|
|
|
Rhophylac®
Rh0(D) Immune Globulin Intravenous (Human)
For Intravenous or Intramuscular Injection
Preservative-free, Latex-free, Ready-to-use Prefilled Syringe
DESCRIPTION
Rhophylac® is a sterile Rh0(D) Immune Globulin Intravenous (Human) solution in a ready-to-use prefilled syringe for intravenous or intramuscular injection. One syringe contains at least 1500 IU (300 mcg) of IgG antibodies to Rh0(D) in a 2 mL solution, sufficient to suppress the immune response to at least 15 mL of Rh-positive RBCs.1 The product potency is expressed in IUs by comparison to the World Health Organization (WHO) standard, which is also the US and the European Pharmacopoeia standard.
Plasma is obtained from healthy Rh0(D)-negative donors who have been immunized with Rh0(D)-positive RBCs. The donors are screened carefully to reduce the risk of receiving donations containing blood-borne pathogens. Each plasma donation used in the manufacture of Rhophylac® is tested for the presence of HBV surface antigen (HBsAg), HIV-1/2, and HCV antibodies. In addition, plasma used in the manufacture of Rhophylac® is tested by FDA-licensed Nucleic Acid Testing (NAT) for HIV and HCV and found to be negative. An investigational NAT for HBV is also performed on all source plasma used and found to be negative; however, the significance of a negative result has not been established. The source plasma is also tested by NAT for hepatitis A virus (HAV) and B19 virus (B19V).
Rhophylac® is produced by an ion-exchange chromatography isolation procedure7, using pooled plasma obtained by plasmapheresis of immunized Rh0(D)-negative US donors. The manufacturing process includes a solvent/detergent treatment step (using tri-n-butyl phosphate and Triton™ X-100) that is effective in inactivating enveloped viruses such as HIV, HCV, and HBV.8,9 Rhophylac® is filtered using a Planova® 15 nanometer (nm) virus filter that has been validated to be effective in removing both enveloped and non-enveloped viruses. Table 3 presents viral clearance and inactivation data from validation studies, expressed as the mean log10 reduction factor.
Table 3: Virus Inactivation and Removal in Rhophylac® | Virus | HIV | PRV | BVDV | MVM |
| HIV, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a model for large, enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for HCV; MVM, minute virus of mice, a model for B19V and other small, non-enveloped DNA viruses. |
| Genome | RNA | DNA | RNA | DNA |
| Envelope | Yes | Yes | Yes | No |
| Size | 80-100 nm | 120-200 nm | 40-70 nm | 18-24 nm |
| Solvent/detergent treatment | ≥6.0 | ≥5.6 | ≥5.4 | Not tested |
| Chromatographic process steps | 4.5 | ≥3.9 | 1.6 | ≥2.6 |
| Virus filtration | ≥6.3 | ≥5.6 | ≥5.5 | 3.4 |
| Overall reduction (log10 units) | ≥16.8 | ≥15.1 | ≥12.5 | ≥6.0 |
Rhophylac® contains a maximum of 30 mg/mL of human plasma proteins, 10 mg/mL of which is human albumin added as a stabilizer. Prior to the addition of the stabilizer, Rhophylac® has a purity greater than 95% IgG. Rhophylac® contains less than 5 mcg/mL of IgA, which is the limit of detection. Additional excipients are approximately 20 mg/mL of glycine and up to 0.25 M of sodium chloride. Rhophylac® contains no preservative. Human albumin is manufactured from pooled plasma of US donors by cold ethanol fractionation, followed by pasteurization.
|
CLINICAL PHARMACOLOGY
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.
ITP
Rhophylac® has been shown to increase platelet counts and to reduce bleeding in non-splenectomized 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.10
Pharmacokinetics
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.11
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®.
ITP
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.12
|
CLINICAL STUDIES
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 – Eight of the women who participated in the pharmacokinetic study (see Clinical Pharmacology [12.3] ) gave birth to an Rh0(D)-positive baby and received the postpartum dose of 1500 IU (300 mcg) of Rhophylac®.11 Antibody tests performed 6 to 8 months later were negative for all women. This suggests that no Rh0(D) immunization occurred.
- Study 2 – 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).13 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.
ITP
In an open-label, single-arm, multicenter study, 98 Rh0(D)-positive adult subjects with chronic ITP and a platelet count of 30 × 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 × 109/L as well as an increase of >20 × 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 × 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 Populations) | Analysis Population | No. Subjects | No. Responders | Primary Response Rate at Day 15 |
| % Responders | 95% Confidence Interval (CI) |
| ITT | 98 | 65 | 66.3% | 56.5%, 74.9% |
| PP | 92 | 62 | 67.4% | 57.3%, 76.1% |
The primary efficacy response rate (ITT population) demonstrated a clinically relevant response to treatment, i.e., the lower bound of the 95% 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 (ITT Population) | Response Rates at Day 15 |
Baseline Platelet count
(× 109/L) | Total No. Subjects | No. (%) Subjects Achieving a Platelet Count of ≥30 × 109/L and an Increase of >20 × 109/L | No. (%) Subjects With an Increase in Platelet Counts to ≥50 × 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) |
| >30Reflects subjects with a platelet count of ≤30 × 109/L at screening but >30 × 109/L immediately before treatment. | 5 | 4 (80.0) | 5 (100.0) |
Overall
(all subjects) | 98 | 65 (66.3) | 54 (55.1) |
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.
|
|
|
|
-- advertisement --
|
