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WARNING
INTRAVASCULAR HEMOLYSIS IN ITP
This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization.
Rhophylac is a sterile Rh0(D) Immune Globulin Intravenous (Human) (anti-D) solution in a ready-to-use prefilled glass 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.2 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-½, and HCV antibodies. In addition, plasma used in the manufacture of Rhophylac is tested by FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV, and HIV-1 and found to be negative. The credit plasma is also tested by NAT for hepatitis A virus (HAV) and B19 virus (B19V).
Rhophylac is produced by an ion-exchange chromatography isolation procedure4, 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.5,6 Rhophylac is filtered using a Planova® 15 nanometer (nm) virus filter that has been validated to be effective in removing both enveloped and nonenveloped viruses. Table 3 presents viral clearance and inactivation data from validation studies, expressed as the mean log10 reduction factor (LRF).
Table 3: Virus Inactivation and Removal in Rhophylac
| HIV | PRV | BVDV | MVM | |
| Virus property | ||||
| Genome | RNA | DNA | RNA | DNA |
| Envelope | Yes | Yes | Yes | No |
| Size (nm) | 80-100 | 120-200 | 40-70 | 18-24 |
| Manufacturing step | Mean LRF | |||
| 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 | ≥ 16.8 | ≥ 15.1 | ≥ 12.5 | ≥ 6.0 |
| 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 and West Nile virus; MVM, minute virus of mice, a model for B19V and other small, non-enveloped DNA viruses. | ||||
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.
REFERENCES
2. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh0(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005;106:1532- 1537.
4. Stucki M, Moudry R, Kempf C, Omar A, Schlegel A, Lerch PG. Characterisation of a chromatographically produced anti-D immunoglobulin product. J Chromatogr B. 1997;700:241-248.
5. Horowitz B, Chin S, Prince AM, Brotman B, Pascual D, Williams B. Preparation and characterization of S/D-FFP, a virus sterilized “fresh frozen plasma”. J Thromb Haemost. 1991;65:1163.
6. Horowitz B, Bonomo R, Prince AM, Chin S, Brotman B, Shulman RW. Solvent/ detergent-treated plasma: a virus-inactivated substitute for fresh frozen plasma. Blood. 1992;79:826-831.
Rhophylac is an Rh0(D) Immune Globulin Intravenous (Human) (anti-D) product that is indicated for the suppression of Rh isoimmunization in non-sensitized Rh0(D)-negative patients and for the treatment of immune thrombocytopenic purpura (ITP) in Rh0(D)- positive patients.
Rhophylac is indicated for suppression of rhesus (Rh) isoimmunization in non-sensitized Rh0(D)-negative women with an Rh-incompatible pregnancy, including:
An Rh-incompatible pregnancy is assumed if the fetus/baby is either Rh0(D)-positive or Rh0(D)-unknown or if the father is either Rh0(D)-positive or Rh0(D)-unknown.
Rhophylac is indicated for the suppression of Rh isoimmunization in Rh0(D)-negative individuals transfused with Rh0(D)-positive red blood cells (RBCs) or blood components containing Rh0(D)-positive RBCs.
Treatment can be given without a preceding exchange transfusion when the transfused blood represents less than 20% of the total circulating RBCs. If the volume exceeds 20%, an exchange transfusion should be considered prior to administering Rhophylac.
Rhophylac is indicated in Rh0(D)-positive, non-splenectomized adult patients with chronic ITP to raise platelet counts.
As with all blood products, patients should be observed for at least 20 minutes following administration of Rhophylac.
Rhophylac should be administered by intravenous or intramuscular injection. If large doses (greater than 5 mL) are required and intramuscular injection is chosen, it is advisable to administer Rhophylac in divided doses at different sites.
Ensure the site of administration will allow the injection to reach the muscle if Rhophylac is administered intramuscularly. Consider intravenous administration if reaching the muscle is of concern [see Postmarketing Experience]. Do not administer Rhophylac subcutaneously into the fatty tissue.
Table 1 provides dosing guidelines based on the condition being treated.
Table 1: Dosing Guidelines for Suppression of Rh
Isoimmunization
| Indication | Timing of Administration | Dose* (Administer by Intravenous or Intramuscular Injection) |
| Rh-incompatible pregnancy | ||
| Routine antepartum prophylaxis | At Week 28-30 of gestation | 1500 IU (300 mcg) |
| Postpartum prophylaxis (required only if the newborn is Rh0(D)-positive) | Within 72 hours of birth | 1500 IU (300 mcg)† |
| Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage) | Within 72 hours of complication | 1500 IU (300 mcg)† |
| Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma) | Within 72 hours of procedure | 1500 IU (300 mcg)† |
| Excessive fetomaternal hemorrhage ( > 15 mL) | Within 72 hours of complication | 1500 IU (300 mcg) plus:
|
| Incompatible transfusions | Within 72 hours of exposure | 100 IU (20 mcg) per 2 mL transfused blood or per 1 mL erythrocyte concentrate |
| IU, international units; mcg, micrograms. * A 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of ≤ 15 mL of Rh0(D)-positive RBCs. † The dose of Rhophylac must be increased if the patient is exposed to > 15 mL of Rh0(D)-positive RBCs; in this case, follow the dosing guidelines for excessive fetomaternal hemorrhage. |
||
For treatment of ITP, ADMINISTER RHOPHYLAC BY THE INTRAVENOUS ROUTE ONLY [see Preparation and Handling]. Do not administer intramuscularly. A 250 IU (50 mcg) per kg body weight dose of Rhophylac is recommended for patients with ITP. The following formula can be used to calculate the recommended amount of Rhophylac to administer:
Dose (IU) x body weight (kg) = Total IU / 1500 IU per syringe = Number of syringes
Rhophylac should be administered at a rate of 2 mL per 15 to 60 seconds.
1500 IU (300 mcg) per 2 mL prefilled, ready-to-use, glass syringe for IV or IM use.
Each product presentation includes a package insert and the following components:
| Presentation | Carton NDC Number | Components |
| 1500 IU (300 mcg) | 44206-300-01 |
|
| 1500 IU (300 mcg) Multipack | 44206-300-10 |
|
Manufactured by: CSL Behring AG, Bern, Switzerland, US License No. 1766. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: May 2015
The most serious adverse reactions in patients receiving Rh0(D) Immune Globulin Intravenous (Human) have been observed in the treatment of ITP and include intravascular hemolysis, clinically compromising anemia, acute renal insufficiency, and, very rarely, DIC and death [see BOXED WARNING, WARNINGS AND PRECAUTIONS].1
The most common adverse reactions observed in the use of Rhophylac for suppression of Rh isoimmunization ( ≥ 0.5% of subjects) are nausea, dizziness, headache, injection-site pain, and malaise.
The most common adverse reactions observed in the treatment of ITP ( > 14% of subjects) are chills, pyrexia/increased body temperature, and headache. Hemolysis (manifested by an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was also observed.
Because clinical studies are conducted under different protocols and widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice.
In two clinical studies, 447 Rh0(D)-negative pregnant women received either an intravenous or intramuscular injection of Rhophylac 1500 IU (300 mcg) at Week 28 of gestation. A second 1500 IU (300 mcg) dose was administered to 267 (9 in Study 1 and 258 in Study 2) of these women within 72 hours of the birth of an Rh0(D)-positive baby. In addition, 30 women in Study 2 received at least one extra antepartum 1500 IU (300 mcg) dose due to obstetric complications [see Clinical Studies].
The most common adverse reactions in study subjects were nausea (0.7%), dizziness(0.5%), headache (0.5%), injection-site pain (0.5%), and malaise (0.5%). A laboratory finding of a transient positive anti-C antibody test was observed in 0.9% of subjects.
In a clinical study, 98 Rh0(D)-positive adult subjects with chronic ITP received anintravenous dose of Rhophylac 250 IU (50 mcg) per kg body weight [see Clinical Studies]. Premedication to alleviate infusion-related side effects was not used except in a single subject who received acetaminophen and diphenhydramine.
Eighty-four (85.7%) subjects experienced 392 treatment-emergent adverse events(TEAEs). Sixty-nine (70.4%) subjects had 186 drug-related TEAEs (defined as TEAEs with a probable, possible, definite, or unknown relationship to the study drug). Within 24 hours of dosing, 73 (74.5%) subjects experienced 183 TEAEs, and 66 (67%) subjects experienced 156 drug-related TEAEs.
Hemolysis (manifested as an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was observed. An increase in blood bilirubin was seen in 21% of subjects. The median decrease in hemoglobin was greatest (0.8 g/dL) at Day 6 and Day 8 following administration of Rhophylac.
Table 2 shows the most common TEAEs observed in the clinical study.
Table 2: Most Common Treatment-Emergent Adverse Events
(TEAEs) in Subjects with ITP
| TEAE | Number of Subjects (%) With a TEAE n=98 |
Number of Subjects (%) With a Drug-Related TEAE* n=98 |
| Chills | 34 (34.7%) | 34 (34.7%) |
| Pyrexia/ Increased body temperature | 32 (32.6%) | 30 (30.6%) |
| Increased blood bilirubin | 21 (21.4%) | 21 (21.4%) |
| Headache | 14 (14.3%) | 11 (11.2%) |
| * Defined as TEAEs with a possible, probable, definite, or unknown relationship to the study drug. | ||
Serious adverse events (SAEs) were reported in 10 (10.2%) subjects. SAEs considered to be drug-related were intravascular hemolytic reaction (hypotension, nausea, chills and headache, and a decrease in haptoglobin and hemoglobin) in two subjects; headache, dizziness, nausea, pallor, shivering, and weakness requiring hospitalization in one subject; and an increase in blood pressure and severe headache in one subject. All four subjects recovered completely.
Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been identified during post-approval use of Rhophylac:
Hypersensitivity reactions, including rare cases of anaphylactic shock or anaphylactoid reactions, headache, dizziness, vertigo, hypotension, tachycardia, dyspnea, nausea, vomiting, rash, erythema, pruritus, chills, pyrexia, malaise, diarrhea and back pain have been reported. Transient injection-site irritation and pain have been observed following intramuscular administration.
There have been reports of lack of effect in patients with a body mass index ≥ 30 when administration via the intramuscular route was attempted [see DOSING AND ADMINISTRATION].
Transient hemoglobinuria has been reported in a patient being treated with Rhophylac for ITP.
Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, rubella, and varicella [see PATIENT INFORMATION].
REFERENCES
1. Pollack W, Ascari WQ, Kochesky RJ, O'Connor RR, Ho TY, Tripodi D. Studies on Rh prophylaxis. 1. relationship between doses of anti-Rh and size of antigenic stimulus. Transfusion. 1971;11:333-339.
Included as part of the PRECAUTIONS section.
Severe hypersensitivity reactions may occur. If symptoms of allergic or early signs of hypersensitivity reactions (including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, discontinue Rhophylac administration immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions to Rhophylac or any of its components.
Rhophylac contains trace amounts of IgA (less than 5 mcg/mL) [see DESCRIPTION]. Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Rhophylac is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reactions [see CONTRAINDICATIONS].
The administration of Rh0(D) immune globulin may affect the results of blood typing, the antibody screening test, and the direct antiglobulin (Coombs') test. Antepartum administration of Rh0(D) immune globulin to the mother can also affect these tests in the newborn infant.
Rhophylac can contain antibodies to other Rh antigens (e.g., anti-C antibodies), which might be detected by sensitive serological tests following administration.
Because Rhophylac is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Rhophylac.
Report any infections thought to be possibly transmitted by Rhophylac to CSL Behring Pharmacovigilance at 1-866-915-6958.
Intravascular hemolysis has occurred in a clinical study with Rhophylac. All cases resolved completely. However, as reported in the literature, some Rh0(D)-positive patients treated with Rh0(D) Immune Globulin Intravenous (Human) for ITP developed clinically compromising anemia, acute renal insufficiency, and, very rarely, disseminated intravascular coagulation (DIC) and death.2 Note: This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization.
Monitor patients in a healthcare setting for at least 8 hours after administrationof Rhophylac. Perform a dipstick urinalysis at baseline, 2 hours and 4 hours after administration, and prior to the end of the monitoring period.
Alert patients to, and monitor them for, the signs and symptoms of intravascular hemolysis, including back pain, shaking chills, fever, and discolored urine or hematuria. Absence of these signs and/or symptoms of intravascular hemolysis within 8 hours do not indicate intravascular hemolysis cannot occur subsequently.
If signs and/or symptoms of intravascular hemolysis are present or suspected after Rhophylac administration, perform post-treatment laboratory tests, including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). DIC may be difficult to detect in the ITP population; the diagnosis is dependent mainly on laboratory testing.
If patients who develop hemolysis with clinically compromising anemia after receiving Rhophylac are to be transfused, Rh0(D)-negative packed RBCs should be used to avoid exacerbating ongoing hemolysis.
The safety of Rhophylac in the treatment of ITP has not been established in patients with pre-existing anemia. Rhophylac may increase the severity of anemia.
Pregnancy Category C. Animal reproduction studies have not been conducted with Rhophylac.
The available evidence suggests that Rhophylac does not harm the fetus or affect future pregnancies or reproduction capacity when given to pregnant Rh0(D)-negative women for suppression of Rh isoimmunization.3
Rhophylac has not been evaluated in pregnant women with ITP.
Rhophylac is used in nursing mothers for the suppression of Rh isoimmunization. No undesirable effects on a nursing infant are expected during breastfeeding.
Rhophylac has not been evaluated in nursing mothers with ITP.
The safety and effectiveness of Rhophylac have not been established in pediatric subjects being treated for an incompatible transfusion. The physician should weigh the potential risks against the benefits of Rhophylac, particularly in girls whose later pregnancies may be affected if Rh isoimmunization occurs.
The safety and effectiveness of Rhophylac have not been established in pediatric subjects with chronic ITP. Dosing in the treatment of children with chronic ITP is expected to be similar to adults.
Rhophylac has not been evaluated for treating incompatible transfusions in subjects 65 years of age and older.
Of the 98 subjects evaluated in the clinical study of Rhophylac for treatment of ITP [see Clinical Studies], 19% were 65 years of age and older. No overall differences in effectiveness or safety were observed between these subjects and younger subjects.
REFERENCES
2. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh0(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005;106:1532- 1537.
3. Thornton JG, Page C, Foote G, Arthur GR, Tovey LAD, Scott JS. Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin. Br Med J. 1989;298:1671-1673.
There are no reports of known overdoses in patients being treated for suppression of Rh isoimmunization or ITP. Patients with incompatible transfusion or ITP who receive an overdose of Rh0(D) immune globulin should be monitored because of the potential risk for hemolysis.
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
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
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.
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
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% 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
(ITT Population)
| 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.
REFERENCES
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.
