Label: RHOPHYLAC- human rho(d) immune globulin solution 

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  • NDC Code(s): 44206-300-01, 44206-300-10, 44206-300-90
  • Packager: CSL Behring AG
  • Category: PLASMA DERIVATIVE
  • DEA Schedule: None
  • Marketing Status: Biologic Licensing Application

Drug Label Information

Updated 10/12

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  • BOXED WARNING(What is this?)

    WARNING: INTRAVASCULAR HEMOLYSIS IN ITP

    This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization.

    • Intravascular hemolysis leading to death has been reported in Rh0(D)-positive patients treated for immune thrombocytopenic purpura (ITP) with Rh0(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 (ARDS).
    • 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 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).
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  • HIGHLIGHTS OF PRESCRIBING INFORMATION
    These highlights do not include all the information needed to use Rhophylac safely and effectively. See full prescribing information for Rhophylac.
     
    Rhophylac
    Rh 0(D) Immune Globulin Intravenous (Human) 1500 IU (300 mcg)
    Solution for Intravenous or Intramuscular Injection
    Initial U.S. Approval: 2004

    WARNING: INTRAVASCULAR HEMOLYSIS IN ITP

    See full prescribing information for complete boxed warning. This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization.

    • Intravascular hemolysis leading to death has been reported in Rh0(D)-positive patients treated for immune thrombocytopenic purpura (ITP) with Rh0(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 (ARDS).
    • 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.

    INDICATIONS AND USAGE

    Rhophylac is an Rh0(D) Immune Globulin Intravenous (Human) indicated for:

    Suppression of Rhesus (Rh) Isoimmunization (1.1) in:

    • Pregnancy and obstetric conditions in non-sensitized, Rh0(D)-negative women with an Rh-incompatible pregnancy, including:
      • Routine antepartum and postpartum Rh prophylaxis
      • Rh prophylaxis in obstetric complications or invasive procedures
    • Incompatible transfusions in Rh0(D)-negative individuals transfused with blood components containing Rh0(D)-positive red blood cells (RBCs)

    Immune Thrombocytopenic Purpura (ITP) (1.2)

    • Raising platelet counts in Rh0(D)-positive, non-splenectomized adults with chronic ITP

    DOSAGE AND ADMINISTRATION

    Suppression of Rh Isoimmunization (2.2)

    Intravenous or intramuscular administration

    • Pregnancy and obstetric conditions
      • Rh-incompatible pregnancy – 1500 IU (300 mcg) at Week 28-30 of gestation and another 1500 IU (300 mcg) within 72 hours of birth of an Rh0(D)-positive baby
      • Obstetric complications/invasive procedures – 1500 IU (300 mcg) within 72 hours of the at-risk event
      • Excessive fetomaternal hemorrhage – 1500 IU (300 mcg) within 72 hours plus 100 IU (20 mcg) per mL fetal RBCs >15 mL (excess transplacental bleeding quantified) or another 1500 IU (300 mcg) (excess transplacental bleeding not quantified)
      • Exposure to >15 mL of Rh0(D)-positive RBCs (in postpartum prophylaxis and obstetric complications/invasive procedures) – Increase the dose based on guidelines for excessive fetomaternal hemorrhage
    • Incompatible transfusions – 100 IU (20 mcg) per 2 mL transfused blood or per 1 mL erythrocyte concentrate within 72 hours of exposure

    ITP (2.3)

    Intravenous administration only

    • Recommended dosage – 250 IU (50 mcg) per kg body weight
    • Rate of administration – 2 mL per 15 to 60 seconds

    DOSAGE FORMS AND STRENGTHS

    1500 IU (300 mcg) per 2 mL prefilled, ready-to-use glass syringe (3)

    CONTRAINDICATIONS

    • History of anaphylactic or severe systemic reaction to human immune globulin products (4)
    • IgA deficient patients with antibodies against IgA and a history of hypersensitivity (4)

    WARNINGS AND PRECAUTIONS

    Both Indications (5.1)

    • IgA deficient patients with known antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions (5.1.1).
    • Rhophylac is made from human blood; therefore it may contain infectious agents; e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (5.1.3).

    Suppression of Rh Isoimmunization (5.2)

    • For postpartum use following an Rh-incompatible pregnancy, administer Rhophylac 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 and symptoms and perform confirmatory laboratory tests (5.3.1).
    • In ITP patients with pre-existing anemia, weigh the benefits of Rhophylac vs. the potential risk of increasing the severity of the anemia (5.3.2).

    ADVERSE REACTIONS

    Suppression of Rh Isoimmunization

    The most common adverse reactions, reported in ≥ 0.5% of subjects, are nausea, dizziness, headache, injection-site pain, and malaise (6.1).

    ITP

    The most common adverse reactions, reported in > 14% of subjects, are chills, pyrexia/increased body temperature, headache, and mild hemolysis (increased bilirubin, decreased hemoglobin, or decreased haptoglobin) (6.1).


    To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

    DRUG INTERACTIONS

    Immunoglobulin administration may transiently interfere with the immune response to live virus vaccines, such as measles, mumps and rubella (7.1).

    USE IN SPECIFIC POPULATIONS

    ITP

    • Pregnancy: No human or animal data. Use only if clearly needed (8.1).

    See 17 for PATIENT COUNSELING INFORMATION.

    Revised: 8/2012

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  • FULL PRESCRIBING INFORMATION: CONTENTS*
  • SPL UNCLASSIFIED SECTION

    Rhophylac®
    Rh0(D) Immune Globulin Intravenous (Human)

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  • 1 INDICATIONS AND USAGE

    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.

    1.1 Suppression of Rh Isoimmunization

    Pregnancy and Obstetric Conditions

    Rhophylac is indicated for suppression of rhesus (Rh) isoimmunization in non-sensitized Rh0(D)-negative women with an Rh-incompatible pregnancy, including:

    • Routine antepartum and postpartum Rh prophylaxis
    • Rh prophylaxis in cases of:
      Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage)
      Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma)

    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.

    Incompatible Transfusions

    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.

    1.2 ITP

    Rhophylac is indicated in Rh0(D)-positive, non-splenectomized adult patients with chronic ITP to raise platelet counts.

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  • 2 DOSAGE AND ADMINISTRATION

    As with all blood products, patients should be observed for at least 20 minutes following administration of Rhophylac.

    2.1 Preparation and Handling

    • Rhophylac is a clear or slightly opalescent, colorless to pale yellow solution. Inspect Rhophylac visually for particulate matter and discoloration prior to administration. Do not use if the solution is cloudy or contains particulates.

    • Prior to intravenous use, ensure that the needle-free intravenous administration system is compatible with the tip of the Rhophylac glass syringe.

    • Do not freeze.

    • Bring Rhophylac to room temperature before use.

    • Rhophylac is for single use only. Dispose of any unused product or waste material in accordance with local requirements.

    2.2 Suppression of Rh Isoimmunization

    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.

    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)
    IU, international units; mcg, micrograms.
    *
    A 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of ≥15 mL of Rh 0(D)-positive RBCs. 2
    The dose of Rhophylac must be increased if the patient is exposed to >15 mL of Rh 0(D)-positive RBCs; in this case, follow the dosing guidelines for excessive fetomaternal hemorrhage.
    Rh-incompatible pregnancy
     
    Routine antepartum prophylaxis
    At Week 28-30 of gestation 1500 IU (300 mcg)
     
    Postpartum prophylaxis
    (required only if the newborn is Rh 0(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:
    • 100 IU (20 mcg) per mL fetal RBCs in excess of 15 mL if excess transplacental bleeding is quantified
      or
    • An additional 1500 IU (300 mcg) dose if excess transplacental bleeding cannot be quantified
    Incompatible transfusions Within 72 hours of exposure 100 IU (20 mcg)
    per 2 mL transfused blood or per 1 mL erythrocyte concentrate

    2.3 ITP

    For treatment of ITP, ADMINISTER RHOPHYLAC BY THE INTRAVENOUS ROUTE ONLY (see Preparation and Handling [2.1]). 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) × 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.

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  • 3 DOSAGE FORMS AND STRENGTHS

    1500 IU (300 mcg) per 2 mL prefilled, ready-to-use, glass syringe

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  • 4 CONTRAINDICATIONS

    • Rhophylac is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin.
    • Rhophylac is contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.
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  • 5 WARNINGS AND PRECAUTIONS

    5.1 Both Indications

    5.1.1 Hypersensitivity

    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.

    Rhophylac contains trace amounts of IgA (less than 5 mcg/mL) (see Description [11]). 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 [4]).

    5.1.2 Interference with Laboratory Tests

    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.

    5.1.3 Transmissible Infectious Agents

    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.

    5.2 Suppression of Rh Isoimmunization

    5.2.1 Postpartum Use Following an Rh-incompatible Pregnancy

    Administer Rhophylac to the mother only. Do not administer to the newborn infant (see Pediatric Use [8.4]).

    5.3 ITP

    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 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.1 Note: This warning does not apply to Rh0(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.

    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.

    5.3.2 Pre-existing Anemia

    The safety of Rhophylac in the treatment of ITP has not been established in patients with pre-existing anemia. The physician must weigh the benefits of Rhophylac against the potential risk of increasing the severity of the anemia.

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  • 6 ADVERSE REACTIONS

    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 [5.3.1]).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. Mild hemolysis (manifested by an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was also observed.

    6.1 Clinical Studies Experience

    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.

    Suppression of Rh Isoimmunization

    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 [14.1]).

    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.

    ITP

    In a clinical study, 98 Rh0(D)-positive adult subjects with chronic ITP received an 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 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.

    Mild 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
    *
    Defined as TEAEs with a possible, probable, definite, or unknown relationship to the study drug.
    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%)

    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.

    6.2 Postmarketing Experience

    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:

    Suppression of Rh Isoimmunization

    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.

    ITP

    Transient hemoglobinuria has been reported in a patient being treated with Rhophylac for ITP.

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  • 7 DRUG INTERACTIONS

    7.1 Live Virus Vaccines

    Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, rubella, and varicella (see Patient Counseling Information [17.1]).

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  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Pregnancy Category C. Animal reproduction studies have not been conducted with Rhophylac.

    Suppression of Rh Isoimmunization

    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

    ITP

    Rhophylac has not been evaluated in pregnant women with ITP.

    8.3 Nursing Mothers

    Suppression of Rh Isoimmunization

    Rhophylac is used in nursing mothers for the suppression of Rh isoimmunization. No undesirable effects on a nursing infant are expected during breastfeeding.

    ITP

    Rhophylac has not been evaluated in nursing mothers with ITP.

    8.4 Pediatric Use

    Suppression of Rh Isoimmunization in Incompatible Transfusions

    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.

    8.5 Geriatric Use

    Suppression of Rh Isoimmunization in Incompatible Transfusions

    Rhophylac has not been evaluated for treating incompatible transfusions in subjects 65 years of age and older.

    ITP

    Of the 98 subjects evaluated in the clinical study of Rhophylac for treatment of ITP (see Clinical Studies [14.2]), 19% were 65 years of age and older. No overall differences in effectiveness or safety were observed between these subjects and younger subjects.

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  • 10 OVERDOSAGE

    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.

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  • 11 DESCRIPTION

    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.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 HBV, HCV, and HIV-1 and found to be negative. 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 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 non-enveloped 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
    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.
    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
    (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.

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  • 12 CLINICAL PHARMACOLOGY

    12.1 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.7

    12.3 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.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.

    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.9

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  • 14 CLINICAL STUDIES

    14.1 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 [12.3]) 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.

    14.2 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% 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)
    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
    *
    Reflects subjects with a platelet count of ≤30 × 10 9/L at screening but >30 × 10 9/L immediately before treatment.
    ≤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)

    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.

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  • 15 REFERENCES

    1. 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.
    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.
    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.
    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.
    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.
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  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    16.1 How Supplied

    • Rhophylac 1500 IU (300 mcg) is supplied in packages of one or ten (10) prefilled, ready-to-use, glass syringe(s), each containing 2 mL liquid for injection. Each syringe is accompanied by a SafetyGlide™ needle for intravenous or intramuscular use.
    Each product presentation includes a package insert and the following components:
    Presentation Carton NDC Number Components
    1500 IU
    (300 mcg)
    44206-300-01
    • Single-use, prefilled 2 mL syringe [NDC 44206-300-90]
    • SafetyGlide needle
    1500 IU
    (300 mcg)
    Multipack
    44206-300-10
    • Ten single-use, prefilled 2 mL syringes [NDC 44206-300-90]
    • Ten SafetyGlide needles

    16.2 Storage and Handling

    • DO NOT FREEZE.
    • Store at 2 to 8°C (36 to 46°F) for a shelf life of 36 months from the date of manufacture, as indicated by the expiration date printed on the outer carton and syringe label.
    • Keep Rhophylac in its original carton to protect it from light.
    • Rhophylac contains no preservatives.
    • The prefilled Rhophylac syringe contains no latex.
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  • 17 PATIENT COUNSELING INFORMATION

    17.1 Both Indications

    • Inform patients to immediately report the following signs and symptoms to their physician: hives, chest tightness, wheezing, hypotension, and anaphylaxis.
    • Inform patients that Rhophylac is made from human blood and may contain infectious agents that can cause disease (e.g., viruses and, theoretically, the CJD agent). Explain that the risk Rhophylac may transmit an infectious agent has been reduced by screening all plasma donors, by testing the donated plasma for certain 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 to viral infections.
    • 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 their healthcare professional of this potential interaction when they are receiving vaccinations.

    17.2 Suppression of Rh Isoimmunization

    • 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 baby's blood type is Rh-positive.

    17.3 ITP

    • Instruct patients being treated with Rhophylac for ITP to immediately report symptoms of intravascular hemolysis, including back pain, shaking chills, fever, discolored urine, decreased urine output, sudden weight gain, edema, and/or shortness of breath.
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  • SPL UNCLASSIFIED SECTION

    Manufactured by:
    CSL Behring AG
    Bern, Switzerland
    US License No. 1766

    Distributed by:
    CSL Behring LLC
    Kankakee, IL 60901 USA

    Triton is a trademark of The Dow Chemical Company
    Planova® is a registered trademark of Asahi Kasei Medical Co., Ltd.
    SafetyGlide is a trademark of Becton, Dickinson and Company

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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - 300 mcg Syringe Label

    NDC 44206-300-90

    300 mcg

    Rh0(D)
    Immune Globulin
    Intravenous (Human)
    Rhophylac
    ®

    1500 IU per 2 mL

    For IV or IM Injection.
    Rx only

    CSL Behring AG
    Bern, Switzerland
    US License No. 1766

    LOT     0000000000
    EXP     MM.YYYY

    Principal Display Panel - 300 mcg Syringe Label
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  • PRINCIPAL DISPLAY PANEL

    PRINCIPAL DISPLAY PANEL - 300 mcg Syringe Carton

    NDC 44206-300-01

    300 mcg

    Rh0(D) Immune Globulin Intravenous (Human)
    Rhophylac®
    1500 IU

    For Intravenous or Intramuscular Injection. Rx only

    CSL Behring

    Principal Display Panel - 300 mcg Syringe Carton
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  • INGREDIENTS AND APPEARANCE
    RHOPHYLAC 
    human rho(d) immune globulin solution
    Product Information
    Product Type PLASMA DERIVATIVE Item Code (Source) NDC:44206-300
    Route of Administration INTRAVENOUS, INTRAMUSCULAR DEA Schedule     
    Active Ingredient/Active Moiety
    Ingredient Name Basis of Strength Strength
    HUMAN RHO(D) IMMUNE GLOBULIN (HUMAN RHO(D) IMMUNE GLOBULIN) HUMAN RHO(D) IMMUNE GLOBULIN 1500 [iU]  in 2 mL
    Inactive Ingredients
    Ingredient Name Strength
    Albumin (Human) 20 mg  in 2 mL
    Human Immunoglobulin A  
    Glycine  
    Sodium Chloride  
    Packaging
    # Item Code Package Description Marketing Start Date Marketing End Date
    1 NDC:44206-300-01 1 in 1 CARTON
    1 NDC:44206-300-90 2 mL in 1 SYRINGE, GLASS
    2 NDC:44206-300-10 10 in 1 CARTON
    2 NDC:44206-300-90 2 mL in 1 SYRINGE, GLASS
    Marketing Information
    Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
    BLA BLA125070 01/06/2009
    Labeler - CSL Behring AG (481152762)
    Establishment
    Name Address ID/FEI Business Operations
    CSL Behring AG 481152762 MANUFACTURE
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