Rho(D) Immune Globulin

Class: Serums
ATC Class: J06BB01
VA Class: IM500
Brands: HyperRHO S/D Full Dose, HyperRHO S/D Mini-Dose, MICRhoGAM, RhoGAM, Rhophylac, WinRho SDF

Warning(s)

  • Risk of Intravascular Hemolysis in Patients with Idiopathic Thrombocytopenic Purpura (ITP)
  • Risk of serious (sometimes fatal) intravascular hemolysis when used in patients with ITP.1 25 36

  • Closely monitor patients in a healthcare setting for ≥8 hours after administration.1 25 Perform dipstick urinalysis at appropriate intervals and monitor for manifestations of hemolysis; however, absence of manifestations within the 8-hour monitoring period does not preclude occurrence of intravascular hemolysis at a later time.1 25

  • If intravascular hemolysis is present or suspected, perform appropriate confirmatory tests.1 25 (See Hemolysis under Cautions.)

Introduction

Specific immune globulin.1 14 15 16 23 25 Rho(D) immune globulin (Rho(D) IG) contains anti-Rho(D) antibody to RBC antigen Rho(D) and is prepared from plasma of Rho(D)-negative donors immunized with Rho(D)-positive RBCs.1 14 15 16 23 25 35

Uses for Rho(D) Immune Globulin

Suppression of Rh Isoimmunization

Used IM or IV to suppress the active antibody response and formation of anti-Rho(D) antibodies (i.e., Rh isoimmunization) in Rho(D)-negative women who have been exposed to Rho(D)-positive blood as the result of pregnancy or other obstetric conditions (e.g., spontaneous or induced abortion, trauma, threatened abortion, ectopic pregnancy, amniocentesis, chorionic villus sampling, pregnancy termination, external cephalic version); prevention of Rh isoimmunization decreases the likelihood of hemolytic disease of the newborn (erythroblastosis fetalis) in a future pregnancy with an Rho(D)-positive fetus.1 14 15 16 25 27

ACOG recommends that Rho(D)-negative women who have not been sensitized to Rho(D) antigen receive Rho(D) IG at approximately 28 weeks of gestation for routine antenatal prophylaxis (unless father of the fetus is Rho(D)-negative), after delivery of an Rho(D)-positive infant, after a first-trimester pregnancy loss, and after invasive obstetric procedures (e.g., amniocentesis, chorionic villus sampling, fetal blood sampling).31 ACOG states use following threatened abortion, second- or third-trimester antenatal bleeding, abdominal trauma, or external cephalic version should be considered based on expert opinion and consensus,31 but evidence generally lacking for these conditions.28

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Also used IM or IV to suppress Rh isoimmunization in Rho(D)-negative individuals following transfusion of Rho(D)-positive blood or blood components containing Rho(D)-positive RBCs (e.g., RBCs, platelets, granulocytes).1 14 16 25 One manufacturer states to consider exchange transfusion prior to administration of Rho(D) IG if the transfused Rho(D)-positive blood represents >20% of the total circulating RBCs.25

Idiopathic Thrombocytopenic Purpura (ITP)

Used IV for the treatment of ITP in Rho(D)-positive, nonsplenectomized patients to increase platelet counts and prevent excessive hemorrhage; WinRho SDF is FDA-labeled for use in adults with chronic ITP, children with acute or chronic ITP, and adults and children with ITP secondary to HIV infection,1 2 3 4 5 6 7 8 9 10 11 12 13 while Rhophylac is labeled for use in adults with chronic ITP.25

In patients in whom a response to Rho(D) IG is obtained, the rise in platelet count is generally rapid (1–3 days) and transient (usually lasting about 1 month).1 25

Safety and efficacy for the treatment of ITP in Rho(D)-negative or splenectomized individuals or for the treatment of thrombocytopenia not related to ITP not established.1 2 3 7

Other therapies (i.e., corticosteroids, immune globulin IV [IGIV]) generally are preferred for treatment of ITP because of the risk of hemolysis associated with Rho(D) IG (see Hemolysis under Cautions); however, Rho(D) IG may be used in carefully selected patients.32 34 36

Initial treatment of choice for ITP secondary to HIV infection is effective viral suppression with highly active antiretroviral therapy; if additional treatment is indicated, some experts suggest corticosteroids, IGIV, or Rho(D) IG may be used.32 37

Rho(D) Immune Globulin Dosage and Administration

Administration

Administer HyperRHO, MICRhoGAM, and RhoGAM by IM injection; do not administer IV.14 15 16 Administer Rhophylac and WinRho SDF by IM or IV injection.1 25

Rho(D) IG may be administered IM or IV for suppression of Rh isoimmunization.1 14 15 16 25 Rho(D) IG must be administered IV for the treatment of ITP.1 25

Monitor patient for ≥20 minutes after administration of Rho(D) IG for suppression of Rh isoimmunization.16 25 Closely monitor patients with ITP for ≥8 hours (see Hemolysis under Cautions).1 25

For suppression of Rh isoimmunization related to an Rh-incompatible pregnancy, administer Rho(D) IG to the mother; do not administer to the infant.1 14 15 16 25

Prior to administration, perform appropriate laboratory tests to assess Rh status of the patient.14 15 Prior to antepartum or postpartum administration for suppression of Rh isoimmunization, determine whether recipient has been sensitized to Rho(D) antigens.27 28

Rhophylac, WinRho SDF: Allow drug to reach room temperature prior to administration.1 25

IM Administration

Preparations of Rho(D) IG that may be administered IM for suppression of Rh isoimmunization include HyperRHO, MICRhoGAM, RhoGAM, Rhophylac, and WinRho SDF.1 14 15 16 25

Administer preferably into the deltoid muscle of the upper arm or lateral thigh muscle.1 14 15 Do not routinely use gluteal region because of the risk of injury to the sciatic nerve; if the gluteal region is used, use only the upper outer quadrant of the gluteal muscle.1 14 15

Rhophylac: When dose is >5 mL (3750 units or 750 mcg), divide and inject into different muscle sites.25

Consult manufacturer's prescribing information for specific procedures and techniques for IM administration.14 15 16 Although some manufacturers recommend that aspiration (i.e., pulling back on the syringe plunger after needle insertion and before injection) be performed to ensure that a blood vessel has not been entered,14 15 the US Public Health Service Advisory Committee on Immunization Practices (ACIP) states this procedure is not required because large blood vessels are not present at recommended IM injection sites.33

IV Administration

For solution compatibility information, see Compatibility under Stability.

Preparations of Rho(D) IG that may be administered IV for suppression of Rh isoimmunization include Rhophylac and WinRho SDF.1 25 For the treatment of ITP, Rhophylac and WinRho SDF must be administered IV.1 25

Commercially available Rho(D) IG can be administered as supplied with no dilution necessary.1 25 If dilution of WinRho SDF is preferred, use 0.9% sodium chloride injection as diluent; do not use 5% dextrose injection or any other diluent.1

Do not mix with other drugs.1

Rate of Administration

Rhophylac: 2 mL per 15–60 seconds.25

WinRho SDF: Administer over 3–5 minutes when used for treatment of ITP, or at a rate of 2 mL per 5–15 seconds for suppression of Rh isoimmunization.1

Dosage

Potency of Rho(D) IG is expressed in terms of international units (IU, units); potency established relative to the US, WHO, and European Pharmacopoeia Anti-D Reference Standard.1 16 25

Dose previously expressed in mcg; 1 mcg equals 5 units.1

A single 1500-unit (300-mcg) dose of Rho(D) IG (i.e., prefilled syringes of HyperRHO S/D Full Dose, RhoGAM, or Rhophylac) contains enough anti-Rho(D) to suppress the immunization potential of 15 mL of Rho(D)-positive RBCs.14 16 25

A single 250-unit (50-mcg) dose of Rho(D) IG (i.e., prefilled syringes of HyperRHO S/D Mini-Dose or MICRhoGAM) contains enough anti-Rho(D) to suppress the immunization potential of 2.5 mL of Rho(D)-positive RBCs.15 16

A single-dose vial of WinRho SDF containing 1500 units (300 mcg) of Rho(D) IG contains enough anti-Rho(D) to suppress the immunization potential of 17 mL of Rho(D)-positive RBCs.1

Pediatric Patients

Idiopathic Thrombocytopenic Purpura (ITP)

Individualize dosage based on clinical response (i.e., platelet count, RBC count, hemoglobin, reticulocyte count).1

Platelet count of 50,000/mm3 generally is considered a satisfactory response; treatment rarely indicated in patients with platelet count >50,000/mm3.1 34

IV

WinRho SDF: Initially, 250 units/kg (50 mcg/kg) as a single injection or in 2 divided doses given on separate days.1 For patients with hemoglobin <10 g/dL, reduce initial dose to 125–200 units/kg (25–40 mcg/kg) to minimize risk of increasing severity of anemia.1 If subsequent therapy needed in patients with adequate response to the initial dose, maintenance dose of 125–300 units/kg (25–60 mcg/kg) is recommended; however, individualize based on platelet count and hemoglobin concentration.1 For patients with an inadequate response to the initial dose, subsequent dose is based on hemoglobin.1 If hemoglobin is >10 g/dL, maintenance dose is 250–300 units/kg (50–60 mcg/kg); if hemoglobin is 8–10 g/dL, maintenance dose is 125–200 units/kg (25–40 mcg/kg).1 (See Hemolysis under Cautions.)

Adults

Suppression of Rh Isoimmunization Related to Rh-incompatible Pregnancy
Routine Antepartum Prophylaxis

For routine prophylaxis in an unsensitized Rho(D)-negative woman, administer recommended dose of Rho(D) IG at approximately 28 weeks of gestation; give a second dose after delivery if neonate is Rho(D)-positive.1 14 16 25 31

If delivery does not occur within 12 weeks after the standard antepartum dose, a second antepartum dose has been recommended to maintain adequate levels of passively acquired anti-Rho(D).16 31

If Rho(D) IG is administered early in pregnancy for any reason, give additional antepartum doses at 12-week intervals to maintain adequate levels of anti-Rho(D) throughout the pregnancy.1 14 16

IM

HyperRHO S/D Full Dose, RhoGAM: 1500 units (300 mcg) at about 26–28 weeks of gestation.14 16

WinRho SDF, Rhophylac: 1500 units (300 mcg) at about 28–30 weeks of gestation.1 25

IV

WinRho SDF, Rhophylac: 1500 units (300 mcg) at about 28–30 weeks of gestation.1 25

Postpartum Prophylaxis

Administer recommended dose to unsensitized Rho(D)-negative woman as soon as possible (within 72 hours) after delivery of an Rho(D)-positive infant.1 14 16 25 31 Administer even if Rho(D) status of infant is not known at 72 hours.1 May be less effective if administered >72 hours after delivery;14 16 31 if >72 hours have elapsed, administer Rho(D) IG as soon as possible, up to 28 days after delivery.1 31

Withhold postpartum dose if an antepartum dose was administered in the preceding 3 weeks, provided a large fetal-maternal hemorrhage has not occurred.14 16 31

The usual postpartum dosage must be increased whenever a large fetal-maternal hemorrhage occurs during delivery.1 14 16 25 (See Excessive Fetal-Maternal Hemorrhage under Dosage and Administration.)

IM

HyperRHO S/D Full Dose, RhoGAM, Rhophylac: 1500 units (300 mcg) after delivery.14 16 25

WinRho SDF: 600 units (120 mcg) after delivery.1

IV

Rhophylac: 1500 units (300 mcg) after delivery.25

WinRho SDF: 600 units (120 mcg) after delivery.1

Termination of Pregnancy

Administer recommended dose to unsensitized Rho(D)-negative woman within 72 hours after termination of pregnancy.1 14 15 16 25

The usual dosage administered following termination of pregnancy must be increased if a large fetal-maternal hemorrhage has occurred.14 16 25 (See Excessive Fetal-Maternal Hemorrhage under Dosage and Administration.)

IM

HyperRHO S/D Mini-Dose, MICRhoGAM: 250 units (50 mcg) as soon as possible after a spontaneous or induced abortion occurring up to and including 12 weeks of gestation.15 16 May use full-dose preparations if minidose preparations not available.14 16

HyperRHO S/D Full Dose, RhoGAM: 1500 units (300 mcg) after a spontaneous or induced abortion occurring beyond 12 weeks of gestation.14 16

Rhophylac: 1500 units (300 mcg) after a spontaneous or induced abortion.25

WinRho SDF: 600 units (120 mcg) after abortion.1

IV

Rhophylac: 1500 units (300 mcg) after a spontaneous or induced abortion.25

WinRho SDF: 600 units (120 mcg) after abortion.1

Other Obstetric Procedures or Complications During Pregnancy

Administer recommended dose to unsensitized Rho(D)-negative woman within 72 hours after the obstetric complication or procedure.1 14 16 25

The usual dosage administered following an obstetric procedure or complication must be increased if a large fetal-maternal hemorrhage has occurred.14 16 25 (See Excessive Fetal-Maternal Hemorrhage under Dosage and Administration.)

If the complication or procedure occurs early in the pregnancy (before 26–28 weeks of gestation), administer additional antepartum doses (e.g., at 12-week intervals) to maintain adequate level of passively acquired anti-Rho(D) throughout the pregnancy.1 14 16 Also administer a full postpartum dose of Rho(D) IG to the mother if the infant is Rho(D)-positive.14 16

If delivery occurs within 3 weeks after an antepartum dose, postpartum dose may be withheld unless a large fetal-maternal hemorrhage has occurred.14 16

IM

HyperRHO S/D Full Dose: 1500 units (300 mcg) after threatened abortion at any stage of gestation, amniocentesis, or abdominal trauma.14

RhoGAM: 1500 units (300 mcg) after threatened abortion beyond 12 weeks of gestation, amniocentesis, percutaneous umbilical blood sampling, chorionic villus sampling, abdominal trauma, or obstetric manipulation.16

MICRhoGAM: 250 units (50 mcg) after threatened abortion occurring at or before 12 weeks of gestation.16 May use full-dose preparation if minidose preparation not available.16

Rhophylac: 1500 units (300 mcg) after obstetric complications (e.g., threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage), invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy), obstetric manipulative procedures (e.g., external version), or abdominal trauma during pregnancy.25

WinRho SDF: 1500 units (300 mcg) immediately after threatened abortion at any stage of gestation; 1500 units (300 mcg) immediately after amniocentesis or chorionic villus sampling in a pregnancy up to 34 weeks of gestation; 600 units (120 mcg) within 72 hours of amniocentesis or other obstetrical manipulation in a pregnancy beyond 34 weeks of gestation.1

IV

Rhophylac: 1500 units (300 mcg) after obstetric complications (e.g., threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage), invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy), obstetric manipulative procedures (e.g., external version), or abdominal trauma during pregnancy.25

WinRho SDF: 1500 units (300 mcg) immediately after threatened abortion at any stage of gestation; 1500 units (300 mcg) immediately after amniocentesis or chorionic villus sampling in a pregnancy up to 34 weeks of gestation; 600 units (120 mcg) within 72 hours of amniocentesis or other obstetrical manipulation in a pregnancy beyond 34 weeks of gestation.1

Excessive Fetal-Maternal Hemorrhage

The usual dosage of Rho(D) IG administered postpartum, after termination of pregnancy, or after other obstetric procedures or complications must be increased if a large fetal-maternal hemorrhage occurs.1 14 16 25

If a large fetal-maternal hemorrhage (>30 mL of whole blood or 15 mL of packed RBCs) is suspected, use an approved laboratory procedure to estimate the number of fetal Rho(D)-positive RBCs in the maternal circulation and to calculate the RBC volume of the hemorrhage.14 16

Administer entire dose within 72 hours of the event.1 14 16 25

IM

HyperRHO S/D Full Dose: If a large fetal-maternal hemorrhage (>15 mL RBCs) occurs, determine the number of prefilled syringes (each syringe contains 1500 units [300 mcg]) needed by dividing the RBC volume of the hemorrhage by 15 mL; if the calculated dose results in a fraction of a prefilled syringe, administer the next whole number of syringes.14 Administer multiple doses at the same time (at different sites) or at spaced intervals, provided the entire dose is administered within 72 hours.14

RhoGAM: Multiple doses required if a large fetal-maternal hemorrhage (>15 mL RBCs) occurs.16 Consider administering more than 100 units (20 mcg) of RhoGAM per 1 mL of Rho(D)-positive RBCs whenever such hemorrhage is suspected or documented.16 Administer multiple doses at the same time (at different sites) or at spaced intervals, provided the entire dose is administered within 72 hours.16

Rhophylac: If a large fetal-maternal hemorrhage (>15 mL RBCs) occurs or is suspected, administer usual 1500-unit (300-mcg) dose plus an additional 100 units (20 mcg) per mL of fetal RBCs in excess of 15 mL if bleeding is quantified or an additional 1500 units (300 mcg) if excess bleeding cannot be quantified.25 Administer large doses (>5 mL [3750 units or 750 mcg]) as divided doses at different sites.25

WinRho SDF: Following massive fetal hemorrhage, administer 60 units (12 mcg) per mL of Rho(D)-positive blood or 120 units (24 mcg) per mL of Rho(D)-positive RBCs.1 Administer 6000 units (1200 mcg) every 12 hours until total dose given.1

IV

Rhophylac: If a large fetal-maternal hemorrhage (>15 mL RBCs) occurs or is suspected, administer usual 1500-unit (300-mcg) dose plus an additional 100 units (20 mcg) per mL of fetal RBCs in excess of 15 mL if bleeding is quantified or an additional 1500 units (300 mcg) if excess bleeding cannot be quantified.25

WinRho SDF: Following massive fetal hemorrhage, administer 45 units (9 mcg) per mL of Rho(D)-positive blood or 90 units (18 mcg) per mL of Rho(D)-positive RBCs.1 Administer 3000 units (600 mcg) every 8 hours until total dose given.1

Suppression of Rh Isoimmunization Following Transfusion of Rh-incompatible Blood or Blood Products

Dosage depends on volume of Rho(D)-positive blood or Rho(D)-positive packed RBCs transfused.1 14 16 25 Calculate the volume of RBCs transfused by multiplying the volume of Rho(D)-positive whole blood administered by the hematocrit of the donor.14

Administer entire dose within 72 hours of exposure.1 14 16 25

IM

HyperRHO S/D Full Dose: Determine the number of prefilled syringes (each syringe contains 1500 units [300 mcg]) needed by dividing the RBC volume transfused by 15 mL; if the calculated dose results in a fraction of a prefilled syringe, administer the next whole number of syringes.14 If multiple syringes are required, the total dose may be given at the same time (at different sites) or at spaced intervals, provided entire dose is administered within 72 hours of exposure.14

MICRhoGAM: 250 units (50 mcg) following exposure to <2.5 mL of Rho(D)-positive RBCs.16

RhoGAM: 1500 units (300 mcg) following exposure to 2.5–15 mL of Rho(D)-positive RBCs.16 Additional dose(s) needed for exposure to >15 mL of Rho(D)-positive RBCs; administer 100 units (20 mcg) per mL of RBCs.16 If the calculated dose results in a fraction of a prefilled syringe, inject the entire contents of the syringe.16 May administer multiple doses at the same time (at different sites) or at spaced intervals, provided entire dose is administered within 72 hours of exposure.16

Rhophylac: 100 units (20 mcg) per 2 mL of Rho(D)-positive blood or per 1 mL of Rho(D)-positive erythrocyte concentrate.25 Administer large doses (>5 mL [3750 units or 750 mcg]) as divided doses at different sites.25

WinRho SDF: 60 units (12 mcg) per mL of Rho(D)-positive blood or 120 units (24 mcg) per mL of Rho(D)-positive RBCs.1 Administer 6000 units (1200 mcg) every 12 hours until total dose given.1

IV

Rhophylac: 100 units (20 mcg) per 2 mL of Rho(D)-positive blood or per 1 mL of Rho(D)-positive erythrocyte concentrate.25

WinRho SDF: 45 units (9 mcg) per mL of Rho(D)-positive blood or 90 units (18 mcg) per mL of Rho(D)-positive RBCs.1 Administer 3000 units (600 mcg) every 8 hours until total dose given.1

Idiopathic Thrombocytopenic Purpura (ITP)

Individualize dosage based on clinical response (i.e., platelet count, RBC count, hemoglobin, reticulocyte count).1

Platelet count of 50,000/mm3 generally is considered a satisfactory response; treatment rarely indicated in patients with platelet count >50,000/mm3.1 34

IV

Rhophylac: 250 units/kg (50 mcg/kg).25 For information on use in patients with anemia, see Hemolysis under Cautions.

WinRho SDF: Initially, 250 units/kg (50 mcg/kg) as a single injection or in 2 divided doses given on separate days.1 For patients with hemoglobin <10 g/dL, reduce initial dose to 125–200 units/kg (25–40 mcg/kg) to minimize risk of increasing severity of anemia.1 If subsequent therapy needed in patients with adequate response to the initial dose, maintenance dose of 125–300 units/kg (25–60 mcg/kg) is recommended; however, individualize based on platelet count and hemoglobin concentration.1 For patients with an inadequate response to the initial dose, subsequent dose is based on hemoglobin.1 If hemoglobin >10 g/dL, maintenance dose is 250–300 units/kg (50–60 mcg/kg); if hemoglobin is 8–10 g/dL, maintenance dose is 125–200 units/kg (25–40 mcg/kg).1 (See Hemolysis under Cautions.)

Special Populations

Hepatic Impairment

No specific dosage recommendations.1 14 15 16 25

Renal Impairment

WinRho SDF: Administer at minimum rate of infusion.1

Geriatric Patients

WinRho SDF: Select dosage with caution (generally starting at the low end of the dosing range) because of age-related decreases in hepatic, renal, and/or cardiac function, and concomitant disease and drug therapy.1

Cautions for Rho(D) Immune Globulin

Contraindications

  • Known anaphylactic or severe systemic reactions to immune globulins.1 25

  • When used for the suppression of Rh isoimmunization, do not administer to the infant1 25 or to Rho(D)-positive individuals.14 15 16 27

  • IgA-deficient patients with antibodies to IgA and history of hypersensitivity.1 25 (See Selective IgA Deficiency under Cautions.)

  • WinRho SDF: Autoimmune hemolytic anemia, preexisting hemolysis, or high risk for hemolysis.1

Warnings/Precautions

Warnings

Hemolysis

Intravascular hemolysis, including some fatalities, reported in patients receiving Rho(D) IG for ITP.1 25 26 36 (See Boxed Warning.) Serious complications (e.g., severe anemia, acute renal insufficiency or failure, multiorgan failure including ARDS, disseminated intravascular coagulation [DIC]) may occur.1 25 26 36

Closely monitor patients with ITP in a healthcare setting for ≥8 hours after administration.1 25 Perform dipstick urinalysis at baseline and after administration at 2 hours, 4 hours, and just prior to the end of monitoring period.1 25 Monitor for signs and symptoms of intravascular hemolysis (e.g., back pain, shaking chills, fever, discolored urine, hemoglobinuria, hematuria).1 25

If necessary, perform appropriate confirmatory tests (e.g., CBCs, plasma hemoglobin, haptoglobin, urine dipstick, renal function tests [e.g., BUN, Scr], LDH, direct and indirect bilirubin, specific tests for DIC [e.g., D-dimer, fibrin degradation products, fibrin split products]).1 25

If transfusion needed, use Rho(D)-negative packed RBCs to avoid exacerbation of the ongoing hemolysis.1 25

Administration of Rho(D) IG to Rho(D)-positive individuals for the treatment of ITP expected to result in extravascular destruction of Rho(D)-positive RBCs (via reticuloendothelial system) and a decrease in hemoglobin concentration.1 2 3 4 5 6 7 8 10 13 25 36

WinRho SDF: When used for the treatment of ITP, reduce dose in individuals with hemoglobulin <10 g/dL.1 Use alternative treatments in individuals with hemoglobulin <8 g/dL.1 (See Idiopathic Thrombocytopenic Purpura [ITP] under Dosage and Administration.) Prior to administration, assess patient's risk of hemolysis with appropriate laboratory tests (e.g., blood type, blood cell count, reticulocyte count, direct antiglobulin test [DAT], dipstick urinalysis); if there is evidence or risk of hemolysis, alternative treatments to Rho(D) IG advised.1 (See Contraindications under Cautions.)

Rhophylac: Safety in the treatment of ITP not established in patients with preexisting anemia.25 Weigh potential benefits against the risk of increasing the severity of anemia.25

Patients receiving Rho(D) IG for suppression of Rh isoimmunization following an Rh-incompatible transfusion may exhibit signs or symptoms of hemolysis;14 16 monitor for clinical or laboratory evidence of hemolysis.16

Sensitivity Reactions

Hypersensitivity

Systemic allergic reactions reported rarely.14 15 16 25 If signs of hypersensitivity including generalized urticaria, tightness of the chest, wheezing, hypotension, or anaphylaxis occur, discontinue immediately25 and institute appropriate therapy (e.g., epinephrine) as indicated.14 15 25

Selective IgA Deficiency

Rho(D) IG preparations may contain trace or small quantities of IgA.1 16 25

Use with caution in individuals with selective IgA deficiency; these individuals may have antibodies to IgA or may develop such antibodies following administration of Rho(D) IG.14 15 Potential for severe hypersensitivity reactions (e.g., anaphylaxis) to IgA in such patients.1 14 15 25 (See Contraindications under Cautions.)

Other Warnings/Precautions

Renal Effects

Renal dysfunction and/or acute renal failure reported in patients receiving IV immune globulins.1

Assess renal function (including BUN and Scr) before initiating Rho(D) IG; ensure patient is not volume depleted.1

Manufacturer of WinRho SDF states to use slowest possible infusion rate in patients at risk for renal dysfunction/failure (e.g., those with diabetes mellitus, age >65 years, volume depletion, sepsis, paraproteinemia, concomitant use of known nephrotoxic drugs) or with any renal impairment.1 Monitor renal function and urine output periodically in these patients.1

Risk of Transmissible Agents in Plasma-derived Preparations

Because Rho(D) IG is prepared from pooled human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV infection, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD).1 14 15 16 25

Improved donor screening, viral-inactivation procedures (e.g., solvent/detergent treatment), and filtration procedures have reduced, but not completely eliminated, risk of pathogen transmission with plasma-derived preparations.1 14 15 16 25

The manufacturing process for Rho(D) IG includes a solvent/detergent inactivation process and a filtering procedure to remove both enveloped and nonenveloped viruses.1 14 15 16 25

Despite these measures, there is still a possibility of disease transmission from plasma-derived preparations of Rho(D) IG.14 15 16 Report any infection believed to have been transmitted by Rho(D) IG to the manufacturer.1 14 15 16 25

Blood Glucose Testing

Rho(D) IG preparations that contain maltose (WinRho SDF) may cause falsely elevated results in blood glucose determinations that use nonspecific methods based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye oxidoreductase.1 (See Specific Drugs and Laboratory Tests under Interactions.)

Thromboembolic Events

Thromboembolic events, sometimes fatal, reported in patients receiving Rho(D) IG.1

Patients at risk include those with history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity.1 Manufacturer of WinRho SDF states to use slowest possible infusion rate in such patients.1

Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity (e.g., those with cryoglobulins, fasting chylomicronemia or markedly high triglycerides, or monoclonal gammopathies).1

Transfusion-related Acute Lung Injury

Transfusion-related acute lung injury (TRALI; noncardiogenic pulmonary edema) reported in patients receiving IV immune globulins, including Rho(D) IG (WinRho SDF).1 Typically occurs within 1–6 hours following administration of blood product and is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever.1

Monitor for adverse pulmonary effects.1 If TRALI is suspected, perform appropriate tests to determine whether anti-neutrophil and anti-HLA antibodies are present in product or patient serum.1

Manage using oxygen therapy and adequate ventilatory support.1

Improper Storage and Handling

Improper storage or handling of immune globulins may affect efficacy.33

Do not administer Rho(D) IG that has been mishandled or has not been stored at the recommended temperature.33 (See Storage under Stability.)

Inspect all immune globulins upon delivery and monitor during storage to ensure that the appropriate temperature is maintained.33 If there are concerns about mishandling, contact the manufacturer or state or local health departments for guidance on whether Rho(D) IG is usable.33

Specific Populations

Pregnancy

Category C.1 14 15 16 25

Rho(D) IG not evaluated systematically in pregnant women with ITP;1 25 32 34 corticosteroids or IGIV generally recommended.32 34

Lactation

Used in nursing women for suppression of Rh isoimmunization; no adverse effects expected during breastfeeding.25

Rho(D) IG not evaluated in nursing women with ITP.1 25

Not known whether distributed into human milk; use caution.1

Pediatric Use

HyperRHO S/D Full Dose, HyperRHO S/D Mini-Dose: Safety and efficacy not established in pediatric patients.14 15

Rhophylac: Safety and efficacy not established for suppression of Rh isoimmunization in pediatric patients given an incompatible transfusion.25 Weigh the potential risks against the benefits, particularly in girls whose later pregnancies may be affected if Rh isoimmunization occurs.25

WinRho SDF: Used in children for the treatment of acute or chronic ITP or ITP secondary to HIV infection.1

Geriatric Use

Rhophylac: When used for the treatment of ITP, no substantial differences in safety and efficacy relative to younger adults.25 Has not been evaluated for the suppression of Rh isoimmunization following incompatible transfusions in geriatric patients ≥65 years of age.25

WinRho SDF: Insufficient experience in patients ≥65 years of age to determine whether they respond differently than younger adults.1 During postmarketing experience, increased risk of serious complications from intravascular hemolysis observed in geriatric patients >65 years of age with comorbid conditions (e.g., cardiorespiratory compromise, renal insufficiency or failure, prothrombotic conditions).1

Common Adverse Effects

Chills,1 25 fever or increased body temperature,1 14 15 16 25 headache,1 25 nausea,25 dizziness,1 25 mild hemolysis (increased bilirubin, decreased hemoglobin),25 injection-site reactions (e.g., swelling, induration, erythema, mild pain or warmth),14 15 16 25 rash,1 16 body aches,16 malaise.25

Interactions for Rho(D) Immune Globulin

Live Vaccines

Antibodies present in immune globulin preparations may interfere with the immune response to measles, mumps, and rubella virus vaccine live (MMR), varicella virus vaccine live, and fixed combination of MMR and varicella vaccine (MMRV);1 14 15 16 25 33 no evidence of interference with the immune response to influenza virus vaccine live intranasal, rotavirus vaccine live oral, yellow fever virus vaccine live, typhoid vaccine live oral, or zoster vaccine live.33 (See Specific Drugs and Laboratory Tests under Interactions.)

Postpartum administration of Rho(D) IG has not been shown to reduce the response to rubella vaccine RA27/3 strain.33 Rubella and varicella immunity are important in women of childbearing potential.33 The ACIP recommends administering the appropriate vaccine immediately after delivery in women susceptible to rubella and/or varicella; do not delay administration because the woman received antepartum or postpartum Rho(D) IG.33 If possible, perform serologic tests ≥3 months after vaccination to ensure immunity to rubella and, if necessary, to measles.16 33

Inactivated Vaccines and Toxoids

Immune globulin preparations not expected to have a clinically important effect on immune responses to inactivated vaccines or toxoids; inactivated vaccines, recombinant vaccines, polysaccharide vaccines, and toxoids may be administered simultaneously with (using different syringes and different injection sites) or at any interval before or after Rho(D) IG.33

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Influenza vaccine

Intranasal live influenza vaccine: No evidence that immune globulin preparations interfere with immune response to the vaccine33

Parenteral inactivated influenza vaccine: Immune globulin preparations not expected to have clinically important effect on immune responses to inactivated vaccines33

Intranasal live influenza vaccine: May be given simultaneously with or at any interval before or after immune globulin preparations33

Parenteral inactivated influenza vaccine: May be given simultaneously with (at a different site) or at any interval before or after immune globulin preparations33

Measles, mumps, rubella, varicella vaccine

Antibodies in Rho(D) IG may interfere with immune response to these live virus vaccines1 14 15 16 25 33

Rubella: No evidence that low postpartum dose of Rho(D) IG interferes with immune response to the vaccine33

Manufacturers generally recommend deferring administration of these live virus vaccines for ≥3 months following administration of Rho(D) IG;1 14 15 16 however, ACIP recommends administering the appropriate vaccine immediately after delivery (despite receipt of Rho[D] IG) in women susceptible to rubella and/or varicella33

Rotavirus vaccine

Oral live rotavirus vaccine: No evidence that immune globulin preparations interfere with immune response to the vaccine33

May be given simultaneously with or at any interval before or after immune globulin preparations33

Tests, antibody screening

Possible positive antibody screening test from the presence of passively acquired anti-D in the maternal blood stream16 25

Tests, blood glucose (based on GDH-PQQ or glucose-dye oxidoreductase)

Maltose-containing Rho(D) IG preparations (e.g., WinRho SDF): Potential for falsely elevated blood glucose test results1

Use test methods not affected by maltose in patients receiving maltose-containing Rho(D) IG preparations 1

Tests, blood typing

May affect blood typing test results in the mother and the infant16 25

Tests, immunohematology (Coombs’ test)

Passively transferred blood group antibodies (e.g., anti-A, anti-B, anti-C, anti-E) may result in positive direct and indirect antiglobulin (Coombs’) test results1

Interpret test results in the context of the patient’s underlying clinical condition and other laboratory results1

Typhoid vaccine

Oral live typhoid vaccine: No evidence that immune globulin preparations interfere with immune response to the vaccine33

Vaccine may be given simultaneously with or at any interval before or after immune globulin preparations33

Yellow fever virus vaccine

No evidence that immune globulin preparations interfere with immune response to the vaccine33

Vaccine may be given simultaneously with (at a different site) or at any interval before or after immune globulin preparations33

Zoster vaccine

No evidence that immune globulin preparations interfere with immune response to the vaccine33

Vaccine may be given simultaneously with (at a different site) or at any interval before or after immune globulin preparations33

Rho(D) Immune Globulin Pharmacokinetics

Absorption

Bioavailability

Following IM administration of Rho(D) IG, peak serum concentrations are achieved in 2–7 days.1 16 25

Following IV administration of Rho(D) IG, peak serum concentrations are achieved in 30 minutes.1

Rhophylac: Bioavailability of Rho(D) IG administered IM is approximately 69% of Rho(D) IG administered IV.25

Distribution

Extent

Not known whether distributed into milk.1

Elimination

Half-life

IM administration: 18–31 days.1 16 25

IV administration: Approximately 16–24 days.1 25

Stability

Storage

Parenteral

Injection

2–8°C.1 14 15 16 25 Do not freeze.1 14 15 16 25

Store Rhophylac in the original carton to protect product from light.25

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility (WinRhoSDF)1

Compatible

Sodium chloride 0.9%

Incompatible

Dextrose 5% in water

Actions

  • Contains anti-Rho(D) antibody to the RBC antigen Rho(D); used to provide temporary passive immunity in Rho(D)-negative individuals exposed to Rho(D)-positive blood from a pregnancy (when fetus is Rho[D]-positive) or from an Rho(D)-positive blood transfusion.1 14 15 16

  • Mechanism by which Rho(D) IG suppresses anti-Rho(D) not fully elucidated;1 14 15 16 25 anti-Rho(D) antibody may bind to Rho(D) antigen thus preventing the primary immune response to Rho(D) and production of anti-Rho(D).a

  • Mechanism by which Rho(D) IG increases platelet counts in the treatment of ITP not fully elucidated;1 2 3 7 20 21 administration of Rho(D) IG to Rho(D)-positive individuals results in formation of anti-Rho(D)-coated RBC complexes that may saturate Fc receptors and decrease Fc-mediated phagocytosis of antibody-coated platelets.1 2 3 4 7 20 21 25

Advice to Patients

  • Instruct patients being treated for ITP to read the patient information leaflet prior to each treatment.1

  • When using RhoGAM, importance of retaining the patient identification card and of presenting this card to healthcare providers.16

  • Instruct patients receiving Rho(D) IG for the treatment of ITP to immediately report signs or symptoms of hemolysis (e.g., back pain, shaking chills, fever, discolored urine, decreased urine output, swelling, shortness of breath) to their clinician.1 25

  • Importance of patients understanding potential risks (e.g., hypersensitivity reactions, possible transmission of infectious agents) and benefits of therapy.1 14 15 16 25

  • Importance of reporting viral infections (e.g., hepatitis, HIV) to clinician.1 25

  • Instruct pregnant women receiving an antepartum dose of Rho(D) IG of the need for a second dose at delivery if the infant is Rho(D)-positive.14 15 25

  • Importance of notifying clinician if signs and symptoms of a hypersensitivity reaction (i.e., generalized urticaria, tightness of the chest, wheezing, hypotension, anaphylaxis) occur.1 16 25

  • Advise patients with selective IgA deficiency that Rho(D) IG contains trace amounts of IgA and potentially could result in life-threatening allergic reactions if used in patients who have developed antibodies to IgA.1 16 25

  • Advise patients receiving WinRho SDF that this preparation contains maltose and may cause falsely elevated glucose readings when blood glucose monitoring systems based on GDH-PQQ or glucose-dye oxidoreductase are used; importance of using glucose-specific test methods not affected by maltose.1

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 14 15 16 25

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including recent vaccinations (e.g., mumps, measles, rubella, varicella) and prescription and OTC drugs, as well as any concomitant illnesses.1 14 15 16 25

  • Importance of informing patients of other important precautionary information.1 14 15 16 25 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Rho(D) Immune Globulin

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection, for IM use only

250 units (50 mcg)

HyperRHO S/D Mini-Dose (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes)

Grifols

MICRhoGAM Ultra-Filtered PLUS (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes)

Ortho-Clinical Diagnostics

1500 units (300 mcg)

HyperRHO S/D Full Dose (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes)

Grifols

RhoGAM Ultra-Filtered PLUS (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes)

Ortho-Clinical Diagnostics

Injection, for IV or IM use

600 units (120 mcg)

WinRho SDF (solvent/detergent-inactivated and virus filtered)

Cangene bioPharma

1500 units (300 mcg)

Rhophylac (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes)

CSL Behring

WinRho SDF (solvent/detergent-inactivated and virus filtered)

Cangene bioPharma

2500 units (500 mcg)

WinRho SDF (solvent/detergent-inactivated and virus filtered)

Cangene bioPharma

5000 units (1000 mcg)

WinRho SDF (solvent/detergent-inactivated and virus filtered)

Cangene bioPharma

15,000 units (3000 mcg)

WinRho SDF (solvent/detergent-inactivated and virus filtered)

Cangene bioPharma

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions April 30, 2014. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Cangene bioPharma. WinRho SDF (Rho [D] immune globulin intravenous [human]) prescribing information. Baltimore, MD; 2010 Dec.

2. Bussel JB, Graziano JN, Kimberly RP et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: analysis of efficacy, toxicity, and mechanism of effect. Blood. 1991; 77:1884-93. [IDIS 281609] [PubMed 1850307]

3. Becker T, Küenzlen E, Salama A et al. Treatment of childhood idiopathic thrombocytopenic purpura with Rhesus antibodies (anti-D). Eur J Pediatr. 1986; 145:166- 9. [PubMed 3021462]

4. Andrew M, VS, Adams M et al. A multicenter study of the treatment of childhood chronic idiopathic thrombocytopenic purpura with anti-D. J Pediatr. 1992; 120:522-7. [IDIS 294740] [PubMed 1313096]

5. Blanchette V, Imbach P, Andrew M et al. Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura. Lancet. 1994; 344:703-7. [IDIS 335198] [PubMed 7915773]

6. Berchtold P, McMillan R. Therapy of chronic idiopathic thrombocytopenic purpura in adults. Blood. 1989; 74:2309-17. [IDIS 307936] [PubMed 2478227]

7. Scaradavou A, Woo B, Woloski BMR et al. Intravenous anti-D treatment of immune thrombocytopenic purpura: experience in 272 patients. Blood. 1997; 89:2689-700. [IDIS 384927] [PubMed 9108386]

8. Rodeghiero F, Schiavotto C, Castaman G et al. A follow-up study of 49 adult patients with idiopathic thrombocytopenic purpura treated with high-dose immunoglobulins and anti-D immunoglobulins. Haematologica. 1992; 77:248-52. [PubMed 1330848]

9. Stasi R, Stipa E, Masi M et al. Long-term observation of 208 adults with chronic idiopathic thrombocytopenic purpura. Am J Med. 1995; 98:436-42. [IDIS 348266] [PubMed 7733121]

10. Landonio G, Galli M, Nosari A et al. HIV-related severe thrombocytopenia in intravenous drug-users: prevalence, response to therapy in a medium-term follow-up, and pathogenetic evaluation. AIDS. 1990; 4:29-34. [PubMed 2156528]

11. Hoffman DM, Caruso RF, Mirando T. Human immunodeficiency virus-associated thrombocytopenia. DICP Ann Pharmacother. 1989; 157-60.

12. Food and Drug Administration. FDA Application: Search Orphan Drug Designations and Approvals. Silver Spring, MD. From FDA website (http://www.accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Accessed 2013 Jul 2.

13. Oksenhendler E, Bierling P, Brossard Y et al. Anti-RH immunoglobulin therapy for human immunodeficiency virus-related immune thrombocytopenic purpura. Blood. 1988; 71:1499-502. [IDIS 241901] [PubMed 2833961]

14. Grifols Therapeutics Inc. HyperRHO S/D Full Dose (Rho [D] immune globulin [human]) prescribing information. Research Triangle Park, NC; 2012 Sep.

15. Grifols Therapeutics Inc. HyperRHO S/D Mini-Dose (Rho [D] immune globulin [human]) prescribing information. Research Triangle Park, NC; 2012 Sep.

16. Ortho-Clinical Diagnostics. Rho-GAM (Rho [D] immune globulin [human]) ultra-filtered PLUS and MICRhoGAM (Rho [D] immune globulin [human]) ultra-filtered PLUS prescribing information. Raritan, NJ; 2012 Nov.

17. Department of Health and Human Services, Food and Drug Administration, Center for Biologics Evaluation and Research (CBER). Guidance for industry. Revised preventive measures to reduce the possible risk of transmission of Creutzfeldt-Jacob disease (CJD) and variant Creutzfeldt-Jacob disease (vCJD) by blood and blood products. January 2002. From FDA website.

18. George JN, Woolf SH, Raskob GE et al. Idiopathic thrombocytopenic purpura: a practice guideline developed by explicit methods for the American Society of Hematology. Blood. 1996; 88:3-40. [IDIS 369636] [PubMed 8704187]

19. The American Society of Hematology ITP Practice Guideline Panel. Diagnosis and treatment of idiopathic thrombocytopenic purpura: recommendations of the American Society of Hematology. Ann Intern Med. 1997; 126:319-26. [IDIS 380159] [PubMed 9036806]

20. Ballow M. Mechanisms of action of intravenous immunoglobulin therapy and potential use in autoimmune connective tissue diseases. Cancer. 1991; 68:1430-6. [IDIS 287086] [PubMed 1878841]

21. Kniker WT. Immunosuppressive agents, γ-globulin, immunomodulation, immunization, and aphresis. J Allergy Clin Immunol. 1989; 84:1104-7. [IDIS 309517] [PubMed 2480974]

23. The United States pharmacopeia, 23rd rev, and The national formulary, 18th ed. Rockville, MD: The United States Pharmacopeial Convention, Inc; 1995:350.

25. CSL Behring. Rhophylac (Rho [D] immune globulin intravenous [human]) prescribing information. Kankakee, IL; 2012 Oct.

26. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rho (D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005; 106:1532-7. [IDIS 542192] [PubMed 15878975]

27. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Management of alloimmunization during pregnancy. Practice Bulletin No. 75. Washington, DC: American College of Obstetricians and Gynecologists; 2006 Aug.

28. US Preventive Services Task Force. Screening for Rh(D) incompatibility: recommendation statement. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2004 Nov.

29. Crowther CA, Middleton P, McBain RD. Anti-D administration in pregnancy for preventing Rhesus alloimmunisation. Cochrane Database Syst Rev. 2013; 2:CD000020. [PubMed 23450526]

30. Okwundu CI, Afolabi BB. Intramuscular versus intravenous anti-D for preventing Rhesus alloimmunization during pregnancy. Cochrane Database Syst Rev. 2013; 1:CD007885. [PubMed 23440818]

31. American College of Obstetricians and Gynecologists (ACOG) Committee on Practice Bulletins. Prevention of RhD alloimmunization. Practice Bulletin No. 4. Washington, DC: American College of Obstetricians and Gynecologists; 1999 May (reaffirmed in 2010).

32. Neunert C, Lim W, Crowther M et al. The American Society of Hematology 2011 evidence-based practice guideline for immune thrombocytopenia. Blood. 2011; 117:4190-207. [PubMed 21325604]

33. National Center for Immunization and Respiratory Diseases. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2011; 60:1-64.

34. Provan D, Stasi R, Newland AC et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010; 115:168-86. [PubMed 19846889]

35. Kumar S. Universal RDH genotyping in fetuses. BMJ. 2008; 336:783. [PubMed 18390495]

36. Despotovic JM, Lambert MP, Herman JH et al. RhIG for the treatment of immune thrombocytopenia: consensus and controversy (CME). Transfusion. 2012; 52:1126-36; quiz 1125. [PubMed 21981825]

37. Ambler KL, Vickars LM, Leger CS et al. Clinical Features, Treatment, and Outcome of HIV-Associated Immune Thrombocytopenia in the HAART Era. Adv Hematol. 2012; 2012:910954. [PubMed 22693513]

a. AHFS Drug Information 2007. McEvoy GK, ed. Rho [D] Immune Globulin. Bethesda, MD: American Society of Health-System Pharmacists; 2007:3313-19.

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