodies, which might be detected by sensitive serological test methods following administration of the product.
Instructions for use and handling and disposal: Rhophylac should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent. Do not use solutions which are cloudy or have deposits. Use only once (one syringe-one patient).
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: Rhophylac must not be mixed with other medicinal products.
Store in a refrigerator (+2 to +8°C). Do not freeze.
Keep the syringe (originally blistered) in the outer carton in order to protect from light.
Shelf-Life: 3 years.
J06BB01 - anti-D (rh) immunoglobulin ; Belongs to the class of specific immunoglobulins. Used in passive immunizations.
Soln for inj (clear, colourless to pale yellow in pre-filled syringe) 300 mcg/2 mL x 1's.