RH(D) IMMUNOGLOBULIN
DESCRIPTION:
Rho(D) Immune Globulin (Human)--Rhogam Full Dose treated with
solvent/detergent is a sterile solution of immune globulin containing antibodies
to Rho(D) for intramuscular administration; it contains no preservative. BayRho-
D Full Dose is prepared by cold ethanol fractionation from human plasma. The
immune globulin is isolated from solubilized Cohn Fraction II. The fraction II
solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate
(TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and
detergent (sodium cholate), the solution is heated to 30 deg C and maintained at
the temperature for not less than 6 hours. After the viral inactivation step,
the reactants are removed by precipitation, filtration and finally
ultrafiltration and diafiltration. Rhogam Full Dose is formulated as a 15-18%
protein solution at a pH of 6.4-7.2 in 0.21-0.32 M glycine. Bay- Rho-D Full Dose
is then incubated in the final container for 21-28 days at 20-27 deg C.
The potency is equal to or greater than that of the U.S. Food and Drug
Administration Reference Rho(D) Immune Globulin. Each single dose vial or
syringe contains sufficient anti-Rho(D) (approximately 300 mcgm*) to effectively
suppress the immunizing potential of 15 mL of Rho(D) positive red blood cells.
(REF. 2-4)
The removal and inactivation of spiked model enveloped and non-enveloped viruses
during the manufacturing process for Rhogam Full Dose has been validated in
laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as
the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was
chosen to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model
Hepatitis B virus and the Herpes viruses; and Reo virus type 3 (Reo) was chosen
to model non-enveloped viruses and for its resistance to physical and chemical
inactivation. Significant removal of model enveloped and non- enveloped viruses
is achieved at two steps in the Cohn fractionation process leading to the
collection of Cohn Fraction II: the precipitation and removal of Fraction III in
the processing of Fraction II + IIIW suspension to Effluent III and the
filtration step in the processing of Effluent III to Filtrate III. Significant
inactivation of enveloped viruses is achieved at the time of treatment of
solubilized Cohn Fraction II with TNBP/sodium cholate.
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*A full dose of Rho(D) Immune Globulin (Human), has traditionally been referred
to as a "300 mcgm" dose and this usage is employed here for convenience in
terminology. IT SHOULD NOT BE CONSTRUED AS THE ACTUAL ANTI-D CONTENT. Each full
dose of Rho(D) Immune Globulin (Human), must contain at least as much anti-D as
1 mL of the U.S. Reference Rho(D) Immune Globulin. Studies performed at the FDA
have shown that the U.S. Reference contains 820 international units (IU) of
anti-D per mL. When the conversion factor determined for the International (WHO)
Reference Preparation (REF. 1) is used, 820 IU per mL is equivalent to 164 mcgm
per mL of anti-D.
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ACTIONS/CLINICAL PHARMACOLOGY:
Rhogam Full Dose is used to prevent isoimmunization in the Rho(D) negative
individual exposed to Rho(D) positive blood as a result of a fetomaternal
hemorrhage occurring during a delivery of an Rho(D) positive infant, abortion
(either spontaneous or induced), or following amniocentesis or abdominal trauma.
Similarly, immunization resulting in the production of anti- Rho(D) following
transfusion of Rh positive red cells to an Rho(D) negative recipient may be
prevented by administering Rho(D) Immune Globulin (Human) (REF.5-6)
Rh hemolytic disease of the newborn is the result of the active immunization of
an Rho(D) negative mother by Rho(D) positive red cells entering the maternal
circulation during a previous delivery, abortion, amniocentesis, abdominal
trauma, or as a result of red cell transfusion. (REF. 7,8) Rhogam Full Dose
acts by suppressing the immune response of Rho(D) negative individuals to Rho(D)
positive red blood cells. The mechanism of action of Rhogam Full Dose is not
fully understood.
The administration of Rho(D) Immune Globulin Human), within 72 hours of a full-
term delivery of an Rho(D) positive infant by an Rho(D) negative mother reduces
the incidence of Rh isoimmunization from 12%-13% to 1%-2% (REF. 9). The 1%-2%
treatment failures are probably due to isoimmunization occurring during the
latter part of pregnancy or following delivery. (REF. 10) Bowman and Pollock
(REF. 11) have reported that the incidence of isoimmunization can be further
reduced from approximately 1.6% to less than 0.1% by administering Rho(D) Immune
Globulin (Human), in two doses, one antenatal at 28 weeks' gestation and another
following delivery.
CLINICAL STUDIES:
In a clinical study in eight healthy human adults receiving another hyperimmune
immune globulin product treated with solvent/detergent, Rabies Immune Globulin
(human), Bay-Rab(TM), prepared by the same manufacturing process, detectable
passive antibody titers were observed in the serum of all subjects by 24 hours
post injection and persisted through the 21 day study period. These results
suggest that passive immunization with immune globulin products is not affected
by the solvent/detergent treatment.
INDICATIONS AND USAGE:
PREGNANCY AND OTHER OBSTETRIC CONDITIONS
Rho(D) Immune Globulin (Human), Rhogam Full Dose is recommended for the
prevention of Rh hemolytic disease of the newborn by its administration to the
Rho(D) negative mother within 72 hours after birth of an Rho(D) positive
infant,(REF. 12) providing the following criteria are met:
1. The mother must be Rho(D) negative, and must not already be sensitized to the
Rho(D) factor.
2. Her child must be Rho(D) positive, and should have a negative direct
antiglobulin test (see PRECAUTIONS).
If Rhogam Full Dose is administered antepartum, it is essential that the
mother receive another dose of Rhogam Full Dose after delivery of an Rho(D)
positive infant.
If the father can be determined to be Rho(D) negative, Rhogam Full Dose need
not be given.
Rhogam Full Dose should be administered within 72 hours to all nonimmunized
Rho(D) negative women who have underdone spontaneous or induced abortion,
following ruptured tubal pregnancy, amniocentesis or abdominal trauma unless the
blood group of the fetus or the father is known to be Rho(D) negative. (REF.
7,8) If the fetal blood group cannot be determined, one must assume that it is
Rho(D) positive, (REF. 2) and Rhogam Full Dose should be administered to the
mother.
TRANSFUSION
Rhogam Full Dose may be used to prevent isoimmunization in Rho(D) negative
individuals who have been transfused with Rho(D) positive red blood cells or
blood components containing red blood cells. (REF. 5,13)
CONTRAINDICATIONS:
None known.
WARNINGS:
NEVER ADMINISTER RHOGAM FULL DOSE INTRAVENOUSLY. INJECT ONLY INTRAMUSCULARLY.
NEVER ADMINISTER TO THE NEONATE.
Rho(D) Immune Globulin (Human), should be given with caution to patients with a
history of prior systemic allergic reactions following the administration of
human immunoglobulin preparations.
The attending physician who wishes to administer Rho(D) Immune Globulin (Human),
to persons with isolated immunoglobulin A (IgA) deficiency must weigh the
benefits of immunization against the potential risks of hypersensitivity
reactions. Such persons have increased potential for developing antibodies to
IgA and could have anaphylactic reactions to subsequent administration of blood
products that contain IgA.
As with all preparations administered by the intramuscular route, bleeding
complications may be encountered in patients with thrombocytopenia or other
bleeding disorders.
PRECAUTIONS:
GENERAL
A large fetomaternal hemorrhage late in pregnancy or following delivery may
cause a weak mixed field positive Du test result. If there is any doubt about
the mother's Rh type, she should be given RHo(D) Immune Globulin (Human). A
screening test to detect fetal red blood cells may be helpful in such cases.
If more than 15 mL of D-positive fetal red blood cells are present in the
mother's circulation, more than a single dose of Rho(D) Immune Globulin (Human),
Rhogam Full Dose is required. Failure to recognize this may result in the
administration of an inadequate dose.
Although systemic reactions to human immunoglobulin preparations are rare,
epinephrine should be available for treatment of acute anaphylactic reactions.
DRUG INTERACTIONS
Other antibodies in the Rho(D) Immune Globulin (Human), preparation may
interfere with the response to live vaccines such as measles, mumps, polio or
rubella. Therefore, immunization with live vaccines should not be given within 3
months after Rho(D) Immune Globulin (Human), administration.
DRUG/LABORATORY INTERACTIONS
Babies born of women given Rho(D) Immune Globulin (Human), antepartum may have a
weakly positive direct antiglobulin test at birth.
Passively acquired anti-Rho(D) may be detected in maternal serum if antibody
screening tests are performed subsequent to antepartum or postpartum
administration of Rho(D) Immune Globulin (Human).
PREGNANCY CATEGORY C
Animal reproduction studies have not been conducted with Rhogam Full Dose. It
is also not known whether Rhogam Full Dose can cause fetal harm when
administered to a pregnant woman or can affect reproduction capacity. Rhogam
Full Dose should be given to a pregnant woman only if clearly needed.
PEDIATRIC USE
Safety and effectiveness in the pediatric population have not been established.
DRUG INTERACTIONS:
Other antibodies in the Rho(D) Immune Globulin (Human), preparation may
interfere with the response to live vaccines such as measles, mumps, polio or
rubella. Therefore, immunization with live vaccines should not be given within 3
months after Rho(D) Immune Globulin (Human), administration.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
Reactions to Rho(D) Immune Globulin (Human), are infrequent in Rho(D) negative
individuals and consist primarily of slight soreness at the site of injection
and slight temperature elevation. While sensitization to repeated injections of
human immune globulin is extremely rare, it has occurred. Elevated bilirubin
levels have been reported in some individuals receiving multiple doses of Rho(D)
Immune Globulin (Human), following mismatched transfusions. This is believed to
be due to a relatively rapid rate of foreign red cell destruction.
DOSAGE AND ADMINISTRATION:
NEVER ADMINISTER RHOGAM FULL DOSE INTRAVENOUSLY. INJECT ONLY INTRAMUSCULARLY.
NEVER ADMINISTER TO THE NEONATE.
PREGNANCY AND OTHER OBSTETRIC CONDITIONS
1. For postpartum prophylaxis, administer one vial or syringe of Rhogam Full
Dose (300 mcgm*), preferably within 72 hours of delivery. Although a lesser
degree of protection is afforded if Rh antibody is administered beyond the 72-
hour period, Rhogam Full Dose may still be given. (REF. 7,14) Full-term
deliveries can vary in their dosage requirements depending on the magnitude of
the fetomaternal hemorrhage. One 300 mcgm* vial or syringe of Rhogam Full Dose
provides sufficient antibody to prevent Rh sensitization if the volume of red
blood cells that has entered the circulation is 15 mL or less. (REF. 2-4) In
instances where a large (greater than 30 mL of whole blood or 15 mL red blood
cells) fetomaternal hemorrhage is suspected, a fetal red cell count by an
approved laboratory technique (e.g., modified Kleihauer- Betke acid elution
stain technique) should be performed to determine the dosage of immune globulin
required. (REF. 8,15) The red blood cell volume of the calculated fetomaternal
hemorrhage is divided by 15 mL to obtain the number of vials or syringes of
Rho(D) Immune Globulin (Human), Rhogam Full Dose for administration. (REF.
3,8,13) If more than 15 mL of red cells is suspected or if the dose calculation
results in a fraction, administer the next higher whole number of vials or
syringes (e.g., if 1.4, give 2 vials or syringes).
2. For antenatal prophylaxis, one 300 mcgm* vial or syringe of Rhogam Full
Dose is administered at approximately 28 weeks gestation. This MUST be followed
by another 300 mcgm* dose, preferably within 72 hours following delivery, if the
infant is Rh positive.
3. Following threatened abortion at any stage of gestation with continuation of
pregnancy, it is recommended that 300 mcgm* of Rhogam Full Dose be given. If
more than 15 mL of red cells is suspected due to fetomaternal hemorrhage, the
same dose modification in No. 1 above applies.
4. Following miscarriage, abortion, or termination of ectopic pregnancy at or
beyond 13 weeks' gestation, it is recommended that 300 mcgm* of Rhogam Full
Dose be given. If more than 15 mL of red blood cells is suspected due to
fetomaternal hemorrhage, the same dose modification in No. 1 above applies. If
pregnancy is terminated prior to 13 weeks' gestation, a single dose of Rhogam
Mini-Dose (approximately 50 mcgm*) may be used instead of Rhogam Full Dose.
5. Following amniocentesis at either 15 to 18 weeks' gestation or during the
third trimester, or following abdominal trauma in the second or third trimester,
it is recommended that 300 mcgm* of Rhogam Full Dose be administered. If there
is a fetomaternal hemorrhage in excess of 15 mL of red cells, the same dose
modification in No. 1 applies.
If abdominal trauma, amniocentesis, or other adverse event requires the
administration of Rhogam Full Dose at 13 to 18 weeks' gestation, another 300
mcgm* dose should be given at 26 to 28 weeks. To maintain protection throughout
pregnancy, the level of passively acquired anti- Rho(D) should not be allowed to
fall below the level required to prevent an immune response to Rh positive red
cells. The half-life of lgG is 23 to 26 days. In any case, a dose of Rhogam
Full Dose should be given within 72 hours after delivery if the baby is Rh
positive. If delivery occurs within three weeks after the last dose, the
postpartum dose may be withheld unless there is a fetomaternal hemorrhage in
excess of 15 mL of red blood cells. (REF. 16)
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*A full dose of Rho(D) Immune Globulin (Human), has traditionally been referred
to as a "300 mcgm" dose and this usage is employed here for convenience in
terminology. IT SHOULD NOT BE CONSTRUED AS THE ACTUAL ANTI-D CONTENT. Each full
dose of Rho(D) Immune Globulin (Human), must contain at least as much anti-D as
1 mL of the U.S. Reference Rho(D) Immune Globulin. Studies performed at the FDA
have shown that the U.S. Reference contains 820 international units (IU) of
anti-D per mL. When the conversion factor determined for the International (WHO)
Reference Preparation (REF. 1) is used, 820 IU per mL is equivalent to 164 mcgm
per mL of anti-D.
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TRANSFUSION
In the case of a transfusion of Rho(D) positive red cells to an Rho(D) negative
recipient, the volume of Rh positive whole blood administered is multiplied by
the hematocrit of the donor unit giving the volume of red blood cells
transfused. The volume of red blood cells is divided by 15 mL which provides the
number of vials or syringes of Rhogam Full Dose to be administered.
If the dose calculated results in a fraction, the next higher whole number of
vials or syringes should be administered (e.g., if 1.4, give 2 vials or 2
syringes). Rhogam Full Dose should be administered within 72 hours after an
incompatible transfusion, but preferably as soon as possible.
INJECTION PROCEDURE
DO NOT INJECT INTRAVENOUSLY. DO NOT INJECT NEONATE. Rho(D) Immune Globulin
(Human), BayRho- D(TM) Full Dose is administered INTRAMUSCULARLY, preferably in
the anterolateral aspects of the upper thigh and the deltoid muscle of the upper
arm. The gluteal region should not be used routinely as an injection site
because of the risk of injury to the sciatic nerve. If the gluteal region is
used, the central region MUST be avoided; only the upper, outer quadrant should
be used. (REF.17)
A. Single Vial or Syringe Dose
INJECT ENTIRE CONTENTS OF THE VIAL OR SYRINGE INTO THE INDIVIDUAL
INTRAMUSCULARLY.
B. Multiple Vial or Syringe Dose
1. Calculate the number of vials or syringes of Rhogam Full Dose to be given
(See Dosage section above).
2. The total volume of Rhogam Full Dose can be given in divided doses at
different sites at one time or the total dose may be divided and injected at
intervals, provided the total dosage is given within 72 hours of the
fetomaternal hemorrhage or transfusion. USING STERILE TECHNIQUE, INJECT THE
ENTIRE CONTENTS OF THE CALCULATED NUMBER OF VIALS OR SYRINGES INTRAMUSCULARLY
INTO THE PATIENT.
Parenteral drug products should be inspected visually for particulate matter and
discoloration prior to administration, whenever solution and container permit.