Cslbehring.vo.llnwd.net

HIGHLIGHTS OF PRESCRIBING INFORMATION
o Exposure to >15 mL of Rh (D)-positive RBCs (in postpartum prophylaxis and These highlights do not include all the information needed to use
obstetric complications/invasive procedures) – Increase the dose based on Rhophylac safely and effectively. See full prescribing information for
guidelines for excessive fetomaternal hemorrhage Rhophylac.
• Incompatible transfusions – 100 IU (20 mcg) per 2 mL transfused blood or per 1 mL erythrocyte concentrate within 72 hours of exposure Rhophylac
ITP (2.3)
Rh (D) Immune Globulin Intravenous (Human) 1500 IU (300 mcg)
Intravenous administration only
Solution for Intravenous or Intramuscular Injection
• Recommended dosage – 250 IU (50 mcg) per kg body weight Initial US Approval: 2004
• Rate of administration – 2 mL per 15 to 60 seconds ------------------------------DOSAGE FORMS AND STRENGTHS--------------------------
WARNING: INTRAVASCULAR HEMOLYSIS IN ITP
1500 IU (300 mcg) per 2 mL prefilled, ready-to-use glass syringe (3) See full prescribing information for complete boxed warning. This --------------------------------------CONTRAINDICATIONS ---------------------------------
warning does not apply to Rh (D)-negative patients treated for the • History of anaphylactic or severe systemic reaction to human immune globulin suppression of Rh isoimmunization. • Intravascular hemolysis leading to death has been reported in Rh (D)-
• IgA deficient patients with antibodies against IgA and a history of hypersensitivity positive patients treated for immune thrombocytopenic purpura (ITP)
with Rh (D) Immune Globulin Intravenous (Human) products.1
---------------------------------WARNINGS AND PRECAUTIONS---------------------------
• Intravascular hemolysis can lead to clinically compromising anemia
Both Indications (5.1)
and multi-system organ failure including acute respiratory distress
• IgA deficient patients with known antibodies to IgA are at greater risk of developing syndrome (ARDS).
severe hypersensitivity and anaphylactic reactions (5.1.1).
• Serious complications, including severe anemia, acute renal insufficiency,
• Rhophylac is made from human blood; therefore it may contain infectious agents; renal failure, and disseminated intravascular coagulation (DIC), have
e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.1.3).
also been reported.
Suppression of Rh Isoimmunization (5.2)
• Closely monitor patients treated for ITP with Rhophylac in a healthcare
• For postpartum use following an Rh-incompatible pregnancy, administer Rhophylac setting for at least 8 hours after administration.
to the mother only. Do not administer to the newborn infant (5.2.1). ITP (5.3)
• Intravascular hemolysis has occurred in a clinical study; monitor patients for signs
----------------------------------INDICATIONS AND USAGE---------------------------------
and symptoms and perform confirmatory laboratory tests (5.3.1).
Rhophylac is an Rh (D) Immune Globulin Intravenous (Human) indicated for: • In ITP patients with pre-existing anemia, weigh the benefits of Rhophylac vs. the Suppression of Rhesus (Rh) Isoimmunization (1.1) in:
potential risk of increasing the severity of the anemia (5.3.2).
• Pregnancy and obstetric conditions in non-sensitized, Rh (D)-negative women with ----------------------------------ADVERSE REACTIONS---------------------------------------
Suppression of Rh Isoimmunization
o Routine antepartum and postpartum Rh prophylaxis The most common adverse reactions, reported in ≥ 0.5% of subjects, are nausea, o Rh prophylaxis in obstetric complications or invasive procedures dizziness, headache, injection-site pain, and malaise (6.1).
• Incompatible transfusions in Rh (D)-negative individuals transfused with blood components containing Rh (D)-positive red blood cells (RBCs) The most common adverse reactions, reported in > 14% of subjects, are chills, pyrexia/ Immune Thrombocytopenic Purpura (ITP) (1.2)
increased body temperature, headache, and mild hemolysis (increased bilirubin, Raising platelet counts in Rh (D)-positive, non-splenectomized adults with chronic ITP decreased hemoglobin, or decreased haptoglobin) (6.1).
-----------------------------DOSAGE AND ADMINISTRATION------------------------------
Suppression of Rh Isoimmunization (2.2)
To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring
Intravenous or intramuscular administration
Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.
fda.gov/medwatch.
o Rh-incompatible pregnancy – 1500 IU (300 mcg) at Week 28-30 of gestation and ---------------------------------DRUG INTERACTIONS----------------------------------------
another 1500 IU (300 mcg) within 72 hours of birth of an Rh (D)-positive baby Immunoglobulin administration may transiently interfere with the immune response to o Obstetric complications/invasive procedures – 1500 IU (300 mcg) within 72 hours live virus vaccines, such as measles, mumps and rubella (7.1).
---------------------------USE IN SPECIFIC POPULATIONS----------------------------------
o Excessive fetomaternal hemorrhage – 1500 IU (300 mcg) within 72 hours plus 100 IU (20 mcg) per mL fetal RBCs >15 mL (excess transplacental bleeding • Pregnancy: No human or animal data. Use only if clearly needed (8.1).
quantified) or another 1500 IU (300 mcg) (excess transplacental bleeding not
quantified)
See 17 for PATIENT COUNSELING INFORMATION. Revised: 08/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
DRUG INTERACTIONS
INDICATIONS AND USAGE
USE IN SPECIFIC POPULATIONS
DOSAGE AND ADMINISTRATION
10 OVERDOSAGE
DOSAGE FORMS AND STRENGTHS
11 DESCRIPTION
4 CONTRAINDICATIONS
12 CLINICAL PHARMACOLOGY
WARNINGS AND PRECAUTIONS
14 CLINICAL STUDIES
15 REFERENCES
Postpartum Use Following an Rh-incompatible Pregnancy 16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
ADVERSE REACTIONS
6.1 Clinical Studies Experience6.2 Postmarketing Experience * Sections or subsections omitted from the full prescribing information are not listed.
CSL Behring
Suppression of Rh Isoimmunization
FULL PRESCRIBING INFORMATION
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 Rhophylac®
advisable to administer Rhophylac in divided doses at different sites.
Table 1 provides dosing guidelines based on the condition being treated.
Rh (D) Immune Globulin
Table 1: Dosing Guidelines for Suppression of Rh Isoimmunization
Intravenous (Human)
Indication
Timing of
Administration
(Administer by
Intravenous or
WARNING: INTRAVASCULAR HEMOLYSIS IN ITP
Intramuscular
This warning does not apply to Rh (D)-negative patients treated for the Injection)
suppression of Rh isoimmunization. Rh-incompatible pregnancy
• Intravascular hemolysis leading to death has been reported in Rh (D)-
positive patients treated for immune thrombocytopenic purpura (ITP)
Routine antepartum prophylaxis At Week 28-30 of gestation with Rh (D) Immune Globulin Intravenous (Human) products.1
• Intravascular hemolysis can lead to clinically compromising anemia and
multi-system organ failure including acute respiratory distress syndrome
• Serious complications, including severe anemia, acute renal insufficiency,
renal failure, and disseminated intravascular coagulation (DIC), have also
been reported.
• Closely monitor patients treated for ITP with Rhophylac in a healthcare
setting for at least 8 hours after administration. 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
pregnancy (e.g., amniocentesis, procedure pain, shaking chills, fever, and discolored urine or hematuria. Absence of
these signs and/or symptoms within 8 hours does not indicate IVH 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).
INDICATIONS AND USAGE
Rhophylac is an Rh (D) Immune Globulin Intravenous (Human) (anti-D) product that is indicated for the suppression of Rh isoimmunization in non-sensitized Rh (D)-negative patients and for the treatment of immune thrombocytopenic purpura (ITP) in Rh (D)- Suppression of Rh Isoimmunization
Rhophylac is indicated for suppression of rhesus (Rh) isoimmunization in non-sensitized Rh (D)-negative women with an Rh-incompatible pregnancy, including: • Routine antepartum and postpartum Rh prophylaxis Incompatible transfusions
– Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from – Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma) IU, international units; mcg, micrograms.
An Rh-incompatible pregnancy is assumed if the fetus/baby is either Rh (D)-positive or * A 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of ≥15 mL of Rh (D)-unknown or if the father is either Rh (D)-positive or Rh (D)-unknown.
† The dose of Rhophylac must be increased if the patient is exposed to >15 mL of Rh (D)-positive RBCs; in this case, follow the dosing guidelines for excessive fetomaternal hemorrhage.
Rhophylac is indicated for the suppression of Rh isoimmunization in Rh (D)-negative individuals transfused with Rh (D)-positive red blood cells (RBCs) or blood components For treatment of ITP, ADMINISTER RHOPHYLAC BY THE INTRAVENOUS ROUTE ONLY
(see Preparation and Handling [2.1]). Do not administer intramuscularly.
Treatment can be given without a preceding exchange transfusion when the transfused A 250 IU (50 mcg) per kg body weight dose of Rhophylac is recommended for patients blood represents less than 20% of the total circulating RBCs. If the volume exceeds with ITP. The following formula can be used to calculate the recommended amount of 20%, an exchange transfusion should be considered prior to administering Rhophylac.
Dose (IU) x body weight (kg) = Total IU / 1500 IU per syringe = Number of syringes Rhophylac is indicated in Rh (D)-positive, non-splenectomized adult patients with chronic Rhophylac should be administered at a rate of 2 mL per 15 to 60 seconds.
DOSAGE FORMS AND STRENGTHS
DOSAGE AND ADMINISTRATION
1500 IU (300 mcg) per 2 mL prefilled, ready-to-use, glass syringe As with all blood products, patients should be observed for at least 20 minutes following 4 CONTRAINDICATIONS
• Rhophylac is contraindicated in patients who have had an anaphylactic or severe Preparation and Handling
systemic reaction to the administration of human immune globulin.
• Rhophylac is a clear or slightly opalescent, colorless to pale yellow solution. Inspect • Rhophylac is contraindicated in IgA-deficient patients with antibodies to IgA and a Rhophylac visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates.
WARNINGS AND PRECAUTIONS
• Prior to intravenous use, ensure that the needle-free intravenous administration system is compatible with the tip of the Rhophylac glass syringe.
Both Indications
5.1.1 Hypersensitivity
• Bring Rhophylac to room temperature before use.
Severe hypersensitivity reactions may occur. If symptoms of allergic or early signs of • Rhophylac is for single use only. Dispose of any unused product or waste material in 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 intravenous or intramuscular injection of Rhophylac 1500 IU (300 mcg) at Week 28 of should be available for immediate treatment of acute hypersensitivity reactions.
gestation. A second 1500 IU (300 mcg) dose was administered to 267 (9 in Study 1 and Rhophylac contains trace amounts of IgA (less than 5 mcg/mL) (see Description [11]). 258 in Study 2) of these women within 72 hours of the birth of an Rh (D)-positive baby. Patients with known antibodies to IgA have a greater risk of developing potentially In addition, 30 women in Study 2 received at least one extra antepartum 1500 IU (300 severe hypersensitivity and anaphylactic reactions. Rhophylac is contraindicated in mcg) dose due to obstetric complications (see Clinical Studies [14.1]).
patients with antibodies against IgA and a history of hypersensitivity reactions (see 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 5.1.2 Interference with Laboratory Tests
finding of a transient positive anti-C antibody test was observed in 0.9% of subjects.
The administration of Rh (D) immune globulin may affect the results of blood typing, ITP the antibody screening test, and the direct antiglobulin (Coombs’) test. Antepartum In a clinical study, 98 Rh (D)-positive adult subjects with chronic ITP received an administration of Rh (D) immune globulin to the mother can also affect these tests in intravenous dose of Rhophylac 250 IU (50 mcg) per kg body weight (see Clinical Studies [14.2]). Premedication to alleviate infusion-related side effects was not used Rhophylac can contain antibodies to other Rh antigens (e.g., anti-C antibodies), which except in a single subject who received acetaminophen and diphenhydramine.
might be detected by sensitive serological tests following administration.
Eighty-four (85.7%) subjects experienced 392 treatment-emergent adverse events 5.1.3 Transmissible Infectious Agents
(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 Because Rhophylac is made from human blood, it may carry a risk of transmitting 24 hours of dosing, 73 (74.5%) subjects experienced 183 TEAEs, and 66 (67%) subjects infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) experienced 156 drug-related TEAEs.
agent. The risk of infectious agent transmission has been reduced by screening plasma Mild hemolysis (manifested as an increase in bilirubin, a decrease in hemoglobin, or a donors for prior exposure to certain viruses, testing for the presence of certain current decrease in haptoglobin) was observed. An increase in blood bilirubin was seen in 21% virus infections, and including virus inactivation/removal steps in the manufacturing of subjects. The median decrease in hemoglobin was greatest (0.8 g/dL) at Day 6 and Day 8 following administration of Rhophylac.
Report any infections thought to be possibly transmitted by Rhophylac to CSL Behring Table 2 shows the most common TEAEs observed in the clinical study.
Pharmacovigilance at 1-866-915-6958.
Table 2: Most Common Treatment-Emergent Adverse Events (TEAEs) in
Suppression of Rh Isoimmunization
Subjects with ITP
5.2.1 Postpartum Use Following an Rh-incompatible Pregnancy
Administer Rhophylac to the mother only. Do not administer to the newborn infant (see
Number of Subjects (%) With
Number of Subjects
(%) With a Drug-
Related TEAE*
5.3.1 Intravascular Hemolysis
Intravascular hemolysis has occurred in a clinical study with Rhophylac. All cases
resolved completely. However, as reported in the literature, some Rh (D)-positive patients treated with Rh (D) Immune Globulin Intravenous (Human) for ITP developed clinically compromising anemia, acute renal insufficiency, and, very rarely, disseminated
intravascular coagulation (DIC) and death.1 Note: This warning does not apply to Rh (D)-
negative patients treated for the suppression of Rh isoimmunization.
Closely monitor patients in a healthcare setting for at least 8 hours after administration of Rhophylac. Perform a dipstick urinalysis at baseline, 2 hours and 4 hours after administration, and prior to the end of the monitoring period.
* 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 Alert patients to, and monitor them for, the signs and symptoms of intravascular hemolysis, to be drug-related were intravascular hemolytic reaction (hypotension, nausea, chills and including back pain, shaking chills, fever, and discolored urine or hematuria. Absence of headache, and a decrease in haptoglobin and hemoglobin) in two subjects; headache, these signs and/or symptoms of intravascular hemolysis within 8 hours do not indicate dizziness, nausea, pallor, shivering, and weakness requiring hospitalization in one subject; intravascular hemolysis cannot occur subsequently. and an increase in blood pressure and severe headache in one subject. All four subjects If signs and/or symptoms of intravascular hemolysis are present or suspected after recovered completely.
Rhophylac administration, perform post-treatment laboratory tests, including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). DIC may be Postmarketing Experience
difficult to detect in the ITP population; the diagnosis is dependent mainly on laboratory Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate If patients who develop hemolysis with clinically compromising anemia after receiving their frequency or establish a causal relationship to product exposure. The Rhophylac are to be transfused, Rh (D)-negative packed RBCs should be used to avoid following adverse reactions have been identified during post-approval use 5.3.2 Pre-existing Anemia
Suppression of Rh IsoimmunizationHypersensitivity reactions, including rare cases of anaphylactic shock or anaphylactoid The safety of Rhophylac in the treatment of ITP has not been established in patients with reactions, headache, dizziness, vertigo, hypotension, tachycardia, dyspnea, nausea, pre-existing anemia. The physician must weigh the benefits of Rhophylac against the vomiting, rash, erythema, pruritus, chills, pyrexia, malaise, diarrhea and back pain have potential risk of increasing the severity of the anemia.
been reported. Transient injection-site irritation and pain have been observed following ADVERSE REACTIONS
The most serious adverse reactions in patients receiving Rh (D) Immune Globulin Intravenous (Human) have been observed in the treatment of ITP and include intravascular Transient hemoglobinuria has been reported in a patient being treated with Rhophylac hemolysis, clinically compromising anemia, acute renal insufficiency, and, very rarely, DIC and death (see Boxed Warning, Warnings and Precautions [5.3.1]).1 DRUG INTERACTIONS
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 7.1
Live Virus Vaccines
Passive transfer of antibodies may transiently impair the immune response to live The most common adverse reactions observed in the treatment of ITP (>14% of subjects) attenuated virus vaccines such as measles, mumps, rubella, and varicella (see Patient are chills, pyrexia/increased body temperature, and headache. Mild hemolysis (manifested Counseling Information [17.1]).
by an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Clinical Studies Experience
Pregnancy Category C. Animal reproduction studies have not been conducted with Because clinical studies are conducted under different protocols and widely varying conditions, adverse reaction rates observed cannot be directly Suppression of Rh Isoimmunizationcompared to rates in other clinical trials and may not reflect the rates The available evidence suggests that Rhophylac does not harm the fetus or affect future observed in practice. pregnancies or reproduction capacity when given to pregnant Rh (D)-negative women In two clinical studies, 447 Rh (D)-negative pregnant women received either an Rhophylac contains a maximum of 30 mg/mL of human plasma proteins, 10 mg/mL of Rhophylac has not been evaluated in pregnant women with ITP.
which is human albumin added as a stabilizer. Prior to the addition of the stabilizer, Nursing Mothers
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/ Rhophylac is used in nursing mothers for the suppression of Rh isoimmunization. No mL of glycine and up to 0.25 M of sodium chloride. Rhophylac contains no preservative. undesirable effects on a nursing infant are expected during breastfeeding.
Human albumin is manufactured from pooled plasma of US donors by cold ethanol fractionation, followed by pasteurization.
Rhophylac has not been evaluated in nursing mothers with ITP.
CLINICAL PHARMACOLOGY
Pediatric Use
Mechanism of Action
Suppression of Rh Isoimmunization in Incompatible Transfusions The safety and effectiveness of Rhophylac have not been established in pediatric subjects The mechanism by which Rh (D) immune globulin suppresses immunization to Rh (D)- being treated for an incompatible transfusion. The physician should weigh the potential positive RBCs is not completely known.
risks against the benefits of Rhophylac, particularly in girls whose later pregnancies may In a clinical study of Rh (D)-negative healthy male volunteers, both the intravenous and be affected if Rh isoimmunization occurs.
intramuscular administration of a 1500 IU (300 mcg) dose of Rhophylac 24 hours after Geriatric Use
injection of 15 mL of Rh (D)-positive RBCs resulted in an effective clearance of Rh (D)- Suppression of Rh Isoimmunization in Incompatible Transfusions positive RBCs. On average, 99% of injected RBCs were cleared within 12 hours following Rhophylac has not been evaluated for treating incompatible transfusions in subjects 65 intravenous administration and within 144 hours following intramuscular administration.
Rhophylac has been shown to increase platelet counts and to reduce bleeding in non- Of the 98 subjects evaluated in the clinical study of Rhophylac for treatment of ITP (see splenectomized Rh (D)-positive subjects with chronic ITP. The mechanism of action is Clinical Studies [14.2]), 19% were 65 years of age and older. No overall differences in thought to involve the formation of Rh (D) immune globulin RBC complexes, which are effectiveness or safety were observed between these subjects and younger subjects.
preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets.7 10 OVERDOSAGE
There are no reports of known overdoses in patients being treated for suppression of
12.3 Pharmacokinetics
Rh isoimmunization or ITP. Patients with incompatible transfusion or ITP who receive an overdose of Rh (D) immune globulin should be monitored because of the potential In a clinical study comparing the pharmacokinetics of intravenous versus intramuscular administration, 15 Rh (D)-negative pregnant women received a single 1500 IU (300 mcg) dose of Rhophylac at Week 28 of gestation.8 11 DESCRIPTION
Following intravenous administration, peak serum levels of Rh (D) immune globulin Rhophylac is a sterile Rh (D) Immune Globulin Intravenous (Human) (anti-D) solution ranged from 62 to 84 ng/mL after 1 day (i.e., the time the first blood sample was taken in a ready-to-use prefilled glass syringe for intravenous or intramuscular injection. One following the antepartum dose). Mean systemic clearance was 0.20 ± 0.03 mL/min, and syringe contains at least 1500 IU (300 mcg) of IgG antibodies to Rh (D) in a 2 mL solution, sufficient to suppress the immune response to at least 15 mL of Rh-positive RBCs.1 The Following intramuscular administration, peak serum levels ranged from 7 to 46 ng/ product potency is expressed in IUs by comparison to the World Health Organization mL and were achieved between 2 and 7 days. Mean apparent clearance was 0.29 ± (WHO) standard, which is also the US and the European Pharmacopoeia standard.
0.12 mL/min, and half-life was 18 ± 5 days. The absolute bioavailability of Rhophylac Plasma is obtained from healthy Rh (D)-negative donors who have been immunized with Rh (D)-positive RBCs. The donors are screened carefully to reduce the risk of receiving Regardless of the route of administration, Rh (D) immune globulin titers were detected in donations containing blood-borne pathogens. Each plasma donation used in the all women up to at least 9 weeks following administration of Rhophylac.
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 Pharmacokinetic studies with Rhophylac were not performed in Rh (D)-positive subjects is tested by FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV, and HIV-1 and found with ITP. Rh (D) immune globulin binds rapidly to Rh (D)-positive erythrocytes.9 to be negative. The source plasma is also tested by NAT for hepatitis A virus (HAV) and CLINICAL STUDIES
Rhophylac is produced by an ion-exchange chromatography isolation procedure4, using Suppression of Rh Isoimmunization
pooled plasma obtained by plasmapheresis of immunized Rh (D)-negative US donors. In two clinical studies, 447 Rh (D)-negative pregnant women received a 1500 IU (300 The manufacturing process includes a solvent/detergent treatment step (using tri-n-butyl mcg) dose of Rhophylac during Week 28 of gestation. The women who gave birth to phosphate and Triton™ X-100) that is effective in inactivating enveloped viruses such an Rh (D)-positive baby received a second 1500 IU (300 mcg) dose within 72 hours of as HIV, HCV, and HBV.5,6 Rhophylac is filtered using a Planova® 15 nanometer (nm) birth.
virus filter that has been validated to be effective in removing both enveloped and non- • Study 1 (Pharmacokinetic Study) – Eight of the women who participated in the enveloped viruses. Table 3 presents viral clearance and inactivation data from validation pharmacokinetic study (see Clinical Pharmacology [12.3]) gave birth to an studies, expressed as the mean log reduction factor (LRF).
Rh (D)-positive baby and received the postpartum dose of 1500 IU (300 mcg) of Table 3: Virus Inactivation and Removal in Rhophylac
Rhophylac.8 Antibody tests performed 6 to 8 months later were negative for all women. This suggests that no Rh (D) immunization occurred.
• Study 2 (Pivotal Study) – In an open-label, single-arm clinical study at 22 centers in Virus property
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 Rh (D)-positive baby, 248 women were evaluated for Rh (D) immunization 6 to 11.5 months postpartum. Manufacturing step
None of these women developed antibodies against the Rh (D) antigen.
In an open-label, single-arm, multicenter study, 98 Rh (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 Overall reduction
who had bleeding at baseline, the regression of hemorrhage defined as any decrease (log units)
from baseline in the severity of overall bleeding status.
HIV, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a model for large, enveloped DNA viruses (e.g., herpes Table 4 presents the primary response rates for the intent-to-treat (ITT) and per-protocol 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.
Primary Response Rates (ITT and PP Populations)
8. Bichler J, Schöndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in pregnant RhD-negative women. BJOG. 2003;110:39-45.
Primary Response Rate at Day
9. Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. Analysis
Population
Subjects
Responders
10. MacKenzie IZ, Bichler J, Mason GC, et al. Efficacy and safety of a new, Confidence
chromatographically purified rhesus (D) immunoglobulin. Eur J Obstetr Gynecol Responders
Interval (CI)
Reprod Biol. 2004;117:154-161.
HOW SUPPLIED/STORAGE AND HANDLING
How Supplied
• Rhophylac 1500 IU (300 mcg) is supplied in packages of one or ten (10) prefilled, The primary efficacy response rate (ITT population) demonstrated a clinically relevant ready-to-use, glass syringe(s), each containing 2 mL liquid for injection. Each syringe response to treatment, i.e., the lower bound of the 95% confidence interval (CI) was is accompanied by a SafetyGlide™ needle for intravenous or intramuscular use.
greater than the predefined response rate of 50%. The median time to platelet response Each product presentation includes a package insert and the following components: was 3 days, and the median duration of platelet response was 22 days.
Presentation
Components
Table 5 presents the response rates by baseline platelet count for subjects in the ITT NDC Number
population.
Table 5:
Response Rates By Baseline Platelet Count (ITT Population)
44206-300-01 • Single-use, prefilled 2 mL syringe (NDC 44206- Response Rates at Day 15
44206-300-10 • Ten single-use, prefilled 2 mL syringes (NDC No. (%) Subjects
Baseline
Achieving a
No. (%) Subjects
Platelet
Total No.
Platelet Count of
With an Increase in
Storage and Handling
Subjects
≥30 x 109/L and
Platelet Counts to
(x 109/L)
an Increase of
≥50 x 109/L
• Store at 2 to 8°C (36 to 46°F) for a shelf life of 36 months from the date of >20 x 109/L
manufacture, as indicated by the expiration date printed on the outer carton and • Keep Rhophylac in its original carton to protect it from light.
• Rhophylac contains no preservatives.
• The prefilled Rhophylac syringe contains no latex.
PATIENT COUNSELING INFORMATION
Both Indications
• Inform patients to immediately report the following signs and symptoms to their physician: hives, chest tightness, wheezing, hypotension, and anaphylaxis.
* Reflects subjects with a platelet count of ≤30 × 109/L at screening but >30 × 109/L immediately before treatment.
• Inform patients that Rhophylac is made from human blood and may contain During the study, an overall regression of hemorrhage was seen in 44 (88%, 95% CI: infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD 76% to 94%) of the 50 subjects with bleeding at baseline. The percentage of subjects agent). Explain that the risk Rhophylac may transmit an infectious agent has been showing a regression of hemorrhage increased from 20% at Day 2 to 64% at Day 15. reduced by screening all plasma donors, by testing the donated plasma for certain There was no evidence of an association between the overall hemorrhage regression rate viruses, and by inactivating and/or removing certain viruses during manufacturing. Advise patients to report any symptoms that concern them and that may be related 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 • Inform patients that Rhophylac may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella), and instruct them to notify 15 REFERENCES
their healthcare professional of this potential interaction when they are receiving 1. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh (D) immune globulin intravenous Suppression of Rh Isoimmunization
administration for immune thrombocytopenic purpura. Blood. 2005;106:1532- • Inform patients receiving the antepartum dose of Rhophylac for suppression of Rh isoimmunization that they will need a second dose within 72 hours of birth if the 2. 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.
• Instruct patients being treated with Rhophylac for ITP to immediately report 3. Thornton JG, Page C, Foote G, Arthur GR, Tovey LAD, Scott JS. Efficacy and long symptoms of intravascular hemolysis, including back pain, shaking chills, fever, term effects of antenatal prophylaxis with anti-D immunoglobulin. Br Med J. discolored urine, decreased urine output, sudden weight gain, edema, and/or 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. CSL Behring AG
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 US License No. 1766Haemost. 1991;65:1163.
6. Horowitz B, Bonomo R, Prince AM, Chin S, Brotman B, Shulman RW. Solvent/ CSL Behring LLC
detergent-treated plasma: a virus-inactivated substitute for fresh frozen plasma. Kankakee, IL 60901 USABlood. 1992;79:826-831.
7. Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Triton™ is a trademark of The Dow Chemical Company Planova® is a registered trademark of Asahi Kasei Medical Co., Ltd.
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Source: http://cslbehring.vo.llnwd.net/o33/u/central/PI/US/Rhophylac/EN/Rhophylac-Prescribing-Information.pdf