VA Class:IM500
ATC Class:J06BB01
Rho(D) immune globulin contains anti-Rho(D) antibody to the red blood cell antigen Rho(D) and is prepared from plasma of Rho(D)-negative donors immunized with Rho(D)-positive red blood cells.1, 14, 15, 16, 23, 25, 35
Rho(D) immune globulin is used 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 fetal red blood cells (RBCs) as the result of pregnancy or other obstetric conditions; prevention of Rh isoimmunization decreases the likelihood of hemolytic disease of the newborn (erythroblastosis fetalis) occurring if the woman has a subsequent pregnancy with an Rho(D)-positive fetus.1, 14, 15, 16, 25, 27 Rho(D) immune globulin also is used to suppress isoimmunization in Rho(D)-negative individuals transfused with Rho(D)-positive blood or blood components (e.g., RBCs, platelets, granulocytes).1, 14, 16, 25 In addition, certain preparations of Rho(D) immune globulin (Rhophylac®, WinRho® SDF) are used to increase platelet counts to prevent excessive hemorrhage in nonsplenectomized, Rho(D)-positive individuals with acute or chronic idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) or ITP secondary to human immunodeficiency virus (HIV) infection.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 25 Rho(D) immune globulin is not indicated as replacement therapy in individuals with immunoglobulin deficiency syndromes.1
Several preparations of Rho(D) immune globulin are commercially available; some preparations may be administered IM or IV (Rhophylac®, WinRho® SDF), while others are labeled for IM use only (MICRhoGAM®, RhoGAM®, HyperRHO® S/D Full Dose, HyperRHO® S/D Mini-Dose).1, 14, 15, 16, 25, 30 When used for the treatment of ITP, Rho(D) immune globulin must be administered IV.1, 25 When used for suppression of Rh isoimmunization, Rho(D) immune globulin may be administered either IV or IM.1, 14, 15, 16, 25
Suppression of Rh Isoimmunization
Rh isoimmunization can occur when an Rho(D)-negative pregnant woman is exposed to Rho(D)-positive fetal RBCs during delivery or as a result of other fetal-maternal hemorrhage (e.g., spontaneous or induced abortion, trauma, threatened abortion, ectopic pregnancy, certain invasive obstetric procedures [e.g., amniocentesis, chorionic villus sampling, pregnancy termination, external cephalic version]).14, 15, 27, 29, 30, 31 During these exposures, Rho(D)-positive fetal RBCs can enter the maternal circulation and stimulate the formation of anti-Rho(D) antibodies; while the current pregnancy usually is unharmed, transplacental passage of these maternal anti-Rho(D) antibodies may result in hemolytic disease of the fetus and newborn if the woman has a subsequent pregnancy with an Rho(D)-positive fetus.14, 27, 29, 30, 31 Rh isoimmunization also can be caused by an Rh-incompatible transfusion when an Rho(D)-negative individual receives Rho(D)-positive RBCs or other blood components containing Rho(D)-positive RBCs.1, 14, 16, 25 In these situations (Rh-incompatible pregnancy or Rh-incompatible transfusion), Rho(D) immune globulin is used to provide passively acquired anti-Rho(D) antibodies and suppress Rh isoimmunization.1, 14, 15, 16, 25, 31 Rho(D) immune globulin is used as a prophylactic measure against Rh isoimmunization and is not effective in altering the course or clinical consequences once Rh isoimmunization has occurred.16
Rho(D) immune globulin is used IM or IV to suppress the active antibody response to Rho(D) and formation of anti-Rho(D) antibodies in unsensitized, Rho(D)-negative women with an Rh-incompatible pregnancy.1, 14, 16, 25, 27, 29, 31 Rh incompatibility is assumed if the fetus/neonate is either Rho(D)-positive or Rho(D)-unknown or if the father is either Rho(D)-positive or Rho(D)-unknown.1, 25 The American College of Obstetricians and Gynecologists (ACOG) and other experts recommend routine antenatal prophylaxis with Rho(D) immune globulin at approximately 28 weeks of gestation in all Rho(D)-negative women who have not been previously sensitized to the Rho(D) antigen, unless the father of the fetus is known to be Rho(D)-negative; the recommended timing of this dose is typically at 28 weeks of gestation, but may range from 26 to 30 weeks of gestation.1, 14, 16, 25, 28, 31 Another dose of Rho(D) immune globulin should be administered within 72 hours after delivery if the neonate is Rho(D)-positive.1, 14, 16, 25, 28, 31 If the Rho(D) type of an infant born to an Rho(D)-negative mother cannot be determined within this time period, the infant should be assumed to be Rho(D)-positive and a postpartum dose of Rho(D) immune globulin should be administered to the mother at 72 hours after delivery.1, 14, 16 If Rho(D) immune globulin is administered at any time during pregnancy because of suspected fetal-maternal hemorrhage (e.g., threatened abortion, amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, abdominal trauma), a postpartum dose must still be administered to the mother following delivery of an Rho(D)-positive infant.1, 14, 16 In addition, if Rho(D) immune globulin is administered early in the pregnancy (before 26-28 weeks of gestation), additional antepartum doses should be administered (e.g., at 12-week intervals) to maintain an adequate level of passively acquired anti-Rho(D) antibody throughout the pregnancy.1, 14, 16
Clinical studies have shown that administration of Rho(D) immune globulin to the mother within 72 hours after delivery of a full-term infant reduces the incidence of development of active antibody response and formation of anti-Rho(D) from 12-13% to 1-2%.1, 14 The 1-2% failure rate probably is due to Rh isoimmunization occurring during the latter part of pregnancy or following delivery.1, 14 The incidence of Rh isoimmunization can be further reduced to about 0.1-0.2% by administering a 2-dose regimen of Rho(D) immune globulin that involves administering an antepartum dose at 28 weeks of gestation in addition to the postpartum dose.1, 14, 16, 29
In a study evaluating use of Rho(D) immune globulin for suppression of Rh isoimmunization in unsensitized, Rho(D)-negative pregnant women in cases when the blood type of the father of the fetus was Rho(D)-positive or unknown, Rho(D) immune globulin doses of 600 units (120 mcg) or 1200 units (240 mcg) were given to the mother at 28 weeks of gestation or, alternatively, doses of 1200 units (240 mcg) were given at both 28 and 34 weeks of gestation.1 A postpartum dose of 600 units (120 mcg) was administered to any of these women who delivered an Rho(D)-positive infant.1 There was no evidence of Rh isoimmunization in women who received both the antepartum and postpartum doses of Rho(D) immune globulin and who were evaluated for Rh isoimmunization 6 months after delivery.1
Rho(D) immune globulin is used to protect against Rh isoimmunization in unsensitized, Rho(D)-negative women following certain obstetric complications (e.g., transplacental hemorrhage, spontaneous or induced abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, placenta previa, abdominal trauma) or invasive procedures (e.g., amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, external cephalic version) associated with a risk of fetal-maternal hemorrhage.1, 14, 15, 16, 25 Rho(D) immune globulin should be administered within 72 hours (but preferably sooner) after the obstetric complication or procedure or any other event causing excessive (greater than 15 mL) fetal-maternal hemorrhage.1, 14, 15, 16, 25
Current ACOG guidelines recommend the administration of Rho(D) immune globulin in unsensitized, Rho(D)-negative women after a first-trimester pregnancy loss or after invasive procedures such as chorionic villus sampling, amniocentesis, or fetal blood sampling.31 While the benefit of routine prophylaxis with Rho(D) immune globulin after other obstetric complications or invasive procedures may be uncertain because of the lack of well-designed clinical trials,28 ACOG guidelines state that prophylactic use of Rho(D) immune globulin should be considered, based on expert opinion and consensus, in unsensitized, Rho(D)-negative women after threatened abortion, second- or third-trimester antenatal bleeding, external cephalic version, or abdominal trauma.31
Because of a smaller fetal RBC mass in the first trimester of pregnancy, a lower dose of Rho(D) immune globulin is required to protect against Rh sensitization from first-trimester events.31 A minidose preparation of Rho(D) immune globulin (HyperRHO® S/D Mini-Dose, MICRhoGAM®) may be used following spontaneous or induced abortions occurring up to the 12th week of gestation; however, the full-dose (standard-dose) preparation of these Rho(D) immune globulin products (HyperRHO® S/D Full Dose, RhoGAM®) is indicated if the pregnancy is terminated at 13 or more weeks of gestation.14, 15, 16 (See Dosage and Administration: Dosage.) Clinical studies have shown that a minidose of Rho(D) immune globulin administered within 3 hours after first-trimester pregnancy termination is 100% effective in preventing Rh isoimmunization.16 Administration of Rho(D) immune globulin more than 3 hours after termination of pregnancy may still be effective since a minidose of Rho(D) immune globulin was effective in suppressing formation of anti-Rho(D) in male volunteers when administered up to 72 hours after infusion of Rho(D)-positive blood.15
Transfusion of Blood or Blood Products
Rho(D) immune globulin (HyperRHO® S/D Full Dose, MICRhoGAM®, RhoGAM®, Rhophylac®, WinRho® SDF) is used to prevent the active antibody response and formation of anti-Rho(D) antibodies in Rho(D)-negative individuals following transfusion of Rho(D)-positive blood or blood components such as RBCs, platelets, or granulocytes prepared from Rho(D)-positive blood.1, 14, 16, 25 Rho(D) immune globulin should be administered within 72 hours after such an incompatible blood transfusion.1, 14, 16, 25 If the transfused Rho(D)-positive blood represents more than 20% of the total circulating RBCs, one manufacturer states that an exchange transfusion should be considered prior to administration of Rho(D) immune globulin.25 It has been estimated that the risk of an Rho(D)-negative individual producing anti-Rho(D) antibodies after receiving 1 unit of Rho(D)-positive packed RBCs is about 80%; administration of at least 20 mcg of Rho(D) immune globulin per mL of Rho(D)-positive RBCs within 72 hours of transfusion of incompatible RBCs can protect against Rho(D) immunization.16 In one clinical study in Rho(D)-negative individuals, Rho(D)-positive RBCs were cleared from the circulation within 8 hours after IV administration of Rho(D) immune globulin (WinRho® SDF); there was no evidence of Rh isoimmunization in these individuals 6 months following the Rho(D)-positive RBC exposure.1 In another study in Rho(D)-negative individuals, IV or IM administration of Rho(D) immune globulin (Rhophylac®; 1500 units or 300 mcg) at 24 hours after injection of 15 mL of Rho(D)-positive RBCs resulted in clearance of 99% of the injected RBCs within 12 hours after IV administration or within 144 hours after IM administration of the drug.25
Idiopathic Thrombocytopenic Purpura
Rho(D) immune globulin (i.e., Rhophylac®, WinRho® SDF) is used IV for the treatment of ITP in Rho(D)-positive, nonsplenectomized patients to increase platelet counts and prevent excessive hemorrha WinRho® SDF is labeled by the US Food and Drug Administration (FDA) 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 WinRho® SDF has been designated an orphan drug by the FDA for the treatment of chronic or acute ITP in children or adults.12 Efficacy of Rho(D) immune globulin for the treatment of ITP has been established only in nonsplenectomized, Rho(D)-positive patients;1, 2, 3, 4, 5, 7, 25 safety and efficacy of the drug for the treatment of ITP in other patient groups (i.e., Rho[D]-negative individuals, splenectomized individuals) or for the treatment of thrombocytopenia not related to ITP have not been established.1, 2, 3, 7 While Rho(D) immune globulin has demonstrated efficacy and safety for the treatment of ITP in adults and children, other therapies (corticosteroids and/or immune globulin IV [IGIV]) generally are preferred because of the risk of hemolysis associated with Rho(D) immune globulin.32, 34 (See Cautions: Hematologic Effects.) Careful patient selection is required when considering the use of Rho(D) immune globulin in patients with ITP.36
In a single-arm, open-label study in nonsplenectomized, Rho(D)-positive adults with chronic ITP (ITP of more than 6 months' duration) who had platelet counts less than 30,000/mm3 or required therapy, Rho(D) immune globulin (WinRho® SDF; 100-375 units/kg or 20-75 mcg/kg) resulted in a positive platelet response (defined as a platelet count increase of at least 20,000/mm3) in 88% of patients during the first 2 courses of Rho(D) immune globulin therapy.1 In this study, peak platelet counts averaged 92,300/mm3 (range: 8000-229,000/mm3).1 Efficacy of Rho(D) immune globulin (Rhophylac®) for the treatment of ITP was evaluated in a single-arm, open-label trial in Rho(D)-positive adults with chronic ITP who had platelet counts of 30,000/mm3 or less.25 A positive platelet response (defined as a platelet count of at least 30,000/mm3 and an increase of more than 20,000/mm3 within 15 days) was achieved in 66.3% of the patients (based on the intent-to-treat population) following administration of a single IV dose of Rho(D) immune globulin (250 units/kg or 50 mcg/kg); the median time to platelet response was 3 days and the median duration of response was 22 days.25 Decreased severity of overall bleeding status was observed in 88% of patients who had evidence of bleeding at baseline.25 When treatment is indicated in adults with ITP, corticosteroids generally are suggested as a first-line treatment option; IGIV or Rho(D) immune globulin may be considered as alternative first-line therapies when corticosteroids are contraindicated.32, 34
In a multicenter, controlled, randomized study in nonsplenectomized, Rho(D)-positive children 6 months to 16 years of age with acute ITP (ITP of less than 6 months' duration) and platelet counts less than 20,000/mm3, efficacy of Rho(D) immune globulin therapy for the treatment of ITP was compared with that of IGIV therapy or corticosteroid (prednisone) therapy.1 A positive platelet response (i.e., platelet counts of 50,000/mm3 or greater) occurred in 84% of those who received Rho(D) immune globulin (125 units/kg or 25 mcg/kg on days 1 and 2); peak platelet counts averaged 319,500/mm3 (range: 61,000-892,000/mm3).1 However, there is some evidence that the platelet response (i.e., number of days with platelet counts of 20,000/mm3 or lower and time to achieve platelet counts of 50,000/mm3) in children who receive Rho(D) immune globulin is slower than in those who receive IGIV or corticosteroid therapy.5, 18 When treatment is indicated in children with ITP, a single dose of IGIV or a short course of corticosteroids generally is recommended as first-line therapy; however, some experts suggest that a single dose of Rho(D) immune globulin may be used as an alternative in Rho(D)-positive, nonsplenectomized children who require treatment.32, 34
In an open-label, multicenter study in nonsplenectomized, Rho(D)-positive children 1-18 years of age with chronic ITP (ITP of more than 6 months' duration) and platelet counts less than 50,000/mm3, Rho(D) immune globulin therapy (125 units/kg or 25 mcg/kg on days 1 and 2 and subsequent doses ranging from 125-275 units/kg or 25-55 mcg/kg) produced a positive platelet response (i.e., platelet count increase to at least 50,000/mm3 and at least double the baseline count) in 79%; peak platelet counts averaged 229,400/mm3 (range: 43,300-456,000/mm3) and duration of response averaged 36.5 days (range: 6-84 days).1, 4 While Rho(D) immune globulin therapy should not be considered curative,4 limited evidence indicates that repeat therapy with Rho(D) immune globulin in children with chronic ITP produces a positive platelet response in most patients.4, 7 Positive platelet responses occurred in 86% of children who were retreated with a single dose of Rho(D) immune globulin when their platelet counts had returned to baseline values; the duration of positive response averaged 6 weeks in these children.4 While other therapies (i.e., single dose of IGIV, short course of corticosteroids) generally are recommended for the first-line treatment of ITP in children, some experts suggest that a single dose of Rho(D) immune globulin may be used as an alternative in Rho(D)-positive, nonsplenectomized children who require treatment.32, 34 Children who respond to these first-line therapies may receive subsequent cycles of such therapy to maintain adequate hemostasis.32, 34
ITP Secondary to HIV Infection
In an open-label study in nonsplenectomized, Rho(D)-positive children and adults with ITP secondary to HIV infection who had platelet counts of 30,000/mm3 or less or required therapy, a positive platelet response (i.e., platelet count increase of at least 20,000/mm3) occurred in 90% of patients during the first 6 courses of Rho(D) immune globulin therapy (100-375 units/kg or 20-75 mcg/kg).1 In this study, the number of Rho(D) immune globulin courses of therapy averaged 7.3 (range 1-57) over a period of 407 days (range: 6-1952 days).1 In patients who received 6 courses of Rho(D) immune globulin, the mean increase in platelet count was 60,900/mm3 (range: 2000-565,000/mm3) and the mean peak platelet count was 81,700/mm3 (range: 16,000-593,000/mm3).1, 2 The 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 that corticosteroids, IGIV, or Rho(D) immune globulin may be used.32, 37 In a limited number of HIV-infected individuals with ITP, the interval between courses of therapy was increased by a median of 10 days (range: 7-16 days) following a change in maintenance therapy from IGIV to Rho(D) immune globulin.2
Rho(D) immune globulin is administered IV or IM.1, 14, 15, 16, 25 Certain preparations (i.e., HyperRHO® S/D Full Dose, HyperRHO® S/D Mini-Dose, MICRhoGAM®, RhoGAM®) are for IM injection only and should not be administered IV.14, 15, 16 Other preparations (i.e., Rhophylac®, WinRho® SDF) may be administered either IV or IM.1, 25 For indications related to the suppression of Rh isoimmunization, Rho(D) immune globulin may be administered IV or IM; however, when used for the treatment of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura), Rho(D) immune globulin must be administered by IV injection.1, 14, 15, 16, 25 Efficacy of Rho(D) immune globulin for suppression of Rh isoimmunization appears to be similar following IV or IM administration.30
For suppression of Rh isoimmunization related to an Rh-incompatible pregnancy, Rho(D) immune globulin is administered to the mother and should not be administered to the infant.1, 14, 15, 16 Prior to administration of Rho(D) immune globulin, appropriate laboratory tests should be performed to assess the Rh status of the woman and determine whether she was previously sensitized to the Rho(D) antigen.14, 15, 27, 28 (See Precautions and Contraindications Related to Use for Suppression of Rh Isoimmunization under Cautions: Precautions and Contraindications.)
Solutions of Rho(D) immune globulin should be inspected visually for particulate matter and discoloration prior to administration.1, 14, 15, 16, 25 Some preparations (Rhophylac®, WinRho® SDF) should be brought to room temperature prior to administration.1, 25 Vials and prefilled syringes of Rho(D) immune globulin are for single use only and contain no preservatives; any unused solution should be discarded.1, 14, 15, 16, 25
IM injections of Rho(D) immune globulin should be made preferably into the deltoid muscle or anterolateral aspects of the upper thigh.1, 14, 15, 33 Because of the risk of injury to the sciatic nerve, the gluteal region should not be used routinely for injections; if the gluteal region is used, only the upper, outer quadrant of the gluteal muscle should be used.1, 14, 15 To ensure delivery into muscle, IM injections should be made at a 90° angle to the skin using a needle length appropriate for the individual's age and body mass, the thickness of adipose tissue and muscle at the injection site, and the injection technique.33
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 that this procedure is not required because large blood vessels are not present at recommended IM injection sites.33
If a large dose (exceeding 5 mL [3750 units or 750 mcg]) of Rhophylac® is required and the IM route is used, the manufacturer states that the dose should be divided and given at different sites.25
The manufacturer's prescribing information should be consulted for specific procedures and techniques of administration.14, 15, 16
Commercially available Rho(D) immune globulin preparations labeled for IV or IM use (Rhophylac®, WinRho® SDF) can be administered IV as supplied without further dilution.1, 25 However, if dilution of WinRho® SDF is preferred, the manufacturer states that 0.9% sodium chloride injection should be used as the diluent; 5% dextrose injection or any other diluent should not be used.1
WinRho® SDF should be administered IV over 3-5 minutes for the treatment of ITP; when used for the suppression of Rh isoimmunization, WinRho® SDF should be administered at a rate of 2 mL per 5-15 seconds.1 In patients with risk factors for renal dysfunction or failure (e.g., diabetes mellitus, age greater than 65 years, volume depletion, sepsis, paraproteinemia, concomitant use of known nephrotoxic drugs) or with any degree of preexisting renal impairment, the minimum practicable rate of infusion should be used.1
Rhophylac® should be administered IV at a rate of 2 mL per 15-60 seconds.25
Rho(D) immune globulin should not be administered IV with other drugs.1
Preparations of Rho(D) immune globulin for IM use only are commercially available in single-dose prefilled syringes containing a full dose (standard dose) of Rho(D) immune globulin (HyperRHO® S/D Full Dose, RhoGAM®) or in single-dose prefilled syringes containing a minidose of Rho(D) immune globulin (HyperRHO® S/D Mini-Dose, MICRhoGAM®).14, 15, 16 Each single-dose prefilled syringe containing a full dose of Rho(D) immune globulin contains enough anti-Rho(D) (approximately 300 mcg) to suppress the immunization potential of 15 mL of Rho(D)-positive packed red blood cells (RBCs).14, 16 Each single-dose prefilled syringe of minidose Rho(D) immune globulin contains enough anti-Rho(D) to suppress the immunization potential of 2.5 mL of Rho(D)-positive packed RBCs or the equivalent (5 mL) of whole blood.15, 16
Single-dose vials of Rho(D) immune globulin for IV or IM administration (WinRho® SDF) containing 1500 units (300 mcg) contain enough anti-Rho(D) to suppress the immunization potential of 17 mL of Rho(D)-positive RBCs.1 Single-dose prefilled syringes of Rho(D) immune globulin for IV or IM administration (Rhophylac®) contain enough anti-Rho(D) (1500 units or 300 mcg) to suppress the immunization potential of at least 15 mL of Rho(D)-positive RBCs.25
Antepartum and Postpartum Prophylaxis of Rh Isoimmunization
For routine antepartum prophylaxis in an unsensitized, Rho(D)-negative woman, Rho(D) immune globulin should be administered at approximately 28 weeks of gestation; a second dose of Rho(D) immune globulin should be administered within 72 hours after delivery if the neonate is Rho(D)-positive.1, 14, 16, 25, 31 In some circumstances, Rho(D) immune globulin may be administered more than 72 hours after delivery, but a lesser degree of protection may result.14, 16, 31 The postpartum dose of Rho(D) immune globulin should be administered to the mother even if the Rh status of the infant is not known at 72 hours.1 If more than 72 hours have elapsed, Rho(D) immune globulin should not be withheld, but should be administered as soon as possible up to 28 days after delivery.1, 31
Whenever a large fetal-maternal hemorrhage occurs during delivery, additional doses of Rho(D) immune globulin are required.14, 16, 25 If a large fetal-maternal hemorrhage (exceeding 30 mL of whole blood or 15 mL of packed RBCs) is suspected, an approved laboratory procedure (e.g., modified Kleihauer-Betke technique) should be performed to estimate the number of fetal Rh-positive RBCs in the maternal circulation and to calculate the packed RBC volume of the fetal-maternal hemorrhage.14, 16
If delivery occurs within 3 weeks after an antepartum dose of Rho(D) immune globulin, the postpartum dose may be withheld, but a test for fetal-maternal hemorrhage should be performed to determine if additional Rho(D) immune globulin is indicated because of a large fetal-maternal hemorrhage.14, 16, 31 If delivery does not occur within 12 weeks after administration of the standard antepartum dose at approximately 28 weeks of gestation, a second antepartum dose has been recommended in order to maintain an adequate level of anti-Rho(D) antibody.16, 31
HyperRHO® S/D Full Dose and RhoGAM®
For suppression of Rh isoimmunization in an unsensitized, Rho(D)-negative woman following delivery of an Rho(D)-positive infant, the usual dosage of HyperRHO® S/D Full Dose and RhoGAM® is one prefilled syringe containing a full dose (1500 units or 300 mcg) of Rho(D) immune globulin.14, 16 The dose should be administered by IM injection, preferably within 72 hours after delivery.14, 16 If multiple doses are required, such as in the case of a large fetal-maternal hemorrhage, the doses may be given at the same time (at different sites) or at spaced intervals, provided the entire dose is administered within 72 hours.14, 16
For routine antepartum prophylaxis in an unsensitized, Rho(D)-negative woman, one single-dose prefilled syringe containing a full dose (1500 units or 300 mcg) of Rho(D) immune globulin (HyperRHO® S/D Full Dose, RhoGAM®) should be administered by IM injection at approximately 26-28 weeks of gestation; a second single-dose prefilled syringe containing a full dose of Rho(D) immune globulin should be administered within 72 hours after delivery if the neonate is Rho(D)-positive.14, 16
Whenever a large fetal-maternal hemorrhage occurs during delivery, the manufacturer of HyperRHO® states that the number of single-dose prefilled syringes containing HyperRHO® S/D Full Dose that are required can be determined by dividing the packed RBC volume of the fetal-maternal hemorrhage by 15 mL; if the calculated dose results in a fraction of a single-dose prefilled syringe, the next whole number of syringes should be administered.14 Because methods used to determine the extent of fetal-maternal hemorrhage are imprecise, the manufacturer of RhoGAM® recommends that a dose of RhoGAM® exceeding 100 units (20 mcg) per mL of Rho(D)-positive RBCs should be considered whenever a large fetal-maternal hemorrhage or RBC exposure is suspected or documented.16
For routine antepartum prophylaxis of Rh isoimmunization in an unsensitized, Rho(D)-negative woman, 1500 units (300 mcg) of Rho(D) immune globulin (WinRho® SDF, Rhophylac®) should be administered IM or IV at 28-30 weeks of gestation.1, 25 Within 72 hours after delivery, 600 units (120 mcg) of WinRho® SDF should be administered IM or IV to the mother if the infant is Rho(D)-positive.1 If Rhophylac® is used, the usual dose after delivery is 1500 units (300 mcg) administered IM or IV.25
In the event of a large fetal-maternal hemorrhage, the manufacturer of Rhophylac® recommends administration of an additional 100 units (20 mcg) per mL of fetal RBCs in excess of 15 mL if bleeding is quantified or an additional 1500-unit (300-mcg) dose if excess transplacental bleeding cannot be quantified.25 Following a massive fetal hemorrhage, the recommended dosage of WinRho® SDF varies depending on whether the drug is given IM or IV.1 If WinRho® SDF is administered by IM injection, the recommended dosage is 60 units (12 mcg) for each 1 mL of Rho(D)-positive whole blood or 120 units (24 mcg) for each 1 mL of Rho(D)-positive packed RBCs; 6000 units (1200 mcg) should be given every 12 hours until the total dose has been administered.1 If WinRho® SDF is administered IV, the recommended dosage is 45 units (9 mcg) for each 1 mL of Rho(D)-positive whole blood or 90 units (18 mcg) for each 1 mL of Rho(D)-positive packed RBCs; 3000 units (600 mcg) should be given every 8 hours until the total dose has been administered.1
Suppression of Rh Isoimmunization Related to Termination of Pregnancy
When Rho(D) immune globulin is used to suppress Rh isoimmunization following termination of pregnancy, the recommended dose should be administered within 72 hours.1, 14, 15, 16, 25 In the event of a large fetal-maternal hemorrhage, the usual dosage of Rho(D) immune globulin must be increased.14, 16, 25 For information on estimation of the extent of hemorrhage and recommended dosages for large fetal-maternal hemorrhages, see Antepartum and Postpartum Prophylaxis of Rh Isoimmunization under Dosage and Administration: Dosage.
HyperRHO® S/D Mini-Dose and MICRhoGAM®
For suppression of Rh isoimmunization after spontaneous or induced abortion occurring up to and including 12 weeks of gestation, the usual dosage of HyperRho® S/D Mini-Dose and MICRhoGAM® is one single-dose prefilled syringe containing a minidose (250 units or 50 mcg) of Rho(D) immune globulin administered by IM injection as soon as possible, within 72 hours following termination of pregnancy.15, 16 A full dose may be administered if the minidose preparation is not available.14, 16
HyperRHO® S/D Full Dose and RhoGAM®
For suppression of Rh isoimmunization after spontaneous or induced abortion occurring at 13 or more weeks of gestation, the usual dosage of HyperRHO® S/D Full Dose and RhoGAM® is one single-dose prefilled syringe containing a full dose (1500 units or 300 mcg) of Rho(D) immune globulin administered by IM injection as soon as possible, within 72 hours following termination of pregnancy.14, 16
After abortion, the usual dosage of WinRho® SDF for suppression of Rh isoimmunization is 600 units (120 mcg).1 If Rhophylac® is used, the usual dosage is 1500 units (300 mcg).25 The dose should be administered IM or IV within 72 hours after termination of pregnancy.1, 25
Suppression of Rh Isoimmunization Related to Other Obstetric Procedures or Complications during Pregnancy
When Rho(D) immune globulin is used to suppress Rh isoimmunization following an obstetric complication or procedure during pregnancy, the recommended dose should be administered within 72 hours of the event.1, 14, 16, 25 If the complication or procedure occurs early in the pregnancy (before 26-28 weeks of gestation), additional antepartum doses should be administered (e.g., at 12-week intervals) to maintain an adequate level of passively acquired anti-Rho(D) antibody throughout the pregnancy.1, 14, 16 In addition, a full dose of Rho(D) immune globulin should be administered to the mother within 72 hours after delivery if the infant is Rho(D)-positive.14, 16 If delivery occurs within 3 weeks after an antepartum dose of the drug, the postpartum dose may be withheld, but a test for fetal-maternal hemorrhage should be performed to determine if additional Rho(D) immune globulin is indicated because of a large fetal-maternal hemorrhage.14, 16
In the event of a large fetal-maternal hemorrhage, the usual dosage of Rho(D) immune globulin used for suppression of Rh isoimmunization following an obstetric complication or procedure must be increased.14, 16, 25 For information on estimation of the extent of hemorrhage and recommended dosages for large fetal-maternal hemorrhages, see Antepartum and Postpartum Prophylaxis of Rh Isoimmunization under Dosage and Administration: Dosage.
HyperRHO® S/D Full Dose, MICRhoGAM®, and RhoGAM®
The usual dosage of HyperRHO® S/D Full Dose or RhoGAM® for suppression of Rh isoimmunization following amniocentesis, percutaneous umbilical blood sampling, chorionic villus sampling, ectopic pregnancy, or other abdominal trauma or obstetric manipulation during pregnancy is one single-dose prefilled syringe containing a full dose (1500 units or 300 mcg) of Rho(D) immune globulin administered by IM injection within 72 hours of the event.14, 16 Following threatened abortion (with continuation of pregnancy) at any stage of gestation, the manufacturer of HyperRHO® S/D Full Dose states that a full dose of Rho(D) immune globulin should be administered.14 The manufacturer of RhoGAM® states that a full dose of Rho(D) immune globulin should be administered if threatened abortion (with continuation of pregnancy) occurs after 12 weeks of gestation, but that a minidose (250 units or 50 mcg) may be given if the event occurs at or before 12 weeks of gestation; a full dose may be administered if the minidose preparation (MICRhoGAM®) is not available.16
After amniocentesis or chorionic villus sampling occurring at up to 34 weeks of gestation, the usual dosage of WinRho® SDF for suppression of Rh isoimmunization is 1500 units (300 mcg) of Rho(D) immune globulin administered IM or IV immediately after the procedure.1 If the drug is administered early in the pregnancy, additional antepartum doses of 1500 units (300 mcg) should be given at 12-week intervals until delivery to maintain an adequate level of passively acquired anti-Rho(D) antibody throughout the pregnancy.1 After amniocentesis or any other manipulation associated with an increased risk of exposure to fetal blood occurring after 34 weeks of gestation, the usual dosage of WinRho® SDF for suppression of Rh isoimmunization is 600 units (120 mcg) of Rho(D) immune globulin administered IM or IV within 72 hours after the event.1 After threatened abortion at any stage of gestation, the usual dosage of WinRho® SDF for suppression of Rh isoimmunization is 1500 units (300 mcg) administered IM or IV immediately.1
If Rhophylac® is used following 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, the usual dosage is 1500 units (300 mcg) of Rho(D) immune globulin administered IM or IV within 72 hours of the event.25
Suppression of Rh Isoimmunization Related to Transfusion of Blood or Blood Products
Following transfusion of Rho(D)-positive blood to an Rho(D)-negative individual, dosage of Rho(D) immune globulin depends on the volume of Rho(D)-positive blood or Rho(D)-positive packed RBCs transfused.1, 14, 16, 25 The volume of Rho(D)-positive whole blood administered should be multiplied by the hematocrit of the donor unit of blood to give the volume of Rho(D)-positive packed RBCs transfused.14
HyperRHO® S/D Full Dose, MICRhoGAM®, and RhoGAM®
The number of single-dose prefilled syringes containing a full dose (1500 units or 300 mcg) of Rho(D) immune globulin (HyperRHO® S/D Full Dose) to be administered by IM injection is determined by dividing the volume of Rho(D)-positive packed RBCs transfused by 15 mL.14
For transfusions of less than 2.5 mL of Rho(D)-positive RBCs, a minidose of Rho(D) immune globulin (MICRhoGAM®) containing 250 units (50 mcg) may be administered; however, a full dose of the drug (RhoGAM® 1500 units or 300 mcg) should be given following transfusions of 2.5-15 mL of Rho(D)-positive RBCs.16 Additional doses should be administered if the patient has been exposed to more than 15 mL of Rho(D)-positive RBCs; in these situations, the manufacturer of RhoGAM® recommends administration of 100 units (20 mcg) of Rho(D) immune globulin per mL of RBC exposure.16
If the calculated dose of Rho(D) immune globulin results in a fraction of a prefilled syringe, the next whole number of single-dose prefilled syringes should be administered.14, 16 Rho(D) immune globulin should be administered within 72 hours after an incompatible transfusion, but preferably as soon as possible.14, 16 If multiple syringes are required, the total dose may be given by IM injection at the same time (at different sites) or at spaced intervals, provided the entire dose is administered within 72 hours.14, 16
Following transfusion of Rho(D)-positive blood or Rho(D)-positive packed RBCs in an Rho(D)-negative individual, Rho(D) immune globulin (WinRho® SDF, Rhophylac®) should be administered IM or IV within 72 hours of exposure.1, 25
Dosage of WinRho® SDF is determined by the volume of Rho(D)-positive blood or Rho(D)-positive RBCs and varies depending on whether the drug is given IM or IV.1 If WinRho® SDF is administered by IM injection, the total dose required for suppression of Rh isoimmunization is 60 units (12 mcg) for each 1 mL of Rho(D)-positive whole blood or 120 units (24 mcg) for each 1 mL of Rho(D)-positive packed RBCs; 6000 units (1200 mcg) should be given every 12 hours until the total dose has been administered.1 If WinRho® SDF is administered IV, the total dose required for suppression of Rh isoimmunization is 45 units (9 mcg) for each 1 mL of Rho(D)-positive whole blood or 90 units (18 mcg) for each 1 mL of Rho(D)-positive packed RBCs; 3000 units (600 mcg) should be given every 8 hours until the total dose has been administered.1
If Rhophylac® is used for suppression of Rh isoimmunization following an incompatible transfusion, the usual IM or IV dosage is 100 units (20 mcg) per 2 mL of transfused blood or 100 units (20 mcg) per mL of erythrocyte concentrate.25
Treatment of Idiopathic Thrombocytopenic Purpura
When used for the treatment of ITP, Rho(D) immune globulin must be administered IV.1, 25
For the treatment of ITP in nonsplenectomized, Rho(D)-positive children and adults, the usual initial dosage of WinRho® SDF is 250 units/kg (50 mcg/kg) given as a single dose or in 2 divided doses on separate days.1 The drug should be administered IV over 3-5 minutes.1 An initial dosage of 125-200 units/kg (25-40 mcg/kg) should be used in individuals with low hemoglobin concentrations (i.e., less than 10 g/dL) to minimize the risk of increasing the severity of anemia.1 Alternative treatments should be used in individuals with hemoglobin concentrations less than 8 g/dL.1 (See Risk of Hemolysis in Patients with Idiopathic Thrombocytopenic Purpura under Cautions: Precautions and Contraindications.)
Platelet counts, erythrocyte counts, hemoglobin concentrations, and reticulocyte counts should be monitored to assess the response to Rho(D) immune globulin and determine the dose and frequency of WinRho® SDF administration required for maintenance therapy.1 If the patient responded to the usual initial dosage of WinRho® SDF, a maintenance dosage of 125-300 units/kg (25-60 mcg/kg) may be administered but should be individualized based on the platelet count and hemoglobin concentration.1 An increase in platelet count to 50,000/mm3 generally is considered to be a satisfactory response; according to expert consensus guidelines, treatment rarely is indicated in patients with platelet counts exceeding 50,000/mm3.1, 34 If the patient had an inadequate response to the usual initial dosage of WinRho® SDF, those with a hemoglobin concentration greater than 10 g/dL should receive a maintenance dosage of 250-300 units/kg (50-60 mcg/kg) and those with a hemoglobin concentration of 8-10 g/dL should receive a maintenance dosage of 125-200 units/kg (25-40 mcg/kg).1 Safety and efficacy of WinRho® SDF doses exceeding 300 units/kg (60 mcg/kg) have not been established for the treatment of ITP.1
If Rhophylac® is used for the treatment of chronic ITP in Rho(D)-positive nonsplenectomized adults, a dose of 250 units/kg (50 mcg/kg) is recommended; the drug should be administered IV at a rate of 2 mL (1500 units or 300 mcg) per 15-60 seconds.25
Adverse reactions to preparations of Rho(D) immune globulin administered by IM injection only (HyperRHO® S/D Full Dose, HyperRHO® S/D Mini-Dose, RhoGAM®, MICRhoGAM®) in unsensitized, Rho(D)-negative individuals are infrequent and mild, and generally consist of local effects at the injection site and slight temperature elevations.14, 15, 16
The most common adverse effects reported in clinical trials evaluating Rhophylac® for suppression of Rh isoimmunization were nausea,25 dizziness,25 headache,25 injection site pain,25 and malaise,25 each occurring in less than 1% of patients.25 In clinical trials evaluating Rhophylac® for the treatment of chronic idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) in adults, drug-related adverse effects occurred in approximately 71% of patients.25 The most common adverse effects were chills,25 pyrexia or increased body temperature,25 headache,25 and increased bilirubin concentration25 (a manifestation of mild hemolysis), each occurring in approximately 14-35% of patients; other manifestations of mild hemolysis (decreased hemoglobin or haptoglobin concentrations) also occurred commonly.25
When WinRho® SDF is administered for suppression of Rh isoimmunization in unsensitized, Rho(D)-negative individuals, adverse reactions occur infrequently (less than 0.1% of patients).1 In the principal efficacy study of WinRho® SDF in pregnant Rho(D)-negative women, there were no reported adverse effects following administration of the drug; however, infusion reactions1 and skin reactions1 have been reported during postmarketing experience.1 In clinical trials of WinRho® SDF in children and adults with acute or chronic ITP or with ITP secondary to human immunodeficiency virus (HIV) infection, approximately 57% of patients reported an adverse effect and about 7% of the Rho(D) immune globulin doses were associated with adverse effects.1 The most frequent drug-related adverse effects reported in these patients were headache,1 chills,1 and fever,1 each occurring in approximately 6-11% of patients.1
Local and Sensitivity Reactions
Adverse reactions to IM preparations of Rho(D) immune globulin in unsensitized, Rho(D)-negative individuals generally consist of local effects at the injection site (swelling, induration, erythema, mild pain or warmth).14, 15, 16 Severe systemic allergic reactions and sensitization due to repeated IM injections occur only rarely.14, 16
Hypersensitivity reactions, including anaphylaxis and anaphylactoid reactions, and injection site reactions (e.g., pain, irritation, induration, pruritus, swelling) also have occurred in patients receiving preparations of Rho(D) immune globulin labeled for IM or IV administration.1, 25
When Rho(D) immune globulin is administered to Rho(D)-positive individuals for the treatment of ITP, adverse effects related to Rho(D)-positive red blood cell (RBC) destruction may occur.2, 3, 4, 5, 6, 7, 8, 10, 13, 36 Intravascular hemolysis resulting in death and other serious complications (e.g., severe anemia, acute renal insufficiency or failure, disseminated intravascular coagulation [DIC]) has been reported in patients with ITP receiving IV therapy with Rho(D) immune globulin.1, 25, 36 Manifestations include back pain, shaking chills, fever, and discolored urine, hematuria, or hemoglobinuria.1, 25 Intravascular hemolysis can lead to clinically compromising anemia and multiorgan failure including acute respiratory distress syndrome (ARDS).1, 25, 36 Postmarketing data suggest that geriatric patients older than 65 years of age with comorbid conditions (e.g., cardiorespiratory compromise, renal failure, prothrombotic disorders) are more likely to experience serious complications from acute hemolytic reactions.1 (See Risk of Hemolysis in Patients with Idiopathic Thrombocytopenic Purpura under Cautions: Precautions and Contraindications.)
Although the exact mechanism of action of Rho(D) immune globulin in the treatment of ITP has not been fully elucidated, it is thought to be related to the formation of anti-Rho(D) antibody-coated RBC complexes and preferential destruction of these complexes by macrophages in the reticuloendothelial system.1 As a consequence, extravascular hemolysis and a resultant decrease in hemoglobin concentrations can occur.1 In clinical studies of WinRho® SDF in patients with ITP, hemoglobin concentrations decreased by an average of 1.2 g/dL from baseline within 7 days after administration of the drug.1 The maximum decrease in hemoglobin concentration averaged 1.7 or 0.81 g/dL in patients receiving doses of 250 units/kg (50 mcg/kg) or 125-200 units/kg (25-40 mcg/kg), respectively.1 The maximum decrease in hemoglobin concentration exceeded 4 g/dL (range: 4.2-6.1 g/dL) in 3.7% of patients.1 Mild hemolysis with increased bilirubin, decreased hemoglobin, and/or decreased haptoglobin concentrations also was reported in clinical studies of Rhophylac® in patients with ITP; increased bilirubin concentrations were observed in 21% of these patients, and the median maximum decrease in hemoglobin concentration was 0.8 g/dL on days 6 and 8 following administration of the drug.25
Administration of Rho(D) immune globulin in individuals who have received transfusions of Rho(D)-positive RBCs also may result in signs and symptoms suggestive of hemolysis (e.g., back pain, fever, nausea and vomiting, hypotension or hypertension, hemoglobinuria or hemoglobinemia, elevated bilirubin and creatinine concentrations, decreased haptoglobin concentrations).14, 16
Thromboembolic events, sometimes fatal, have been reported in patients receiving Rho(D) immune globulin.1 Patients at risk include those with a 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 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Other adverse cardiovascular effects reported in patients receiving Rho(D) immune globulin include cardiac arrest,1 cardiac failure,1 myocardial infarction,1 tachycardia,1, 25 hypotension,25 edema,1 and increased blood pressure.25
Transfusion-related acute lung injury (TRALI; noncardiogenic pulmonary edema), characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever, has been reported in patients receiving IV immune globulins, including Rho(D) immune globulin (WinRho® SDF).1 Symptoms typically appear within 1-6 hours following administration of blood products, and can be managed with oxygen therapy and adequate ventilatory support.1 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.) ARDS1 and dyspnea25 also have been reported in patients receiving Rho(D) immune globulin.1, 25
Adverse renal effects, including renal failure or impairment,1 anuria,1 chromaturia,1 hematuria,1 and hemoglobinuria,1 have been reported in patients with ITP receiving Rho(D) immune globulin.1 (See Other Precautions and Contraindications under Cautions: Precautions and Contraindications.)
Headache,1 chills,1 fever,1 asthenia,1 infection,1 and dizziness1 were reported in clinical trials in up to 14% of patients with ITP receiving WinRho® SDF.1 In clinical trials in patients with ITP receiving Rhophylac®, chills and pyrexia/increased body temperature were reported in approximately 32-35% of patients and headache was reported in approximately 14% of patients.25 Other adverse effects reported in patients with ITP receiving Rho(D) immune globulin include nausea,1, 25 chest pain,1 fatigue,1 pallor,25 shivering,25 weakness,25 edema,1 jaundice,1 adverse musculoskeletal effects (myalgia, muscle spasm, pain in extremities),1 and hyperhidrosis.1
In clinical trials of Rhophylac® for suppression of Rh isoimmunization, headache,25 dizziness,25 nausea,25 malaise,25 and transiently positive anti-C antibody test results25 were each reported in less than 1% of patients receiving the drug.25 Vertigo,25 vomiting,25 rash,1, 16, 25 erythema,25 pruritus,1, 25 chills,25 slight temperature elevations,14, 15, 16 pyrexia,25 body aches,16 diarrhea,25 and back pain25 also have been reported in patients receiving Rho(D) immune globulin for suppression of Rh isoimmunization.1, 14, 15, 16, 25
Precautions and Contraindications
Risk of Hypersensitivity Reactions
Rho(D) immune globulin generally is contraindicated in individuals with known hypersensitivity, including anaphylactic or severe systemic reactions, to preparations containing human immune globulin.1, 25 Although not a specific contraindication, the manufacturers of some Rho(D) immune globulin preparations (i.e., RhoGAM®, MICRhoGAM®, HyperRHO® S/D) state that the drug should be administered with caution in patients who have had prior systemic allergic reactions to human immune globulin.14, 15, 16
Some manufacturers recommend that patients be observed for at least 20 minutes after receiving Rho(D) immune globulin.16, 25 Patients should be informed of early signs of hypersensitivity, including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis.1, 16, 25 Although systemic reactions to Rho(D) immune globulin are rare, epinephrine should be available for treatment of an acute anaphylactic reaction if it occurs.1, 14, 15, 25 If manifestations of a hypersensitivity reaction occur, administration of Rho(D) immune globulin should be discontinued and appropriate treatment instituted.1, 25
Rho(D) immune globulin may contain trace or small quantities of immunoglobulin A (IgA).1, 16, 25 The benefits of Rho(D) immune globulin must be weighed against the potential risks of hypersensitivity reactions in patients with isolated IgA deficiency, since these individuals may have serum antibodies to IgA (or develop antibodies following administration of Rho(D) immune globulin) and anaphylaxis could result following administration of Rho(D) immune globulin or other blood products containing IgA.14, 15, 16 Rhophylac® and WinRho® SDF are contraindicated in IgA-deficient patients with antibodies to IgA and a history of hypersensitivity.1, 25
Precautions and Contraindications Related to Use for Suppression of Rh Isoimmunization
When used for suppression of Rh isoimmunization related to pregnancy, Rho(D) immune globulin is indicated only in unsensitized, Rho(D)-negative individuals1, 14, 15, 16, 25 and should not be administered to Rho(D)-positive individuals or Rho(D)-negative individuals who have been previously sensitized to Rho(D) antigens, as evidenced by the presence of anti-Rho(D) antibody in their serum.1, 14, 15, 16 Some manufacturers state that the drug is contraindicated in Rho(D)-positive individuals.16
Prior to administration of Rho(D) immune globulin for suppression of Rh isoimmunization related to pregnancy, appropriate laboratory tests should be performed to determine the Rh status of the woman and assess whether she has previously been sensitized to Rho(D) antigens.30 The fact that results of these laboratory tests may be affected by a large fetal bleed into the maternal circulation late in pregnancy or following delivery, antepartum administration of Rho(D) immune globulin, or a transfusion accident should be considered.1, 14, 16 A screening test to detect fetal RBCs may be helpful in some cases.1, 14 If there is doubt concerning the Rh status of the mother or whether she already has been sensitized to the Rho(D) antigen, Rho(D) immune globulin should be administered.14, 16
Patients receiving the drug for suppression of Rh isoimmunization following an Rh-incompatible transfusion should be monitored clinically and by laboratory tests for evidence of hemolysis.16
Risk of Hemolysis in Patients with Idiopathic Thrombocytopenic Purpura
When Rho(D) immune globulin is used for the treatment of ITP in Rho(D)-positive individuals, adverse effects related to the destruction of antibody-coated Rho(D)-positive RBCs by the reticuloendothelial system (i.e., extravascular hemolysis), most notably a decrease in hemoglobin concentration, can be expected.1, 36
Because intravascular hemolysis resulting in death and other serious complications also has been reported in Rho(D)-positive patients with ITP receiving IV therapy with Rho(D) immune globulin, such patients should be closely monitored in a healthcare setting for at least 8 hours after the drug is administered.1, 25 Patients should be monitored for signs and symptoms of intravascular hemolysis (e.g., back pain, shaking chills, fever, discolored urine, hematuria); however, absence of these manifestations within the 8-hour monitoring period does not indicate that intravascular hemolysis may not occur at a later time.1, 25, 26 In addition, dipstick urinalysis should be performed at baseline and after administration of the drug (at 2 hours, 4 hours, and just prior to the end of the monitoring period).1, 25 If intravascular hemolysis occurs or is suspected, appropriate laboratory tests should be performed to confirm the diagnosis; these tests should include plasma hemoglobin, haptoglobin, LDH, and bilirubin (direct and indirect), and specific tests for DIC (e.g., D-dimer, fibrin degradation products, fibrin split products).1, 25
In addition, the manufacturer of WinRho® SDF recommends that patients with ITP and low initial hemoglobin concentrations (i.e., less than 10 g/dL) receive a reduced dosage of the drug to minimize the risk of increasing the severity of anemia.1 (See Treatment of Idiopathic Thrombocytopenic Purpura under Dosage and Administration: Dosage.) Alternative treatments should be used in individuals with hemoglobin concentrations less than 8 g/dL.1 The manufacturer of WinRho® SDF also recommends that prior to treatment, a patient's risk of hemolysis should be assessed with appropriate laboratory tests (e.g., blood type, blood cell count, reticulocyte count, direct antiglobulin test [DAT], dipstick urinalysis).1 If there is any evidence (or risk) of hemolysis, use of alternative treatments to Rho(D) immune globulin is advised.1 The manufacturer of Rhophylac® states that safety of the drug in the treatment of ITP has not been established in patients with preexisting anemia; the potential benefits should be weighed against the risk of increasing the severity of anemia.25
If transfusion with packed RBCs is necessary for the treatment of anemia in ITP patients who received Rho(D) immune globulin, Rho(D)-negative packed RBCs should be used so as not to exacerbate intravascular hemolysis.1, 25
Risk of Transmissible Agents in Plasma-derived Preparations
Because Rho(D) immune globulin is prepared from human plasma, it is a potential vehicle for transmission of human viruses, including the causative agents of viral hepatitis and HIV, and theoretically may carry a risk of transmitting the causative agent of Creutzfeldt-Jakob disease (CJD) or variant CJD (vCJD).1, 14, 15, 16, 17, 25 The risk of transmission of recognized blood-borne viral infections from Rho(D) immune globulin is considered remote since plasma donors have been screened and tested for prior exposure to certain pathogens or present infection with certain viruses (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], HIV).1, 14, 15, 16, 25 In addition, the manufacturing processes for Rho(D) immune globulin preparations include certain chemical (solvent/detergent) treatment procedures and purification steps (e.g., viral filtration) that decrease viral infectious potential.1, 14, 15, 16, 25 Solvent/detergent inactivation processes can inactivate lipid-enveloped viruses such as HBV, HCV, HIV, and West Nile virus, and virus filtration steps are effective in the removal of some non-lipid-enveloped viruses.1, 16, 25 Despite these measures, there is still a possibility of transmission of infectious pathogens from plasma-derived preparations of Rho(D) immune globulin, including transmission of unknown agents that may be present in these preparations.14, 15, 16 Any infection believed to have been transmitted by Rho(D) immune globulin should be reported to the manufacturer.1, 14, 15, 16, 25
For further information on precautions related to transmissible agents in plasma-derived preparations, see Risk of Transmissible Agents in Plasma-derived Preparations under Cautions: Precautions and Contraindications, in Albumin Human 16:00.
Other Precautions and Contraindications
Because of the risk of transfusion-related acute lung injury (TRALI; noncardiogenic pulmonary edema) in patients receiving IV immune globulins, patients should be monitored for adverse pulmonary effects during treatment with Rho(D) immune globulin.1 If TRALI is suspected, appropriate tests should be performed to determine whether anti-neutrophil and anti-HLA antibodies are present in the immune globulin preparation or the patient's serum.1 TRALI should be managed using oxygen therapy and adequate ventilatory support.1
Because of a risk of thromboembolic complications during or following treatment with WinRho® SDF and other IV immune globulins, patients with a preexisting risk of thromboembolism should receive WinRho® SDF at the slowest possible rate of IV infusion; such patients include those with a 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 In addition, a baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity (e.g., those with cryoglobulins, fasting chylomicronemia or markedly high triglycerides, or monoclonal gammopathies).1
Because acute renal dysfunction and renal failure have occurred in patients receiving IV immune globulins, the manufacturer of WinRho® SDF recommends that renal function be assessed (including measurements of BUN and serum creatinine) prior to initiating Rho(D) immune globulin; clinicians should ensure that patients are not volume depleted before the start of therapy.1 WinRho® SDF should be administered at the slowest possible infusion rate in patients with risk factors for renal dysfunction or failure.1 (See IV Administration under Dosage and Administration: Administration.) Renal function and urine output should be monitored periodically in such patients.1
Improper storage or handling of immune globulins may affect efficacy.33 Rho(D) immune globulin that has been mishandled or has not been stored at the recommended temperature should not be administered.33 Rho(D) immune globulin should be stored at 2-8°C.1, 14, 15, 16, 25 All immune globulins should be inspected upon delivery and monitored during storage to ensure that the appropriate temperature is maintained.33 If there are concerns about mishandling, the manufacturer or state or local health departments should be contacted for guidance on whether Rho(D) immune globulin is usable.33
For suppression of Rh isoimmunization related to pregnancy, Rho(D) immune globulin is administered to the mother and should not be administered to the neonate.1, 14, 15, 16, 25
Safety and efficacy of HyperRHO® S/D Full Dose and HyperRHO® S/D Mini-Dose have not been established in pediatric patients.14, 15 Safety and efficacy of Rhophylac® have not been established for suppression of Rh isoimmunization in pediatric patients given an incompatible transfusion; the potential risks and benefits of the drug should be weighed when considering use in pediatric patients, particularly in girls whose later pregnancies may be affected if Rh isoimmunization occurs.25
WinRho® SDF is used in children for the treatment of acute or chronic ITP or ITP secondary to HIV infection.1 (See Uses: Idiopathic Thrombocytopenic Purpura.)
Clinical studies of WinRho® SDF did not include sufficient numbers of patients 65 years of age or older to determine whether they respond differently than younger adults.1 Postmarketing data indicate that geriatric patients older than 65 years of age with comorbid conditions (e.g., cardiorespiratory compromise, renal insufficiency or failure, prothrombotic conditions) may have a greater risk of developing serious or fatal complications from intravascular hemolysis.1 The manufacturer of WinRho® SDF therefore states that dosage should be selected with caution in geriatric patients, usually initiating therapy at the low end of the dosage ran the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in this age group should be considered.1
Rhophylac® has not been evaluated in patients 65 years of age or older for suppression of Rh isoimmunization related to Rh-incompatible transfusions.25 In clinical studies of the drug in patients with ITP, 19% of patients were 65 years of age or older; no overall differences in efficacy or safety were observed between these patients and younger adults.25
Pregnancy, Fertility, and Lactation
Animal reproduction studies have not been performed with Rho(D) immune globulin.1, 14, 15, 16, 25 Available evidence suggests that administration of Rho(D) immune globulin for the suppression of Rh isoimmunization during pregnancy does not have adverse effects on the fetus or future pregnancies and does not adversely affect the reproduction capacity of the mother.1, 16, 25 Rho(D) immune globulin has not been evaluated systematically in pregnant women with ITP;1, 25, 32, 34 when treatment is indicated, therapy with corticosteroids and/or immune globulin IV (IGIV) generally is recommended.32, 34 Infants born to women who received antepartum Rho(D) immune globulin may have a weakly positive direct antiglobulin (Coombs') test at birth.14, 16, 25
Rhophylac® is used in nursing women for the suppression of Rh isoimmunization; no adverse effects are expected during breastfeeding.25 Rho(D) immune globulin has not been evaluated in nursing women with ITP.1, 25 It is not known whether Rho(D) immune globulin is distributed into human milk; because many drugs are distributed into milk, caution is advised when Rho(D) immune globulin is administered to nursing women.1
Antibodies present in immune globulin preparations may interfere with immune responses to some live virus vaccines, including measles, mumps, and rubella virus vaccine live (MMR), varicella virus vaccine live, and the fixed combination of MMR and varicella virus vaccine live (MMRV).1, 14, 15, 16, 25, 33 The manufacturers state that these vaccines generally should not be administered simultaneously with or for 3 months following administration of Rho(D) immune globulin.1, 14, 15, 16 However, the low dose of Rho(D) immune globulin administered postpartum for suppression of Rh isoimmunization has not been shown to reduce the response to rubella virus vaccine containing the RA 27/3 strain of live, attenuated rubella virus.33 Because of the importance of rubella and varicella immunity in women of childbearing potential, the US Public Health Service Advisory Committee on Immunization Practices (ACIP) recommends that the appropriate vaccine be administered immediately after delivery in women who are susceptible to rubella and/or varicella; administration of these vaccines should not be delayed because of receipt of antepartum or postpartum Rho(D) immune globulin.16, 33 If possible, serologic tests should be performed at least 3 months after vaccination to ensure immunity to rubella and, if necessary, to measles.16, 33
There is no evidence that immune globulin preparations interfere with immune responses to influenza virus vaccine live intranasal, rotavirus vaccine live oral, typhoid vaccine live oral, yellow fever virus vaccine live, or zoster vaccine live.33 When indicated, these live vaccines may be given simultaneously with (at a different anatomic site) or at any interval before or after Rho(D) immune globulin.33
Inactivated Vaccines and Toxoids
Immune globulin preparations are not expected to have a clinically important effect on immune responses to inactivated vaccines or toxoids; therefore, 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 administration of Rho(D) immune globulin.33
Direct and Indirect Antiglobulin (Coombs') Tests
Some infants born to women who received Rho(D) immune globulin prior to delivery may have a weakly positive direct antiglobulin (Coombs') test at birth.14, 16, 25
Because Rho(D) immune globulin can contain trace amounts of antibodies to other blood group antigens (e.g., anti-A, anti-B, anti-C, anti-E), patients receiving Rho(D) immune globulin may have passively acquired antibodies to such antigens that are detectable in direct and indirect antiglobulin (Coombs') tests.1, 25
Rho(D) immune globulin 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 Test methods that are not affected by maltose should be used to monitor blood glucose concentrations in patients receiving maltose-containing Rho(D) immune globulin preparations.1
Overdosage of Rho(D) immune globulin has been associated with hematologic effects including hemoglobin decreases in excess of 1.2 g/dL in Rho(D)-positive patients with idiopathic thrombocytopenic purpura (ITP), hemolytic reactions, intravascular hemolysis, and death.1
If an overdosage of Rho(D) immune globulin occurs in an Rho(D)-negative patient being treated for an incompatible blood transfusion, the patient should be monitored using clinical and biologic parameters because of the risk of hemolytic anemia.16, 25 If an overdosage occurs in other Rho(D)-negative individuals receiving Rho(D) immune globulin for suppression of Rh isoimmunization, the frequency and severity of adverse effects probably would be similar to effects reported with normal dosage.16
Suppression of Rh Isoimmunization
Rho(D) immune globulin contains anti-Rho(D) antibody to the red blood cell (RBC) antigen Rho(D) and is used to suppress the active antibody response and formation of anti-Rho(D) in Rho(D)-negative women exposed to Rho(D)-positive blood as the result of a pregnancy involving an Rho(D)-positive fetus or transfusion with Rho(D)-positive blood.1, 14, 15, 16 Exposure to Rho(D)-positive blood can occur in Rho(D)-negative pregnant women as a result of fetal-maternal hemorrhage during delivery of an Rho(D)-positive infant or during other obstetric complications or procedures (e.g., spontaneous or induced abortion, amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, ruptured tubal pregnancy, transplacental hemorrhage, other abdominal trauma) when the fetus or products of conception are Rho(D) positive.1, 14, 15, 16 The exact mechanism of action of Rho(D) immune globulin in the suppression of formation of anti-Rho(D) is not fully known.1, 14, 15, 16, 25 Anti-Rho(D) antibody contained in Rho(D) immune globulin may bind to Rho(D) antigen that enters the circulation during fetal-maternal hemorrhage or blood transfusion, and thereby prevent stimulation of the primary immune response to Rho(D) and subsequent active production of anti-Rho(D).
Exposure of an Rho(D)-negative mother to Rho(D)-positive RBCs occurs most frequently during delivery in the third stage of labor when fetal RBCs enter the maternal circulation. However, fetal-maternal hemorrhage has been noted as early as the second trimester of pregnancy and may increase in extent and frequency as gestation proceeds. The risk of formation of anti-Rho(D) reportedly is higher in women undergoing induced abortions than in those who have spontaneous abortions.15
Idiopathic Thrombocytopenic Purpura
The mechanism by which Rho(D) immune globulin increases platelet counts in the treatment of idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura) has not been fully elucidated.1, 2, 3, 7, 20, 21 Administration of Rho(D) immune globulin to Rho(D)-positive individuals results in the formation of anti-Rho(D)-coated RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen.1, 25 This results in Fc receptor blockade and decreased Fc-mediated phagocytosis of antibody-coated platelets.1, 2, 3, 4, 7, 20, 21, 25 Other immunomodulating effects also may be involved.2, 4, 20, 21 Following initiation of Rho(D) immune globulin therapy, platelet counts usually increase within 1-2 days and peak within 7-14 days.1, 2 The duration of platelet response typically is about 3-4 weeks.25, 34 Rarely, the increase in platelet counts may last 6 months or longer.3, 4
Following IM or IV administration of a dose of 600 units (120 mcg) of Rho(D) immune globulin as WinRho® SDF in a limited number of Rho(D)-negative individuals, peak plasma concentrations of 18-19 ng/mL were attained 5-10 days after the IM dose and peak plasma concentrations of 36-48 ng/mL were attained within 2 hours after the IV dose.1 The calculated area under the concentration-time curve (AUC) was the same for both routes of administration.1 Passively acquired anti-Rho(D) antibodies are detectable in the circulation of pregnant women for no longer than 6 weeks following a dose of 600 units (120 mcg) of WinRho® SDF.1
Following IM or IV administration of a dose of 1500 units (300 mcg) of Rho(D) immune globulin as Rhophylac® in Rho(D)-negative pregnant women at week 28 of gestation, peak serum concentrations ranged from 7-46 ng/mL and were attained 2-7 days after the IM dose or ranged from 62-84 ng/mL and were attained 1 day after the IV dose.25 The absolute bioavailability of the IM dose was 69%.25 Regardless of route, Rho(D) immune globulin titers were detected in all women up to at least 9 weeks following the dose.25 Pharmacokinetic studies have not been performed with Rhophylac® in Rho(D)-positive patients with idiopathic thrombocytopenic purpura (ITP; also known as immune thrombocytopenic purpura).25
Following IM injection of a single dose of 1840 units (368 mcg) of Rho(D) immune globulin as RhoGAM® in Rho(D)-negative individuals, a mean peak plasma concentration of 54 ng/mL was obtained within approximately 4 days.16
In Rho(D)-negative individuals who received WinRho® SDF, the half-life of anti-Rho(D) was about 30 days following IM administration and about 24 days following IV administration.1 In pregnant Rho(D)-negative women who received Rhophylac®, the half-life was 18 days following IM administration and 16 days following IV administration.25 In Rho(D)-negative individuals who received RhoGAM®, the half-life was 30.9 days following IM administration.16
Rho(D) immune globulin is prepared from human plasma containing anti-Rho(D) antibody to the red blood cell (RBC) antigen Rho(D).23 Commercially available Rho(D) immune globulin meets standards established by the Center for Biologics Evaluation and Research of the US Food and Drug Administration (FDA).23 Rho(D) immune globulin for IM administration is prepared by cold alcohol fractionization of pooled human plasma.14, 15, 16 Rho(D) immune globulin for IV or IM administration is prepared from pooled human plasma using an anion-exchange column chromatography method.1, 25 Plasma donors have been screened and tested for prior exposure or present infection with certain viruses (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], human immunodeficiency virus [HIV]).1, 14, 15, 16, 25 In addition, the manufacturing processes used for Rho(D) immune globulin include certain chemical (solvent/detergent) treatment procedures and purification steps (e.g., viral filtration) that decrease the risk of transmission of viral infection.1, 14, 15, 16, 25 However, no method has been shown to be totally effective in removing the risk of viral infectivity from plasma-derived preparations.1, 14, 15, 16, 25
Potency of Rho(D) immune globulin is expressed in terms of international units (IU, units) by comparison with the US, WHO, and European Pharmacopoeia Anti-D Reference Standard.1, 16, 25 Potency and dosage previously were expressed in mcg, with 1 mcg equivalent to 5 units.1
Rho(D) immune globulin for IM administration contains 10-18% protein, of which not less than 90% is immunoglobulin G (gamma globulin, IgG).23
HyperRHO® S/D Mini-Dose and HyperRHO® S/D Full Dose are sterile, colorless to pale yellow or pink solutions for IM administration; the solutions contain 15-18% protein stabilized with 0.21-0.32 M glycine and have a pH of 6.4-7.2.14, 15 The manufacturing process for HyperRHO® includes a chemical (solvent/detergent) inactivation procedure and precipitation, filtration, and ultrafiltration and diafiltration purification steps to decrease the risk of transmission of viruses and other infectious agents (i.e., causative agents of Creutzfeldt-Jakob disease [CJD] and variant Creutzfeldt-Jakob [vCJD] disease).14, 15 HyperRHO® S/D Mini-Dose and HyperRHO® S/D Full Dose do not contain thimerosal or any other preservatives.14, 15
HyperRHO® S/D Full Dose is commercially available in single-dose prefilled syringes that contain 1500 units (300 mcg) of Rho(D) immune globulin; each prefilled syringe contains enough anti-Rho(D) to suppress the immunization potential of 15 mL of Rho(D)-positive packed RBCs.14 HyperRHO® S/D Mini-Dose is commercially available in single-dose prefilled syringes that contain 250 units (50 mcg) of Rho(D) immune globulin; each prefilled syringe contains enough anti-Rho(D) to suppress the immunization potential of 2.5 mL of Rho(D)-positive packed RBCs or the equivalent (5 mL) of whole blood.15
MICRhoGAM® and RhoGAM® are sterile solutions for IM administration that contain approximately 5% IgG, 0.29% sodium chloride, 0.01% polysorbate 80, 15 mg/mL of glycine, and small amounts of immunoglobulin A (IgA) (i.e., less than 15 mcg per dose).16 The manufacturing process for MICRhoGAM® and RhoGAM® includes a chemical (solvent/detergent) procedure and a virus filtration step designed to reduce the risk of transmission of enveloped and nonenveloped viruses.16 MICRhoGAM® and RhoGAM® do not contain human albumin, thimerosal, or any other preservatives.16
RhoGAM® is commercially available in single-dose prefilled syringes that contain 1500 units (300 mcg) of Rho(D) immune globulin; each prefilled syringe contains enough anti-Rho(D) to suppress the immunization potential of up to 15 mL of Rho(D)-positive RBCs.16 MICRhoGAM® is commercially available in single-dose prefilled syringes that contain 250 units (50 mcg) of Rho(D) immune globulin; each prefilled syringe contains enough anti-Rho(D) to suppress the immunization potential of up to 2.5 mL of Rho(D)-positive RBCs.16
Rhophylac® is a clear or slightly opalescent, colorless to pale yellow solution for IV or IM administration.25 The solution contains a maximum of 30 mg/mL of human plasma proteins of which 10 mg/mL is human albumin (added as a stabilizer); the purity of the solution is more than 95% IgG prior to the addition of albumin.25 Rhophylac® contains less than 5 mcg/mL of IgA, 20 mg/mL of glycine, and up to 0.25 M sodium chloride.25 Rhophylac® does not contain thimerosal or any other preservatives.25 The manufacturing process for Rhophylac® includes a chemical (solvent/detergent) procedure and a filtration step designed to reduce the risk of transmission of enveloped and nonenveloped viruses.25
Rhophylac® is commercially available in single-dose prefilled syringes that contain 1500 units (300 mcg) of Rho(D) immune globulin.25 Each prefilled syringe contains enough anti-Rho(D) to suppress the immunization potential of at least 15 mL of Rho(D)-positive RBCs.25
WinRho® SDF is a sterile solution of IgG fraction containing antibodies to Rho(D) for IV or IM administration.1 WinRho® SDF contains approximately 5 mcg/mL of IgA.1 WinRho® SDF is stabilized with 10% maltose and 0.03% polysorbate 80, but does not contain thimerosal or any other preservative.1 The manufacturing process for WinRho® SDF includes a chemical (solvent/detergent) procedure and a filtration step designed to reduce the risk of transmission of enveloped and nonenveloped viruses.1 An anion-exchange chromatography step is employed to further remove small non-lipid-enveloped viruses.1
WinRho® SDF is commercially available as single-dose vials labeled as containing 600 units (120 mcg), 1500 units (300 mcg), 2500 units (500 mcg), 5000 units (1000 mcg), or 15,000 units (3000 mcg) of Rho(D) immune globulin.1 Vials labeled as containing 1500 units (300 mcg) contain enough anti-Rho(D) to suppress the immunization potential of approximately 17 mL of Rho(D)-positive RBCs.1
Commercially available Rho(D) immune globulin solutions in prefilled syringes or single-dose vials should be refrigerated at 2-8°C and should not be frozen.1, 14, 15, 16, 25
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
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) | |
MICRhoGAM® Ultra-Filtered PLUS (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes) | ||||
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) | ||
1500 units (300 mcg) | Rhophylac® (solvent/detergent-inactivated and virus filtered; available in single-dose prefilled syringes) | |||
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® Drug Information. © Copyright, 1959-2025, Selected Revisions April 30, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
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