Rhophylac Mechanism of Action

Pharmacotherapeutic group: immune sera and immunoglobulins: Anti-D (Rh) immunoglobulin. ATC Code: J06BB01.
Pharmacology: Pharmacodynamics: Mechanism of action: Rhophylac contains specific IgG antibodies against the Rh(D) antigen of human erythrocytes.
Prevention of Rh(D) isoimmunisation: 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 RBCs is not known. Suppression may be related to the clearance of the Rh(D) positive RBCs 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 RBCs were cleared 2 hours after intravenous administration of Rhophylac. After intramuscular administration, a similar degree of RBC clearance was measured after 12 hours.
Clinical Efficacy: The efficacy, safety and pharmacokinetics of Rhophylac are supported by the results of 3 clinical studies that have shown that ante- and postpartum administration of Rhophylac effectively prevents Rh(D) immunization. In one clinical study, Rhophylac 200 micrograms (1000 IU) were administered postpartum in 139 per protocol patients. In the other 2 clinical studies, Rhophylac 300 micrograms (1500 IU) were administered antepartum in 408 per protocol subjects and in addition postpartum (6 to 11 months after the birth) in 256 subjects who gave birth to an Rh(D)-positive baby. None of the pregnant women included in these studies developed antibodies against the Rh(D) antigen.
In two clinical studies in Rh(D)-negative women, Rhophylac was administered in 28^th week of pregnancy and within 72 hours of the birth of a Rh(D)-positive child. 207 per protocol subjects were given the antepartum dose of Rhophylac 300 intravenously, and 201 per protocol subjects were given it intramuscularly. In more than 99% of cases, the method of post- and antepartum administration was the same.
Paediatric population: The safety and efficacy of Rhophylac have not been established in clinical studies in paediatric patients after incompatible transfusion of Rh(D) positive blood or other products containing Rh(D) positive RBCs.
Pharmacokinetics: Absorption and Distribution: Measurable levels of antibodies are obtained approximately 4 hours after intramuscular injection. 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. Measurable levels of antibodies are obtained immediately after intravenous injection. IgG is quickly distributed between plasma and extravascular fluid. 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: Human anti-D immunoglobulin has a half-life of about 3 to 4 weeks. This half-life may vary individually from patient to patient. 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: 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. The potential for mutagenic effects of immunoglobulins have not been studied.