RhoGAM Ultra-Filtered Plus

Name: RhoGAM Ultra-Filtered Plus

Description

RhoGAM and MICRhoGAM Rho(D) Immune Globulin (Human) are sterile solutions containing immunoglobulin G (IgG) anti-D (anti-Rh) for use in preventing Rh immunization. They are manufactured from human plasma containing anti-D. A single dose of RhoGAM contains sufficient anti-D (300 µg or 1500 IU) to suppress the immune response to up to 15 mL of Rh-positive red blood cells.4,15 A single dose of MICRhoGAM contains sufficient anti-D (50 µg or 250 IU) to suppress the immune response to up to 2.5 mL of Rh-positive red blood cells. The anti-D dose is measured by comparison to the RhoGAM in-house reference standard, the potency of which is established relative to the U.S./World Health Organization/European Pharmacopoeia Standard Anti-D Immunoglobulin Rho(D) Immune Globulin (Human) CBER Lot 4: NIBSC Lot 01/572 (285 IU/ampoule).16

Plasma for RhoGAM is typically sourced from a donor center owned and operated by Ortho-Clinical Diagnostics. All donors are carefully screened by history and laboratory testing to reduce the risk of transmitting blood-borne pathogens from infected donors. Each plasma donation is tested and found to be non-reactive for the presence of hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C (HCV) and human immunodeficiency viruses (HIV) 1 and 2. Additionally, plasma is tested by FDA licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and the results must be negative. Plasma is also tested by investigational NAT for hepatitis B (HBV) and must be non-reactive. However, the significance of a negative result has not been established. Plasma is tested by NAT for hepatitis A virus and parvovirus B19.

Fractionation of the plasma is performed by a modification of the cold alcohol procedure that has been shown to significantly lower viral titers.10 Following plasma fractionation, a viral clearance filtration step and a viral inactivation step are performed. The viral filtration step removes viruses via a size-exclusion mechanism utilizing a patented Viresolve 180 ultrafiltration membrane with defined pore-size distribution of 12-18 nanometers to remove enveloped and non-enveloped viruses. Following viral filtration, quality control tests (CorrTest and diffusion test) are performed on the Viresolve 180 ultrafiltration membrane to insure filter integrity.17 The viral inactivation step utilizes Triton X-100 and tri-n-butyl phosphate (TNBP) to inactivate enveloped viruses such as HCV, HIV and West Nile Virus (WNV)10,18 (Patent Pending).

The donor selection process, the fractionation process, the viral filtration step and the viral inactivation process increase product safety by reducing the risk of transmission of enveloped and non-enveloped viruses. Rho(D) Immune Globulin (Human) intended for intramuscular use and prepared by cold alcohol fractionation has not been shown to transmit hepatitis or other infectious diseases.19 There have been no documented cases of infectious disease transmission by RhoGAM or MICRhoGAM.

Laboratory spiking studies10,20 have shown that the cumulative viral removal and inactivation capability of the RhoGAM / MICRhoGAM manufacturing process is as follows:

Virus HIV BVDV PRV PPV EMC WNV HAV
Lipid Enveloped Yes Yes Yes No No Yes No
Size (nm) 80-120 40-70 120-200 18-24 25-30 40-60 27-32
Genome SS-RNA SS-RNA DS-DNA SS-DNA SS-RNA SS-RNA SS-RNA
Fractionation > 7.98 7.29 > 11.74 8.30 ND ND ND
Viral Filtration > 5.60 5.40 > 6.20 3.30 4.16 ND > 5.07
Viral Inactivation > 4.28 > 4.90 > 5.58 N/A N/A > 7.05 N/A
Total Viral Reduction > 17.86 > 17.59 > 23.52 11.60 4.16 > 7.05 > 5.07
Units = log10 reduction
HIV       Human Immunodeficiency Virus, Model for HIV-1 and 2 and Human T-cell Lymphotropic Virus (HTLV) 1 and 2
BVDV    Bovine Viral Diarrhea Virus, Model for Hepatitis C Virus
PRV      Pseudorabies Virus, Model for Herpes Viruses
PPV      Porcine Parvovirus, Model for Parvovirus B19
EMC     Encephalomyocarditis Virus, Model for Hepatitis A Virus
WNV     West Nile Virus
HAV      Hepatitis A Virus
ND        Not Determined
N/A       Not Applicable

The safety of Rho(D) Immune Globulin (Human) has been further shown in an empirical study of viral marker rates in female blood donors in the United States.21 This study revealed that Rh-negative donors, of whom an estimated 55-60% had received Rho(D) Immune Globulin (Human) for pregnancy-related indications, had prevalence and incidence viral marker rates similar to those of Rh-positive female donors who had not received Rho(D) Immune Globulin (Human).

The final product contains 5 ± 1% IgG, 2.9 mg/mL sodium chloride, 0.01% Polysorbate 80 (non-animal derived) and 15 mg/mL glycine. Small amounts of IgA, typically less than > 15 µg per dose, are present.10 The pH range is 6.20 - 6.55 and IgG purity is 98%. The product contains no added human serum albumin (HSA), no thimerosal or other preservatives and utilizes a latex-free delivery system.

REFERENCES

4  Pollack W, Ascari WQ, Crispen JF, O'Connor RR, Ho TY. Studies on Rh prophylaxis. II. Rh immune prophylaxis after transfusion with Rh-positive blood. Transfusion 1971;11:340-44.

15  Pollack W, Ascari WQ, Kochesky RJ, O'Connor RR, Ho T Y, Tripodi D. Studies on Rh prophylaxis. I. Relationship between doses of anti-Rh and size of antigenic stimulus. Transfusion 1971;11:333-39.

16  Thorpe SJ, Sands D, Fox B, Behr-Gross ME, Schaffner G, Yu MW. A global standard for anti-D immunoglobulin: international collaborative study to evaluate a candidate preparation. Vox Sang 2003;85:313-21.

17  Phillips MW, DiLeo AJ. A Validatible Porosimetric Technique for verifying the integrity of virus-retentive membranes. Biologicals 1996;24:243-53.

18  Horowitz B, Wiebe ME, Lippin A, Stryker MH. Inactivation of viruses in labile blood derivatives. I. Disruption of lipid-enveloped viruses by tri (n-butyl) phosphate detergent combinations. Transfusion 1985; 25(6):516-22.

19  Tabor E. The epidemiology of virus transmission by plasma derivatives: clinical studies verifying the lack of transmission of hepatitis B and C viruses and HIV type 1. Transfusion 1999;39:1160-68.

20  Van Holten RW, Ciavarella D, Oulundsen G, Harmon F, Riester S. Incorporation of an additional viral-clearance step into a human immunoglobulin manufacturing process. Vox Sang 2002;83:227-33.

21  Watanabe KK, Busch MP, Schreiber GB, Zuck TF. Evaluation of the safety of Rh Immunoglobulin by monitoring viral markers among Rh-negative female blood donors. Vox Sang 2000;8:1-6.

22  Crispen J. Immunosuppression of small quantities of Rh-positive blood with MICRhoGAM in Rh-negative male volunteers. In: Proceedings of a symposium on Rh antibody mediated immunosuppression. Raritan, NJ: Ortho Research Institute of Medical Sciences, 1975:51-54.

23  Bowman JM, Chown B, Lewis M, Pollock JM. Rh isoimmunization during pregnancy: antenatal prophylaxis. Can Med Assoc J 1978;118:623-27.

24  Bowman JM, Pollock JM. Antenatal prophylaxis of Rh isoimmunization: 28-weeks' gestation service program. Can Med Assoc J 1978;118:627-30.

25  Stewart FH, Burnhill MS, Bozorgi N. Reduced dose of Rh immunoglobulin following first trimester pregnancy termination. Obstet Gynecol 1978;51:318-22.

26  Pollack W, Gorman JG, Freda VJ, Ascari WQ, Allen AE, Baker WJ. Results of clinical trials of RhoGAM in women. Transfusion 1968;8:151-53.

27  Freda VJ, Gorman JG, Pollack W, Bowe E. Prevention of Rh hemolytic disease - ten years' clinical experience with Rh immune globulin. New Engl J Med 1975; 292:1014-16.

How supplied

Dosage Forms and Strength

  • RhoGAM® Ultra-Filtered PLUS (rho(d) immune globulin (human)) - 300 µg (1500 IU)* - Prefilled Syringes
  • MICRhoGAM® Ultra-Filtered PLUS (rho(d) immune globulin (human)) - 50 µg (250 IU)* - Prefilled Syringes

*The anti-D content of RhoGAM / MICRhoGAM is expressed as µg per dose or as International Units (IU) per dose. The conversion factor is 1 µg = 5 IU.8

Storage and Handling

RhoGAM Ultra-Filtered PLUS (rho(d) immune globulin (human)) package sizes:

  • 1 prefilled single-dose syringe of RhoGAM (Product Code 780501) NDC 0562-7805-01 1 package insert, 1 control form, 1 patient identification card
  • 5 prefilled single-dose syringes of RhoGAM (Product Code 780505) NDC 0562-7805-05 5 package inserts, 5 control forms, 5 patient identification cards
  • 25 prefilled single-dose syringes of RhoGAM (Product Code 780525) NDC 0562-7805-25 25 package inserts, 25 control forms, 25 patient identification cards

MICRhoGAM Ultra-Filtered PLUS (rho(d) immune globulin (human)) package sizes:

  • 1 prefilled single-dose syringe of MICRhoGAM (Product Code 780601) NDC 0562-7806-01 1 package insert, 1 control form, 1 patient identification card
  • 5 prefilled single-dose syringes of MICRhoGAM (Product Code 780605) NDC 0562-7806-05 5 package inserts, 5 control forms, 5 patient identification cards
  • 25 prefilled single-dose syringes of MICRhoGAM (Product Code 780625) NDC 0562-7806-25 25 package inserts, 25 control forms, 25 patient identification cards

Store at 2 to 8°C. Do not store frozen. Do not use after the expiration date printed the syringe.

REFERENCES

1  Samson D, Mollison PL. Effect on primary Rh immunization of delayed administration of anti-Rh. Immunol 1975;28:349-57.

2  Garratty G, ed. Hemolytic disease of the newborn. Arlington, VA: American Association of Blood Banks, 1984:78.

3  Urbaniak SJ. Statement from the Consensus Conference on Anti-D Prophylaxis, The Royal College of Physicians of Edinburgh & The Royal College of Obstetricians and Gynaecologists, UK. Vox Sang 1998;74:127-28.

4  Pollack W, Ascari WQ, Crispen JF, O'Connor RR, Ho TY. Studies on Rh prophylaxis. II. Rh immune prophylaxis after transfusion with Rh-positive blood. Transfusion 1971;11:340-44.

5  Bayliss KM, Kueck DB, Johnson ST, Fueger JT, McFadden PW, Mikulski D, Gottschall JL. Detecting fetomaternal hemorrhage: a comparison of five methods. Transfusion 1991;31:303-7.

6  Kumpel BM. Quantification of anti-D and fetomaternal hemorrhage by flow cytometry (editorial). Transfusion 2000;40:6-9.

7  AABB Technical Manual. 15th ed. Bethesda, Maryland: AABB, 2005.

8  Gunson HH, Bowell PJ, Kirkwood TBL. Collaborative study to recalibrate the International Reference Preparation of anti-D immunoglobulin. J Clin Pathol 1980;33:249-53.

Ortho-Clinical Diagnostics,Inc. A Johnson & Johnson company, Raritan, New Jersey 08869. Issued March 2007. FDA rev date: n/a

Warnings

  • For intramuscular use only, do not inject intravenously.
  • In the case of postpartum use, the product is intended for maternal administration.
  • Do not inject the newborn infant.
  • Patients should be observed for at least 20 minutes after administration.
  • Administer with caution to patients who have had prior severe systemic allergic reactions to human immune globulin.
  • RhoGAM / MICRhoGAM contain a small quantity of IgA. There is a potential risk of hypersensitivity in IgA deficient individuals.
  • Patients treated for Rh-incompatible transfusion should be monitored by clinical and laboratory means for signs and symptoms of a hemolytic reaction.
  • Store at 2 to 8°C. Do not store frozen.
  • Do not use after the expiration date printed on the syringe.

Use of Plasma Derived Products

RhoGAM and MICRhoGAM are made from human plasma and may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing plasma for the presence of certain current virus infections and by using pathogen removal and inactivation techniques during the manufacturing process. All of the above steps are designed to increase product safety by reducing the risk of pathogen transmission. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. All infections thought by a physician possibly to have been transmitted by these products should be reported by the physician or other healthcare provider in the United States to Ortho-Clinical Diagnostics, Inc. at 1-800-421-3311. Outside the United States, the company distributing these products should be contacted. The physician should discuss the risks and benefits of these products with the patient.

What is rho (d) immune globulin (hyperrho s/d full dose, hyperrho s/d mini dose, micrhogam, micrhogam ultra-filtered plus, rhogam, rhogam ultra-filtered plus, rhophylac, winrho sdf)?

RHo (D) immune globulin is a sterilized solution made from human blood. Rh is a substance that most people have in their blood (Rh positive) but some people don't (Rh negative). A person who is Rh negative can be exposed to Rh positive blood through a mismatched blood transfusion or during pregnancy when the baby has the opposite blood type. When this exposure happens, the Rh negative blood will respond by making antibodies that will try to destroy the Rh positive blood cells. This can cause medical problems such as anemia (loss of red blood cells), kidney failure, or shock.

RHo (D) immune globulin is used to prevent an immune response to Rh positive blood in people with an Rh negative blood type. RHo (D) immune globulin may also be used in the treatment of immune thrombocytopenic purpura (ITP).

RHo (D) immune globulin may also be used for purposes not listed in this medication guide.

Where can i get more information?

Your doctor or pharmacist can provide more information about RHo (D) immune globulin.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Every effort has been made to ensure that the information provided by Cerner Multum, Inc. ('Multum') is accurate, up-to-date, and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. Multum information has been compiled for use by healthcare practitioners and consumers in the United States and therefore Multum does not warrant that uses outside of the United States are appropriate, unless specifically indicated otherwise. Multum's drug information does not endorse drugs, diagnose patients or recommend therapy. Multum's drug information is an informational resource designed to assist licensed healthcare practitioners in caring for their patients and/or to serve consumers viewing this service as a supplement to, and not a substitute for, the expertise, skill, knowledge and judgment of healthcare practitioners. The absence of a warning for a given drug or drug combination in no way should be construed to indicate that the drug or drug combination is safe, effective or appropriate for any given patient. Multum does not assume any responsibility for any aspect of healthcare administered with the aid of information Multum provides. The information contained herein is not intended to cover all possible uses, directions, precautions, warnings, drug interactions, allergic reactions, or adverse effects. If you have questions about the drugs you are taking, check with your doctor, nurse or pharmacist.

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How is RHo (D) immune globulin given?

RHo (D) immune globulin is injected into a muscle or a vein. You will receive this injection in a clinic or hospital setting.

Your breathing, blood pressure, oxygen levels, and other vital signs will be watched closely after you receive immune globulin. Your urine may also need to be tested every 2 to 4 hours for at least 8 hours.

For treatment during pregnancy, this medicine is usually given at regular intervals during the last half of the pregnancy, and again after the baby is born.

For treatment of a mismatched blood transfusion, the medicine is given when symptoms of an immune response appear (when the body starts making Rh antibodies).

To be sure this medicine is helping your condition, you may need frequent blood tests. You may not notice any change in your symptoms, but your blood work will help your doctor determine how long to treat you with RHo (D) immune globulin.

RHo (D) immune globulin can cause false results with certain lab tests for glucose (sugar) in the blood. Tell any doctor who treats you that you are using this medicine.

RHo (D) immune globulin side effects

Get emergency medical help if you have any of these signs of an allergic reaction: rash or hives; feeling light-headed, chest tightness, difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have:

  • fever, chills, shaking, back pain, unusual weakness, red or pink urine;

  • pale or yellowed skin, dark colored urine;

  • rapid breathing, rapid heart rate, confusion, feeling short of breath;

  • signs of kidney failure--little or no urinating, swelling, rapid weight gain; or

  • signs of a blood clot--sudden numbness or weakness, slurred speech, problems with vision or balance, chest pain, coughing up blood, swelling with redness and warmth in one or both legs.

Common side effects may include:

  • nausea, diarrhea, vomiting, stomach pain;

  • headache, dizziness;

  • drowsiness, weakness, general ill feeling;

  • joint or muscle pain;

  • flushing (warmth, redness, or tingly feeling);

  • mild itching or skin rash;

  • increased sweating; or

  • pain or tenderness where the medicine was injected.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

What other drugs will affect RHo (D) immune globulin?

Other drugs may interact with RHo (D) immune globulin, including prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

RhoGAM Ultra-Filtered PLUS - Clinical Pharmacology

Mechanism of Action

RhoGAM and MICRhoGAM act by suppressing the immune response of Rh-negative individuals to Rh-positive red blood cells. The mechanism of action is unknown. RhoGAM, MICRhoGAM and other Rho(D) Immune Globulin (Human) products are not effective in altering the course or consequences of Rh immunization once it has occurred.

Pharmacokinetic Properties

Pharmacokinetic studies after intramuscular injection were performed on sixteen Rh-negative subjects receiving a single dose of (368 μg or 1840 IU) RhoGAM.10 Plasma anti-D levels were monitored for thirteen weeks using a validated Automated Quantitative Hemagglutination method with sensitivity of approximately 1 ng/mL. The following mean pharmacokinetic parameters were obtained from data collected over the first ten weeks of a thirteen-week study:

Parameter Mean SD Units
Maximum plasma concentration obtained (Cmax) 54.0 13.0 ng/mL
Time to attain Cmax (Tmax) 4 days
Elimination half-life (T1/2) 30.9 13.8 days
Volume of distribution (Vd) 7.3 1.5 liters
Clearance (CL) 150.4 53.3 mL/day

Obstetrical Use

The Rh-negative obstetrical patient may be exposed to red blood cells from her Rh-positive fetus during the normal course of pregnancy or after obstetrical procedures or abdominal trauma.

Use after Rh-Incompatible Transfusion

An Rh-negative individual transfused with one unit of Rh-positive red blood cells has about an 80% likelihood of producing anti-D.4 However, Rh immunization can occur after exposure to < 1 mL of Rh-positive red blood cells. Protection from Rh immunization is accomplished by administering ≥ 20 μg of RhoGAM or MICRhoGAM per mL of Rh-positive red blood cells within 72 hours of transfusion of incompatible red blood cells.13,22

How supplied / storage and handling

RhoGAM Ultra-Filtered PLUS package sizes

  • 1 prefilled single-dose syringe of RhoGAM (Product Code 780501)
    NDC 0562-7805-01
    1 package insert, 1 control form, 1 patient identification card
  • 5 prefilled single-dose syringes of RhoGAM (Product Code 780505)
    NDC 0562-7805-05
    5 package inserts, 5 control forms, 5 patient identification cards
  • 25 prefilled single-dose syringes of RhoGAM (Product Code 780525)
    NDC 0562-7805-25
    25 package inserts, 25 control forms, 25 patient identification cards

MICRhoGAM Ultra-Filtered PLUS package sizes

  • 1 prefilled single-dose syringe of MICRhoGAM (Product Code 780601)
    NDC 0562-7806-01
    1 package insert, 1 control form, 1 patient identification card
  • 5 prefilled single-dose syringes of MICRhoGAM (Product Code 780605)
    NDC 0562-7806-05
    5 package inserts, 5 control forms, 5 patient identification cards
  • 25 prefilled single-dose syringes of MICRhoGAM (Product Code 780625)
    NDC 0562-7806-25
    25 package inserts, 25 control forms, 25 patient identification cards

Store at 2 to 8°C. Do not store frozen. Do not use after the expiration date printed on the syringe.

Patient Counseling Information

As with all immune globulin preparations, the physician should discuss the risks and benefits with the patient. The most common adverse reactions are local reactions including swelling, induration, redness and mild pain at the site of injection, and a small number of patients have noted a slight elevation in temperature.

Systemic reactions to RhoGAM or MICRhoGAM are extremely rare, however allergic responses to RhoGAM or MICRhoGAM may occur. Patients should be observed for at least 20 minutes after administration. Patients should be informed of the early signs of hypersensitivity reactions including hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis.

The physician should provide the patient with a completed RhoGAM Patient Identification Card and advise the patient to retain the card and present it to other health care providers when appropriate.

SUMMARY OF REVISIONS
Section Revision
10 DESCRIPTION Modified parvovirus and hepatitis A virus testing.

U.S. LICENSE 1236

Ortho-Clinical Diagnostics, Inc.
a Johnson&Johnson company
Raritan, New Jersey 08869

© OCD 2007
Printed in U.S.A.
Made by methods of
U.S. Pat. 6,096,872
Patent Pending

Revised February 2008
631203003

PATIENT IDENTIFICATION CARD

Name _____________________________________________________________________________________________________________

Address _____________________________________________________________________________________________________________

I AM Rh NEGATIVE. I have received a protective injection of RhoGAM® or MICRhoGAM® Rho(D) Immune Globulin (Human) Ultra-Filtered PLUS.

IMPORTANT: Anti-Rh antibody (also called anti-D) will be present in my blood for several weeks after the injection, and may be detectable by laboratory testing. The presence of this passive anti-Rh antibody does not disqualify me from receiving additional injections of RhoGAM or MICRhoGAM as indicated and prescribed by my physician.

©Ortho-Clinical Diagnostics, Inc. 2007

Rho(D) Immune Globulin (Human)
RhoGAM® and MICRhoGAM®
Ultra-Filtered PLUS

This 3-part form contains:

  • Directions for Use
  • Patient Control Form
  • Patient Identification Card

U.S. LICENSE 1236

Ortho-Clinical Diagnostics, Inc.
a Johnson&Johnson company
Raritan, New Jersey 08869

631203003

Date of Injection of RhoGAM or MICRhoGAM

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