"The U.S. Food and Drug Administration today approved Tretten, Coagulation Factor XIII A-Subunit (Recombinant), the first recombinant product for use in the routine prevention of bleeding in adults and children who have a rare clotting disorder, k"...
Mechanism Of Action
Suppression Of Rh Isoimmunization
The mechanism by which Rh0(D) immune globulin suppresses immunization to Rh0(D)- positive RBCs is not completely known.
In a clinical study of Rh0(D)-negative healthy male volunteers, both the intravenous and intramuscular administration of a 1500 IU (300 mcg) dose of Rhophylac 24 hours after injection of 15 mL of Rh0(D)-positive RBCs resulted in an effective clearance of Rh0(D)- positive RBCs. On average, 99% of injected RBCs were cleared within 12 hours following intravenous administration and within 144 hours following intramuscular administration.
Rhophylac has been shown to increase platelet counts and to reduce bleeding in nonsplenectomized Rh0(D)-positive subjects with chronic ITP. The mechanism of action is thought to involve the formation of Rh0(D) immune globulin RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets.7
Suppression Of Rh Isoimmunization
In a clinical study comparing the pharmacokinetics of intravenous versus intramuscular administration, 15 Rh0(D)-negative pregnant women received a single 1500 IU (300 mcg) dose of Rhophylac at Week 28 of gestation.8
Following intravenous administration, peak serum levels of Rh0(D) immune globulin ranged from 62 to 84 ng/mL after 1 day (i.e., the time the first blood sample was taken following the antepartum dose). Mean systemic clearance was 0.20 ± 0.03 mL/min, and half-life was 16 ± 4 days.
Following intramuscular administration, peak serum levels ranged from 7 to 46 ng/ mL and were achieved between 2 and 7 days. Mean apparent clearance was 0.29 ± 0.12 mL/min, and half-life was 18 ± 5 days. The absolute bioavailability of Rhophylac was 69%.
Regardless of the route of administration, Rh0(D) immune globulin titers were detected in all women up to at least 9 weeks following administration of Rhophylac.
Pharmacokinetic studies with Rhophylac were not performed in Rh0(D)-positive subjects with ITP. Rh0(D) immune globulin binds rapidly to Rh0(D)-positive erythrocytes.9
Suppression Of Rh Isoimmunization
In two clinical studies, 447 Rh0(D)-negative pregnant women received a 1500 IU (300 mcg) dose of Rhophylac during Week 28 of gestation. The women who gave birth to an Rh0(D)-positive baby received a second 1500 IU (300 mcg) dose within 72 hours of birth.
- Study 1 (Pharmacokinetic Study) – Eight of the women who participated in the pharmacokinetic study [see CLINICAL PHARMACOLOGY] gave birth to an Rh0(D)-positive baby and received the postpartum dose of 1500 IU (300 mcg) of Rhophylac.8 Antibody tests performed 6 to 8 months later were negative for all women. This suggests that no Rh0(D) immunization occurred.
- Study 2 (Pivotal Study) – In an open-label, single-arm clinical study at 22 centers in the US and United Kingdom, 432 pregnant women received the antepartum dose of 1500 IU (300 mcg) of Rhophylac either as an intravenous or intramuscular injection (two randomized groups of 216 women each).10 Subjects received an additional 1500 IU (300 mcg) dose if an obstetric complication occurred between the routine antepartum dose and birth or if extensive fetomaternal hemorrhage was measured after birth. Of the 270 women who gave birth to an Rh0(D)-positive baby, 248 women were evaluated for Rh0(D) immunization 6 to 11.5 months postpartum. None of these women developed antibodies against the Rh0(D) antigen.
In an open-label, single-arm, multicenter study, 98 Rh0(D)-positive adult subjects with chronic ITP and a platelet count of 30 x 109/L or less were treated with Rhophylac. Subjects received a single intravenous dose of 250 IU (50 mcg) per kg body weight.
The primary efficacy endpoint was the response rate defined as achieving a platelet count of ≥ 30 x 109/L as well as an increase of > 20 x 109/L within 15 days after treatment with Rhophylac. Secondary efficacy endpoints included the response rate defined as an increase in platelet counts to ≥ 50 x 109/L within 15 days after treatment and, in subjects who had bleeding at baseline, the regression of hemorrhage defined as any decrease from baseline in the severity of overall bleeding status.
Table 4 presents the primary response rates for the intent-to-treat (ITT) and per-protocol (PP) populations.
Table 4: Primary Response Rates (ITT and PP
|Analysis Population||No. Subjects||No. Responders||Primary Response Rate at Day 15|
|% Responders||95% Confidence Interval (CI)|
The primary efficacy response rate (ITT population) demonstrated a clinically relevant response to treatment, i.e., the lower bound of the 95% confidence interval (CI) was greater than the predefined response rate of 50%. The median time to platelet response was 3 days, and the median duration of platelet response was 22 days.
Table 5 presents the response rates by baseline platelet count for subjects in the ITT population.
Table 5: Response Rates By Baseline Platelet Count
|Baseline Platelet count (x 109/L)||Total No. Subjects||Response Rates at Day 15|
|No. (%) Subjects Achieving a Platelet Count of ≥ 30 x 109/L and an Increase of > 20 x 109/L||No. (%) Subjects With an Increase in Platelet Counts to ≥ 50 x 109/L|
|≤ 10||38||15 (39.5)||10 (26.3)|
|> 10 to 20||28||22 (78.6)||17 (60.7)|
|> 20 to 30||27||24 (88.9)||22 (81.5)|
|> 30*||5||4 (80.0)||5 (100.0)|
|Overall (all subjects)||98||65 (66.3)||54 (55.1)|
|* Reflects subjects with a platelet count of ≤ 30 × 109/L at screening but > 30 × 109/L immediately before treatment.|
During the study, an overall regression of hemorrhage was seen in 44 (88%, 95% CI: 76% to 94%) of the 50 subjects with bleeding at baseline. The percentage of subjects showing a regression of hemorrhage increased from 20% at Day 2 to 64% at Day 15. There was no evidence of an association between the overall hemorrhage regression rate and baseline platelet count.
Approximately half of the 98 subjects in the ITT population had evidence of bleeding at baseline. Post-baseline, the percentage of subjects without bleeding increased to a maximum of 70.4% at Day 8.
7. Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci. 2003;28:249-255.
8. Bichler J, Schöndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in pregnant RhD-negative women. BJOG. 2003;110:39-45.
9. Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. 1998;35:14-22.
10. MacKenzie IZ, Bichler J, Mason GC, et al. Efficacy and safety of a new, chromatographically purified rhesus (D) immunoglobulin. Eur J Obstetr Gynecol Reprod Biol. 2004;117:154-161.
Last reviewed on RxList: 3/18/2016
This monograph has been modified to include the generic and brand name in many instances.
Additional Rhophylac Information
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.