Rhesonativ

Rhesonativ

anti-d immunoglobulins

Manufacturer:

Octapharma

Distributor:

Pharmaniaga Marketing
Full Prescribing Info
Contents
Human anti-D immunoglobulin.
Description
Each mL contains human anti-D immunoglobulin 625 IU (125 μg), human protein content 165 mg, thereof, immunoglobulin G, at least 95%.
The content of IgA does not exceed 0.05% of the total protein content.
Excipients/Inactive Ingredients: Glycine, sodium chloride, sodium acetate, water for injections.
Action
Pharmacotherapeutic Group: Immune sera and immunoglobulins: Anti-D (Rh) immunoglobulin. ATC Code: J06B B01.
Pharmacology: Pharmacodynamics: Anti-D immunoglobulin contains specific antibodies (IgG) against the D (Rh) antigen of human erythrocytes.
During pregnancy, and especially at the time of childbirth, fetal red blood cells may enter the maternal circulation. When the woman is Rh(D)-negative and the fetus 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 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 soon enough after exposure to Rh(D)-positive fetal 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.
Studies in Patients with Postpartum Prophylaxis (Study 1-6) and in Patients with Antenatal Prophylaxis (Study 7): Clinical trials with Rhesonativ were initiated with the aim to evaluate the efficacy and safety of the product. The following table provides an overview on the most important findings in terms of efficacy: See Table 1.

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From these studies it can be reasonably concluded that treatment with Rhesonativ provides effective anti–D prophylaxis.
Study in Transfusion of Rh-Incompatible Blood Components: Study 8 assessed the efficacy of Rhesonativ in 21 Rh-negative volunteers who were injected with Rh-positive, ABO-compatible fetal red cells in amounts corresponding to 10 mL cord blood (1 case), 25 mL (10 cases) and 50 mL (10 cases). Two to 3 days later 260 μg of Rhesonativ were given intramuscularly. Six months (in 1 case 9 months) after the start of the experiment no serologic evidence for Rh-immunization was found in any individual. Six months to 2.5 years later, 8 subjects of the 25 mL group and all 10 subjects of the 50 mL group received 5 mL Rh-positive, ABO-compatible cord blood. After 2 to 3 days, 260 respectively 333 μg Rhesonativ were injected. After another 6 months (in 1 case after 8 months) no Rh-antibodies were detected in any subject.
From these experimental findings it was concluded that Rh-prophylaxis is achieved with 10 μg of anti-D immunoglobulin per mL of fetal blood. It was concluded that, as far as Rh-immunization due to fetomaternal haemorrhage at the end of the pregnancy is concerned, a dose of 260 μg Rhesonativ prevents serologically detectable Rh-immunisation in at least 998 Rh–negative mothers out of a thousand.
Pharmacokinetic Study with Rhesonativ: The basic pharmacokinetics and turnover of Rhesonativ were investigated in fifteen Rh– negative pregnant women who were given Rhesonativ intramuscularly at 28 weeks' gestation. The doses were 125 μg in 8 and 250 μg in 7 of the women. In addition three non-pregnant Rh-negative women were given the smaller dose.
The biological half life of anti-D IgG after an intramuscular injection of 125 μg in these women was in line with what could be expected from the literature.
Pharmacokinetics: Measurable levels of antibodies are obtained approximately 20 minutes after intramuscular injection. Peak serum levels are usually achieved 2 to 3 days later.
The half-life in the circulation of individuals with normal IgG levels is 3 to 4 weeks. This half-life may vary from patient to patient.
IgG and IgG complexes are broken down in cells of the reticuloendothelial system.
Toxicology: Preclinical Safety Data: There are no nonclinical safety data for human anti-D immunoglobulin.
Indications/Uses
Prevention of Rh(D) Immunisation in Rh(D) Negative Women: Antenatal Prophylaxis: Planned antenatal prophylaxis; antenatal prophylaxis following complications of pregnancy including abortion/threatened abortion, ectopic pregnancy or hydatidiform mole, intrauterine fetal death (IUFD), transplacental haemorrhage (TPH) resulting from ante-partum haemorrhage (APH), amniocentesis, chorionic biopsy or obstetric manipulative procedures eg, external version, invasive interventions, cordocentesis, blunt abdominal trauma or fetal therapeutic intervention.
Postnatal 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.
Dosage/Direction for Use
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 Rhesonativ.
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. For specific study details see Pharmacology: Pharmacodynamics under Actions.
Planned Antenatal Prophylaxis: A single dose (eg, 250 μg or 1250 IU) at 28-30 weeks of gestation or two doses at 28 and 34 weeks.
Antenatal Prophylaxis Following Complications of Pregnancy: A single dose (eg, 125 μg or 625 IU before the 12th week of pregnancy) (eg, 250 μg or 1250 IU after the 12th week of pregnancy) should be administered as soon as possible and within 72 hours and if necessary repeated at 6-12 week intervals throughout the pregnancy.
After amniocentesis and chorionic biopsy a single dose (eg, 250 μg or 1250 IU) should be administered.
Postnatal Prophylaxis: According to general recommendations, currently administered doses range from 100-300 micrograms or 500-1500 IU. For specific study details see Pharmacology: Pharmacodynamics under Actions. If the lower dose (100 micrograms or 500 IU) is administered then testing of the amount of fetal maternal haemorrhage should be performed.
Standard dose: 1250 IU (250 μg).
For postnatal use, the product should be administered to the mother as soon as possible within 72 hours of delivery of an 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 feto-maternal haemorrhage [>4 ml (0.7-0.8% of women)] is suspected eg, in the event of fetal/neonatal anaemia or intrauterine fetal death, its extent should be determined by a suitable method eg, Kleihauer-Betke acid elution test to detect fetal 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 fetal 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. 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 (15000 IU) is sufficient in the case of larger incompatible transfusions independent of whether the transfusion volume is greater than 300 mL of Rh (D) positive red blood cells.
The use of an alternative intravenous product is recommended as it will achieve adequate plasma levels immediately. If no intravenous product is available, the large dose should be administered intramuscularly over a period of several days.
Administration: Rhesonativ should be injected intramuscularly.
If large total doses (>2 mL for children or >5 mL for adults) are required, it is advisable to administer them in divided doses at different injection sites.
In case of haemorrhagic disorders where intramuscular injections are contraindicated, Rhesonativ may be administered subcutaneously if no intravenous product is available. Careful manual pressure with a compress should be applied to the site after injection.
Overdosage
No data are available on overdosage. Patients with incompatible transfusion who receive an overdose of anti-D immunoglobulin, should be monitored clinically and by biological parameters, because of the risk of haemolytic reaction.
In other Rh(D) negative individuals, overdosage should not lead to more frequent or more severe undesirable effects than the normal dose.
Contraindications
Hypersensitivity to the active substance(s) or to any of the excipients.
Special Precautions
Do not inject this product intravenously (risk of shock). Injections have to be given intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel.
In case of postnatal use, Rhesonativ 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.
Patients should be observed for at least 20 minutes after administration and for at least 1 hour after an accidental intravenous injection.
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.
If symptoms of allergic or anaphylactic type reactions occur, immediate discontinuation of the administration is required.
True hypersensitivity reactions are rare but allergic reactions 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, current medical standards for shock treatment should be observed.
Rhesonativ contains a small quantity of IgA. Although anti-D immunoglobulin has been used successfully to treat selected IgA deficient individuals, the attending physician must weigh the benefit against the potential risks of hypersensitivity reactions. Individuals deficient in IgA have a potential for development of IgA antibodies and anaphylactic reactions after administration of blood components containing IgA.
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.
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, and for the non-enveloped virus HAV.
The measures taken may be of limited value against non-enveloped viruses such as 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 Rhesonativ 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.
This medicinal product contains less than 1 mmol sodium (23 mg) per dose (5 mL) ie, essentially 'sodium-free'.
Effects on Ability to Drive and Use Machines: No effects on ability to drive and use machines have been observed.
Use In Pregnancy & Lactation
Rhesonativ is intended for use in pregnancy.
Adverse Reactions
Local pain and tenderness can be observed at the injection site; this can be prevented by dividing larger doses over several injection sites.
Occasionally fever, malaise, headache, cutaneous reactions and chills occur. In rare cases: Nausea, vomiting, hypotension, tachycardia and allergic or anaphylactic type reactions, including dyspnoea and shock, are reported, even when the patient has shown no hypersensitivity to previous administration.
For information on viral safety, see Precautions.
Very common (>1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000), not known (cannot be estimated from the available data) (see Table 2).

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Drug Interactions
Live Attenuated Virus Vaccines: Active immunisation with live virus vaccines (e.g. measles, mumps or rubella) 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 2-4 weeks of a live virus vaccination, then the efficacy of such a vaccination may be impaired.
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 eg, 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.
Caution For Usage
Special Precautions for Disposal and Other Handling: The product should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent and pale-yellow to light-brown. Do not use solutions that are cloudy or have deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products.
Storage
Store in a refrigerator (2°C-8°C). Protect from light.
Shelf-Life:
30 months.
ATC Classification
J06BB01 - anti-D (rh) immunoglobulin ; Belongs to the class of specific immunoglobulins. Used in passive immunizations.
Presentation/Packing
Soln for inj (amp) 625 IU/mL x 2 mL x 1's.
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