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Anti-D Immunoglobulins

Sub-sections

• http://www.medicinescomplete.com/mc/...images/dot.gifDrug Nomenclature
• http://www.medicinescomplete.com/mc/...images/dot.gifAdverse Effects and Precautions
• http://www.medicinescomplete.com/mc/...images/dot.gifInteractions
• http://www.medicinescomplete.com/mc/...mages/plus.gifUses and Administration
• http://www.medicinescomplete.com/mc/...mages/plus.gifPreparations

Anti-D Immunoglobulins

Drug Nomenclature

Date of monograph revision: 19-Aug-1997; 28-Sep-1998; 19-Apr-2001; 11-Dec-2001; 22-Jun-2004; 16-Jun-2006; 31-Jul-2008; (last modified: 28-Feb-2009)
Synonyms: Inmunoglobulinas anti-D
ATC code: J06BB01
Pharmacopoeias: Many pharmacopoeias, including Eur. (see http://www.medicinescomplete.com/mc/...mages/xref.gif) and US, have monographs.
Ph. Eur. 6.4 (Human Anti-D Immunoglobulin; Immunoglobulinum Humanum Anti-D; Anti-D (Rh_o) Immunoglobulin BP 2009). A liquid or freeze-dried preparation containing immunoglobulins, mainly immunoglobulin G (IgG). It is intended for intramuscular administration. It is obtained from plasma from D-negative donors who have been immunised against the D-antigen. It contains specific antibodies against the erythrocyte D-antigen and may also contain small quantities of other blood group antibodies, such as anti-C, anti-E, anti-A, and anti-B. Normal immunoglobulin may be added. The liquid and freeze-dried preparations should be stored, protected from light, in a colourless, glass container. The freeze-dried preparation should be stored in an airtight container.
Ph. Eur. 6.4 (Human Anti-D Immunoglobulin for Intravenous Administration; Immunoglobulinum Humanum Anti-D ad Usum Intravenosum; Anti-D Immunoglobulin for Intravenous Use BP 2009). A liquid or freeze-dried preparation containing immunoglobulins, mainly immunoglobulin G (IgG). It is obtained from plasma from D-negative donors who have been immunised against the D-antigen. It contains specific antibodies against the erythrocyte D-antigen and may also contain small quantities of other blood group antibodies. Human normal immunoglobulin for intravenous administration may be added. Storage requirements are similar to those for Human Anti-D Immunoglobulin, except that the freeze-dried preparation is stored at a temperature not exceeding 25 degrees.
USP 32 (Rh_o (D) Immune Globulin). A sterile solution of globulins derived from human plasma containing antibody to the erythrocyte factor Rh_o (D). It contains 10 to 18% of protein, of which not less than 90% is gamma globulin. It contains glycine as a stabilising agent, and a suitable preservative. It should be stored at 2 degrees to 8 degrees.



Adverse Effects and Precautions

As for immunoglobulins in general, http://www.medicinescomplete.com/mc/...mages/xref.gif.
In patients given anti-D immunoglobulin for idiopathic thrombocytopenic purpura (ITP) there have been rare reports of back pain, shaking chills, fever, and discoloured urine; such signs and symptoms may be associated with intravascular haemolysis. Serious and sometimes fatal complications of intravascular haemolysis including anaemia, acute renal insufficiency, or disseminated intravascular coagulation have been rarely reported. Most reported cases of haemolysis occurred within 4 hours of the dose.
For the treatment of ITP, anti-D immunoglobulin is contra-indicated in rhesus-negative or splenectomised patients. Patients with ITP who need a blood transfusion should be given rhesus-negative red blood cells so as not to exacerbate ongoing haemolysis. Those with low initial haemoglobin concentrations (less than 10 g/dL) should be given a reduced dosage of the immunoglobulin to minimise the risk of severe anaemia.
When given for prophylaxis of rhesus sensitisation, anti-D immunoglobulin should not be used in rhesus-positive individuals.



Interactions

As for immunoglobulins in general, http://www.medicinescomplete.com/mc/...mages/xref.gif.



Uses and Administration

Anti-D immunoglobulin is used to prevent a rhesus-negative mother actively forming antibodies to fetal rhesus-positive red blood cells that may pass into the maternal circulation during childbirth, abortion, or certain other sensitising events. In subsequent rhesus-positive pregnancies these antibodies could produce haemolytic disease of the newborn (erythroblastosis foetalis). The injection of anti-D immunoglobulin is not effective once the mother has formed anti-D antibodies. Anti-D immunoglobulin is also used in the management of some blood disorders, primarily idiopathic thrombocytopenic purpura.
Anti-D immunoglobulin products are available either for intramuscular use only or for intramuscular or intravenous use. Doses differ for these products and the manufacturer's recommendation should be followed for commercial products.
In the UK, recommendations produced by expert groups relate to the use of a non-proprietary product produced by the National Blood Transfusion Service. They recommend that postnatal prophylaxis with anti-D immunoglobulin should always be given to rhesus-negative mothers with no anti-D antibodies in their serum and who have just delivered rhesus-positive infants. It should be given as soon as possible after delivery but may give some protection even if treatment is delayed beyond 72 hours. A dose of 500 units (100 micrograms) by intramuscular injection will clear up to 4 mL of fetal red cells. An additional dose may be required depending on the amount of transplacental bleeding; for bleeds exceeding 4 mL an additional 125 units for each mL of red cells will be required.
For routine antenatal prophylaxis, two intramuscular doses of at least 500 units of anti-D immunoglobulin should be given at 28 and 34 weeks' gestation. Postnatal prophylaxis is still necessary.
There is also a risk of sensitisation during pregnancy from spontaneous, induced, or threatened abortion, amniocentesis, or external version. Any rhesus-negative woman at risk of transplacental haemorrhage during pregnancy and not known to be sensitised should be given an intramuscular dose of 250 units at up to 20 weeks' gestation and 500 units of anti-D immunoglobulin after 20 weeks' gestation.
Anti-D immunoglobulin is also given to rhesus-negative women of child-bearing potential after the inadvertent transfusion of Rh-incompatible blood, or after receiving blood components containing rhesus-positive red cells or organ donations from rhesus-positive donors. The dose is based on the amount of red blood cells transfused; an intramuscular dose up to 125 units/mL of transfused cells may be used.
In the USA, doses of anti-D immunoglobulin have traditionally been higher than in the UK; dosage recommendations are based on a standard dose that is capable of suppressing the immune response to 15 mL of incompatible red blood cells. One-sixth of this dose may be used up to 12 weeks of gestation for sensitising episodes.
For idiopathic thrombocytopenic purpura, a usual initial dose of 250 units/kg (50 micrograms/kg) of a licensed anti-D immunoglobulin product is given by intravenous injection; it may be given in two divided doses on separate days if desired. Maintenance doses usually range between 125 to 300 units/kg (25 to 60 micrograms/kg) depending on the clinical response. A reduced initial dose of 125 to 200 units/kg (25 to 40 micrograms/kg) is recommended in patients with pre-existing anaemia (haemoglobin below 10 g/dL).


Haemolytic disease of the newborn

Rhesus (Rh) incompatibility, in particular Rh(D) incompatibility, is a major cause of potentially severe haemolytic disease of the newborn, although other blood group antibodies may also cause the disease. The use of anti-D immunoglobulin to suppress the production of anti-D antibodies in a Rh(D)-negative mother in response to leakage of red blood cells across the placenta from a Rh(D)-positive fetus has produced a major reduction in the incidence of this disorder.
Prophylaxis. Postnatal prophylaxis of Rh(D)-negative mothers after the birth of a Rh(D)-positive infant is well established. In 1971, WHO1 suggested a standard intramuscular dose of 200 to 300 micrograms but stated that a 100-microgram dose was likely to have a success rate only slightly inferior to that of a 200-microgram dose, thus allowing optimum use to be made of a limited resource. Clinical experience in the UK has confirmed the efficacy of the 100-microgram (500 units) intramuscular dose and this is the amount officially recommended in the UK in such situations.2,3 Doses do, however, vary considerably in other countries: 200 to 300 micrograms (1000 to 1500 units) is given in the USA and in many European countries, and 125 micrograms (625 units) is used in Australia.
Despite the success of anti-D immunoglobulin prophylaxis, sensitisations have continued to occur. There are several possible reasons for this, the main one being immunisation during pregnancy where there has been no overt sensitising event. Postpartum doses may be omitted due to oversight or loss to follow-up. Assessment of the volume of any transplacental haemorrhage is essential to avoid inadequate dosing. Significantly large feto-maternal haemorrhage is likely to occur after traumatic deliveries including caesarean section, manual removal of the placenta, still-birth or intra-uterine death, abdominal trauma during the third trimester, delivery of twins, or unexplained hydrops fetalis.
The efficacy of postpartum prophylaxis is not in question but opinions differ on the need for prophylaxis during pregnancy. It is generally agreed that prophylaxis is necessary in all non-sensitised Rh(D)-negative women after therapeutic terminations at any stage of pregnancy, including medical termination utilising mifepristone, after ectopic pregnancy, spontaneous complete or incomplete miscarriage after 12 weeks' gestation, or threatened miscarriage after 12 weeks' gestation as evidenced by abnormal bleeding or abdominal pain. Recommendations have been made by the British Committee for Standards in Haematology for the management of these sensitising events.3
Prophylaxis should also be given to all non-sensitised Rh(D)-negative women after the following sensitising events during pregnancy: invasive prenatal diagnosis including amniocentesis, chorion villus sampling, or fetal blood sampling; other intra-uterine procedures such as insertion of shunts or embryo reduction; antepartum haemorrhage; external cephalic version of the fetus; closed abdominal injury; or intra-uterine death.2,3 A dose of 50 micrograms (250 units) is recommended for prophylaxis after these events up to 20 weeks of pregnancy, and at least 100 micrograms (500 units) thereafter.
In the UK routine antenatal prophylaxis at 28 and 34 weeks' gestation is recommended for all Rh(D)-negative women2-4 and should be given irrespective of whether anti-D prophylaxis had been given for other sensitising events during the same pregnancy or previous pregnancies.3
Treatment. In mild cases, the resultant hyperbilirubinaemia can be managed with phototherapy. In severe cases, exchange transfusions may be necessary and intra-uterine transfusions may be considered in pregnancies of less than about 34 weeks' gestation; beyond this, premature delivery is often preferable.5 Some clinicians have reported treatment failures with intra-uterine transfusions but have found intravenous normal immunoglobulin 400 mg/kg daily for 5 days every 2 to 3 weeks to the mother to be effective. There are several case reports6,7 of beneficial responses using similar doses, but no benefit was seen in 4 patients receiving 1000 mg/kg once a week.8 This dose, however, appeared to reduce the severity of the disease in a patient with Kell sensitisation.8 Reductions in bilirubin concentrations have been reported with intravenous normal immunoglobulin 500 mg/kg as a single dose in newborn infants,9 and a systematic review10 found that such treatment reduced the number of infants requiring exchange transfusion and the duration of hospital stay and phototherapy needed. Reports in small numbers of infants11-15 suggest that epoetins may be of value in controlling anaemia which develops 2 to 8 weeks after birth.

For further information on the substances mentioned above, see:

• Anti-D Immunoglobulins, http://www.medicinescomplete.com/mc/...mages/xref.gif
• Epoetins http://www.medicinescomplete.com/mc/...mages/xref.gif
• Normal Immunoglobulins, http://www.medicinescomplete.com/mc/...mages/xref.gif

2. 1. WHO. Prevention of Rh sensitization: report of a WHO scientific group. WHO Tech Rep Ser 468 1971. PubMed Also available at: online (accessed 03/10/07)
3. 2. McClelland DBL, ed. Handbook of transfusion medicine: Blood Transfusion Services of the United Kingdom. 4th ed. London: The Stationery Office, 2007. Also available at: online (accessed 02/10/07)
4. 3. Parker J, et al. Guidelines for the use of prophylactic anti-D immunoglobulin: British Committee for Standards in Haematology. (issued 5th December, 2006). Available at: online (accessed 27/07/07)
5. 4. National Institute for Clinical Excellence. Guidance on the use of routine antenatal anti-D prophylaxis for RhD-negative women: Technology Appraisal Guidance 41 (issued May 2002). Available at online (accessed 15/07/08)
6. 5. Whittle MJ. Rhesus haemolytic disease. Arch Dis Child 1992; 67: 65–8. PubMed
7. 6. Berlin G, et al. Rhesus haemolytic disease treated with high-dose intravenous immunoglobulin. Lancet 1985; i: 1153. PubMed
8. 7. de la Cámara C, et al. High-dose intravenous immunoglobulin as the sole prenatal treatment for severe Rh immunization. N Engl J Med 1988; 318: 519–20. PubMed
9. 8. Chitkara U, et al. High-dose intravenous gamma globulin: does it have a role in the treatment of severe erythroblastosis fetalis? Obstet Gynecol 1990; 76: 703–8. PubMed
10. 9. Rübo J, et al. High-dose intravenous immune globulin therapy for hyperbilirubinemia caused by Rh hemolytic disease. J Pediatr 1992; 121: 93–7. PubMed
11. 10. Gottstein R, Cooke RWI. Systematic review of intravenous immunoglobulin in haemolytic disease of the newborn. Arch Dis Child Fetal Neonatal Ed 2003; 88: F6–F10. PubMed
12. 11. Ohls RK, et al. Recombinant erythropoietin as treatment for the late hyporegenerative anemia of Rh hemolytic disease. Pediatrics 1992; 90: 678–80. PubMed
13. 12. Scaradavou A, et al. Suppression of erythropoiesis by intrauterine transfusions in hemolytic disease of the newborn: use of erythropoietin to treat the late anemia. J Pediatr 1993; 123: 279–84. PubMed
14. 13. Ovali F, et al. Management of late anemia in Rhesus hemolytic disease: use of recombinant human erythropoietin (a pilot study). Pediatr Res 1996; 39: 831–4. PubMed
15. 14. Zuppa AA, et al. Recombinant erythropoietin in the prevention of late anaemia in intrauterine transfused neonates with Rh-haemolytic disease. Fetal Diagn Ther 1999; 14: 270–4. PubMed
16. 15. Dhodapkar KM, Blei F. Treatment of hemolytic disease of the newborn caused by anti-Kell antibody with recombinant erythropoietin. J Pediatr Hematol Oncol 2001; 23: 69–70. PubMed

Idiopathic thrombocytopenic purpura

Normal immunoglobulin is used for chronic idiopathic thrombocytopenic purpura (http://www.medicinescomplete.com/mc/...mages/xref.gif), and anti-D immunoglobulin has been found to have similar properties. The potential role of anti-D immunoglobulin in the treatment of idiopathic thrombocytopenic purpura has been discussed in several reviews.1-3 In general, despite many studies showing the clinical efficacy and low toxicity of intravenous anti-D immunoglobulin, its precise role has not been defined for a number of reasons. Firstly, the optimal dose has not been established: doses used have ranged from 12.5 to 25 micrograms/kg daily, given for at least 2 days, in early studies to later more promising single doses of 50 to 75 micrograms/kg. Secondly, no study has shown anti-D immunoglobulin to be as effective as corticosteroid therapy for initial treatment. Furthermore, despite suggestions that anti-D immunoglobulin may be safer and easier to give than normal immunoglobulin, good comparative data is scanty. Clinical studies have, however, shown the safety and efficacy of intravenous anti-D immunoglobulin in Rh(D)-positive, non-splenectomised patients with idiopathic thrombocytopenic purpura.1 A prospective, randomised clinical study4 in Rh(D)-positive children with idiopathic thrombocytopenic purpura found that a single intravenous dose of 75 micrograms/kg raised the platelet count more rapidly than a single intravenous dose of 50 micrograms/kg, and was as effective as a single intravenous dose of 800 mg/kg of normal immunoglobulin.

2. 1. Scaradavou A, Bussel JB. Clinical experience with anti-D in the treatment of idiopathic thrombocytopenic purpura. Semin Hematol 1998; 35 (suppl 1): 52–7. PubMed
3. 2. Sandler SG. Treating immune thrombocytopenic purpura and preventing Rh alloimmunization using intravenous rho (D) immune globulin. Transfus Med Rev 2001; 15: 67–76. PubMed
4. 3. Sandler SG. Intravenous Rh immune globulin for treating immune thrombocytopenic purpura. Curr Opin Hematol 2001; 8: 417–20. PubMed Correction. ibid. 2002; 9: 179.
5. 4. Tarantino MD, et al. Single dose of anti-D immune globulin at 75μg/kg is as effective as intravenous immune globulin at rapidly raising the platelet count in newly diagnosed immune thrombocytopenic purpura in children. J Pediatr 2006; 148: 489–94. PubMed

Preparations

Single-ingredient Preparations

The symbol ¤ denotes a preparation which is discontinued or no longer actively marketed.
Argentina: BayRho-D¤; Igantid; Immunorho; Kam Rho-D; Partoben; Partogamma; Rhesogamma; Australia: WinRho; Austria: Partobulin; Partogloman¤; Rhesogam; Belgium: Rhesuman¤; RhoGAM; WinRho; Brazil: BayRho-D¤; Matergam; Partogama¤; Rhesonativ¤; WinRho¤; Canada: BayRho-D¤; Hyperrho S/D; HypRho-D¤; WinRho; Chile: BayRho-D¤; Igamad; Immunorho; Rhesogamma P; Czech Republic: Igamad; Partobulin; Rhesonativ; Rhophylac; Denmark: Rhesogamma P¤; Rhesonativ; Rhophylac; Finland: Rhophylac; France: Rhophylac; Germany: HypRho-D¤; Partobulin; Rhesogam¤; Rhesonativ; Rhophylac; Greece: Rhesogamma P; Rhophylac; WinRho; Hong Kong: BayRho-D; Partobulin; Rhesuman¤; RhoGAM; WinRho; Hungary: Rhesonativ; RhoGAM; India: Matergam-P; Indonesia: HyperRho S/D; Ireland: Rhesonativ¤; Israel: BayRho-D; IgRho¤; KamRho-D; Rhophylac; WinRho; Italy: Gamma-Men¤; Haima-D¤; Igamad; Immunorho; Parto-Gamma¤; Partobulin; Rhesogamma¤; Rhesonativ¤; Rhesuman¤; Rhophylac; Venogamma Anti-Rho (D)¤; WinRho; Malaysia: Rhesonativ¤; Mexico: BayRho-D¤; Octaglob D; Probi-Rho D¤; Rhesogamma P; Rhophylac; Netherlands: RheDQuin; Rhesonativ; Rhophylac; WinRho; Norway: Rhesogamma¤; Rhesonativ; Rhophylac; New Zealand: RhoGAM; WinRho; Philippines: WinRho; Poland: Gamma Anty D; Partobulin; Portugal: Igantid¤; Rhesonativ; Rhesuman¤; Rhophylac; WinRho; Russia: HyperRHO S/D (ГиперРОУ С/Д); South Africa: Rhesugam; Singapore: BayRho-D¤; Spain: Beriglobina Anti D-P¤; Gamma Anti D; Gamma Glob Anti Rh¤; Gammaglob Anti D¤; Globulina Lloren Anti RH¤; Inmunogamma Anti D¤; Inmunoglob Anti D¤; Partobulina¤; Rhesogamma; Rhesuman¤; Sweden: Rhesogamma¤; Rhesonativ; Rhophylac; Switzerland: Partobuline¤; Rhesuman¤; Rhophylac; Thailand: Igamad; Rhesuman¤; Turkey: BayRho-D; Partobulin; Rhesogamma P; Rhesuman; RhoGAM; United Kingdom: D-Gam; Partobulin; Rhophylac; WinRho; United States: Gamulin Rh¤; HyperRho S/D; MICRhoGAM; Mini-Gamulin Rh¤; Rhesonativ¤; RhoGAM; Rhophylac; WinRho; Venezuela: RhoGAM¤;



Pharmacopoeial Preparations

Ph. Eur.: Human Anti-D Immunoglobulin for Intravenous Administration; Human Anti-D Immunoglobulin; USP 32: Rh_o (D) Immune Globulin;