Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism of Action RhoGAM (rho(d) immune globulin (human)) and MICRhoGAM (rho(d) immune globulin (human)) act by suppressing the immune response of Rh-negative individuals to Rh-positive red blood cells. The mechanism of a ction is unknown. RhoGAM, MICRhoGAM (rho(d) immune globulin (human)) and other Rho(D) Immune Globulin (Human) products are not effective in altering the course or consequences of Rh immunization once it has occurred. 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. Clinical studies have proven that the incidence of Rh immunization as a result of pregnancy was reduced to 1-2% from 12-13% when RhoGAM (rho(d) immune globulin (human)) was given within 72 hours following delivery.10,11 Antepartum administration of Rh immune globulin at 28 weeks, as well as within 72 hours of delivery, has been shown to reduce the Rh immunization rate to about 0.1-0.2%.12,13 Clinical studies demonstrated that administration of MICRhoGAM (rho(d) immune globulin (human)) within three hours following abortion was 100% effective in preventing Rh immunization.14 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.3 However, Rh immunization can occur after exposure to < 1 mL of Rh-positive red blood cells. Protection from Rh immunization is accomplished by administering the appropriate dose of RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) , which is > 20 μg per mL of Rh-positive red blood cells, within 72 hours of transfusion of incompatible red cells.2,15 (See DOSAGE AND ADMINISTRATION section.) Pharmacokinetic Properties Pharmacokinetic studies after intramuscular injection were performed on eight Rh-negative subjects.16 Six subjects received a single dose (300 μg) of RhoGAM (rho(d) immune globulin (human)) , while two subjects received four doses (1200 μg). Plasma anti-D levels were monitored for four months using a validated method with sensitivity of approximately 1 ng/mL. The parameters measured and/or calculated included the following:

RhoGAM® Ultra-Filtered - 300 μg (1500 IU*) MICRhoGAM (rhod immune globulin human) ® Ultra-Filtered - 50 μg (250 IU*) (Rho(D) Immune Globulin (Human)) For Intramuscular Injection Only. Preservative-free, latex-free delivery system DESCRIPTION RhoGAM (rhod immune globulin human) ® and MICRhoGAM (rhod immune globulin human) ® Rho(D) Immune Globulin (Human) are sterile solutions containing 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 (rhod immune globulin human) contains sufficient anti-D (approximately 300 μg or 1500 IU)* to suppress the immune response to 15 mL (or less) of Rh-positive red blood cells.2,3 A single dose of MICRhoGAM (rhod immune globulin human) contains sufficient anti-D (approximately 50 μg or 250 IU)* to suppress the immune response to 2.5 mL (or less) of Rh-positive red blood cells. The anti-D dose is measured by comparison to the RhoGAM (rhod immune globulin human) in-house reference standard, the potency of which is established relative to the US/WHO/EP Standard Anti-D Immunoglobulin Rho(D) Immune Globulin (Human) CBER Lot 4: NIBSC Lot 01/572 (285 IU/ampoule). All donors are carefully screened by history and laboratory testing to reduce the risk of transmitting blood-borne pathogens from infected donors. Fractionation of the plasma is performed by a modification of the cold alcohol procedure that has been shown to significantly lower viral titers.4 Following fractionation, an additional viral-clearance filtration step is incorporated into the manufacturing process. This 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. The ultrafiltration step utilizes tangential flow filtration to permit filtration of IgG while effectively retarding enveloped and non-enveloped viruses above the pore-size distribution cutoff. The filter is inert to the product. Non-enveloped viruses are known to be resistant to chemical and physical inactivation.5,6 Laboratory spiking studies have shown that the cumulative viral removal capability of the RhoGAM (rhod immune globulin human) /MICRhoGAM (rhod immune globulin human) manufacturing process exceeds 13 logs for human immunodeficiency virus (HIV). Clearance of model viruses for hepatitis C virus (HCV), hepatitis B virus (HBV) and parvovirus B19 (a non-enveloped virus) exceeds 11 logs.4 The donor selection process, the fractionation process and the Viresolve ultrafiltration step are designed to 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 reported to transmit hepatitis or other infectious diseases.7 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.8 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). However, even after the fractionation and virus-filtration steps, there remains a risk of contracting blood-borne pathogens from a plasma-derived product. The final product contains approximately 5 ±1% gamma globulin, 2.9 mg/mL sodium chloride, 0.01% polysorbate 80 and 15 mg/mL glycine. Small amounts of IgA, typically less than 15 μg per dose, are present.9 The pH range is 6.20-6.55. The product contains no preservative and utilizes a latex-free delivery system. REFERENCES *The anti-D content of RhoGAM (rhod immune globulin human) /MICRhoGAM (rhod immune globulin human) is expressed as μg per dose or as International Units (IU) per dose. The conversion factor is 1 μg = 5 IU.1 †Viresolve is a trademark of Millipore Corporation. 1. 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. 2. Pollack W, Ascari WQ, Kochesky RJ, O'Connor RR, Ho TY, Tripodi D. Studies on Rh prophylaxis. I. Relationship between doses of anti-Rh and size of antigenic stimulus. Transfusion 1971;11:333-39. 3. 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. 4. Data on file at Ortho-Clinical Diagnostics, Inc. 5. Prowse C, Ludlam CA, Yap PL. Human parvovirus B19 and blood products. Vox Sang 1997;72:1-10. 6. Mannucci PM, Gdovin S, Gringeri A, Colombo M, Mele A, Schinaia N, Ciavarella N, Emerson SU, Purcell RH. Transmission of hepatitis A to patients with hemophilia by Factor VIII concentrates treated with organic solvent and detergent to inactivate viruses. Ann Intern Med 1994;120:1-7. 7. 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. 8. 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. 9. Data on file at Ortho-Clinical Diagnostics, Inc.

INDICATIONS Pregnancy and Other Obstetrical Conditions in Rh-Negative Women, Unless the Father or Baby are Conclusively Rh Negative Pregnancy/delivery of an Rh-positive baby irrespective of the ABO groups of the mother and baby Abortion/threatened abortion at any stage of gestation Ectopic pregnancy Antepartum fetal-maternal hemorrhage (suspected or proven) resulting from antepartum hemorrhage (e.g., placenta previa), amniocentesis, chorionic villus sampling, percutaneous umbilical blood sampling, other obstetrical manipulative procedure (e.g., version) or abdominal trauma Transfusion of Rh incompatible blood or blood products Transfusion Prevention of Rh immunization in any Rh-negative person after incompatible transfusion of Rh-positive blood or blood products (e.g., red blood cells, platelet concentrates, granulocyte concentrates) DOSAGE AND ADMINISTRATION For intramuscular use only. Do not inject RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) intravenously. In the case of postpartum use, the product is intended for maternal administration. Do not inject the newborn infant. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. A single dose (approximately 50 μg)* is contained in each prefilled syringe of MICRhoGAM (rho(d) immune globulin (human)) . This dose will suppress the immune response to 2.5 mL of Rh-positive red blood cells. MICRhoGAM (rho(d) immune globulin (human)) is therefore indicated within 72 hours after termination of pregnancy up to and including 12 weeks' gestation. At or beyond 13 weeks' gestation, RhoGAM (rho(d) immune globulin (human)) should be administered instead of MICRhoGAM (rho(d) immune globulin (human)) . A single dose (approximately 300 μg)* is contained in each prefilled syringe of RhoGAM (rho(d) immune globulin (human)) . This is the usual dose for the indications associated with pregnancy unless there is clinical or laboratory evidence of a fetal-maternal hemorrhage (FMH) in excess of 15 mL of Rh-positive red blood cells. RhoGAM (rho(d) immune globulin (human)) should be administered within 72 hours of known or suspected exposure to Rh-positive red blood cells. The indications and recommended dosage for RhoGAM (rho(d) immune globulin (human)) and MICRhoGAM (rho(d) immune globulin (human)) are summarized in the following table. Indications and Recommended Dosage Indication Indicated Dosea (approximately) Postpartum (if the newborn is Rh-positive) 300 μgb Antepartum: Prophylaxis at 26 to 28 weeks' gestationc 300 μg Antepartum: Amniocentesis, chorionic villus sampling 300 μg (CVS) and percutaneous umbilical blood sampling (PUBS) Antepartum: Abdominal trauma or obstetrical manipulation 300 μg Antepartum: Ectopic pregnancyd 300 μg Antepartum: Abortion or threatened abortion at any stage of gestation with continuation of pregnancyd 300 μg Transfusion of Rh-incompatible blood or blood productsd 300 μg a Additional doses of RhoGAM (rho(d) immune globulin (human)) are indicated when the patient has been exposed to > 15 mL of Rh-positive red blood cells. This may be determined by use of qualitative or quantitative tests for FMH (see below). b See DESCRIPTION section. c If antepartum prophylaxis is indicated, it is essential that the mother receive a postpartum dose if the infant is Rh-positive. d If abortion or termination of pregnancy occurs up to and including 12 weeks' gestation, or less than 2.5 mL of Rh-incompatible red blood cells were administered, a single dose of MICRhoGAM (rho(d) immune globulin (human)) Rho(D) Immune Globulin (Human) (approximately 50 μg)* may be used instead of RhoGAM (rho(d) immune globulin (human)) . If RhoGAM (rho(d) immune globulin (human)) is administered for one of the above indications early in pregnancy (before 26 to 28 weeks), there is an obligation to maintain a level of passively acquired anti-D by administration of RhoGAM (rho(d) immune globulin (human)) at 12-week intervals. RhoGAM (rho(d) immune globulin (human)) should be administered within 72 hours of delivery or exposure to Rh-positive red blood cells. There is little information concerning the effectiveness of Rh Immune Globulin when given beyond this 72-hour period. In one study, Rh Immune Globulin provided protection against Rh immunization in about 50% of subjects when given 13 days after exposure to Rh-positive cells.21 If delivery occurs within three weeks after the last antepartum dose, the postpartum dose may be withheld, but a test for FMH should be performed to determine if exposure to >15 mL of red cells has occurred.22 Multiple doses of RhoGAM (rho(d) immune globulin (human)) are required if an FMH exceeds 15 mL. Patients in whom FMH is suspected should be tested for FMH by qualitative or quantitative methods.23 In efficacy studies, RhoGAM (rho(d) immune globulin (human)) was shown to suppress Rh immunization in all subjects when given at a dose of >20 μg per mL of Rh-positive red blood cells.3 Thus, a single dose of RhoGAM (rho(d) immune globulin (human)) will suppress the immune response after exposure to <15 mL of Rh-positive red blood cells. However, in clinical practice, laboratory methods used to determine the amount of exposure (volume of transfusion or FMH) to Rh-positive red blood cells are imprecise.24,25 Therefore, administration of more than 20 μg of RhoGAM (rho(d) immune globulin (human)) per mL of Rh-positive red blood cells should be considered whenever a large FMH or red blood cell exposure is suspected or documented.25 When multiple doses are required, consult your pharmacy for pooling directions. Multiple doses may be administered at the same time or at spaced intervals, as long as the total dose is administered within three days of exposure. Administer injection. Administer injection per standard protocol. Note: When administering an intramuscular injection, place fingers in contact with syringe barrel through windows in shield to prevent possible premature activation of safety guard. Slide safety guard over needle. After injection, use free hand to slide safety guard over needle. An audible “click” indicates proper activation. Keep hands behind needle at all times. HOW SUPPLIED RhoGAM (rho(d) immune globulin (human)) is available in packages containing: 1 prefilled single-dose syringe of RhoGAM (rho(d) immune globulin (human)) (Product Code 780701) NDC 0562-7807-01 1 package insert 1 control form 1 patient identification card and 5 prefilled single-dose syringes of RhoGAM (rho(d) immune globulin (human)) (Product Code 780710) NDC 0562-7807-06 5 package inserts 5 control forms 5 patient identification cards and 25 prefilled single-dose syringes of RhoGAM (rho(d) immune globulin (human)) (Product Code 780715) NDC 0562-7807-26 25 package inserts 25 control forms 25 patient identification cards MICRhoGAM (rho(d) immune globulin (human)) is available in packages containing: 1 prefilled single-dose syringe of MICRhoGAM (rho(d) immune globulin (human)) (Product Code 780801) NDC 0562-7808-01 1 package insert 1 control form 1 patient identification card and 5 prefilled single-dose syringes of MICRhoGAM (rho(d) immune globulin (human)) (Product Code 780810) NDC 0562-7808-06 5 package inserts 5 control forms 5 patient identification cards and 25 prefilled single-dose syringes of MICRhoGAM (rho(d) immune globulin (human)) (Product Code 780815) NDC 0562-7808-26 25 package inserts 25 control forms 25 patient identification cards Storage Store at 2 to 8°C. Do not store frozen. REFERENCES 3. 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. 20. Data on file at Ortho-Clinical Diagnostics, Inc. 21. Samson D, Mollison PL. Effect on primary Rh immunization of delayed administration of anti-Rh. Immunol 1975;28:349-57. 22. Garratty G, ed. Hemolytic disease of the newborn. Arlington, VA: American Association of Blood Banks, 1984:78. 23. 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. 24. 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. 25. Kumpel BM. Quantification of anti-D and fetomaternal hemorrhage by flow cytometry (editorial). Transfusion 2000;40:6-9. Ortho-Clinical Diagnostics, Inc, Raritan, New Jersey 08869, Revised October 2005. FDA revision date: n/a

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Patients who receive RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) for Rh-incompatible transfusion should be monitored by clinical and laboratory means due to the risk of a hemolytic reaction. CONTRAINDICATIONS Individuals known to have had an anaphylactic or severe systemic reaction to human globulin should not receive RhoGAM (rho(d) immune globulin (human)) , MICRhoGAM (rho(d) immune globulin (human)) or any other Rho(D) Immune Globulin (Human).

SIDE EFFECTS Adverse events (AE) after administration of RhoGAM (rho(d) immune globulin (human)) Ultra-Filtered and MICRhoGAM (rho(d) immune globulin (human)) Ultra-Filtered are reported infrequently. The most frequently reported AEs are anti-D formation and skin reactions, such as swelling, induration, redness and mild pain at the site of injection. Systemic allergic reactions to RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) are extremely rare. There have been no reported fatalities due to anaphylaxis or any other cause related to RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) administration. As with any Rho(D) Immune Globulin (Human), administration to patients who have received Rh-positive red blood cells may result in signs and symptoms of a hemolytic reaction, including fever, back pain, nausea and vomiting, hypo- or hypertension, hemoglobinuria/emia, elevated bilirubin and creatinine and decreased haptoglobin. DRUG INTERACTIONS No information provided.

WARNINGS RhoGAM (rho(d) immune globulin (human)) and MICRhoGAM (rho(d) immune globulin (human)) are made from human plasma. Because these products are made from human blood, they 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 for the presence of certain current virus infections and by removing certain viruses during the manufacturing process. Following fractionation, an additional viral-clearance filtration step is incorporated into the manufacturing process. This filtration step removes viruses via a size-exclusion mechanism utilizing a patented Viresolve 180 ultrafiltration membrane with a defined pore-size distribution of 12-18 nanometers. The filter is inert to the product. This virus removal process has been shown in laboratory spiking studies to reduce the levels of some viruses ranging from18-200 nanometers in size, including enveloped viruses as well as non-enveloped viruses.4 All of the above steps are designed to increase product safety by reducing the risk of transmission of lipid-enveloped and non-lipid-enveloped viruses. 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. RhoGAM (rho(d) immune globulin (human)) and MICRhoGAM (rho(d) immune globulin (human)) are manufactured and distributed by Ortho-Clinical Diagnostics, Inc., Raritan, NJ 08869. PRECAUTIONS For intramuscular use only. Do not inject RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) 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. Allergic responses to RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) may occur. Patients should be informed of the early signs of hypersensitivity reactions, including hives, generalized urticaria, tightness of the chest, wheezing, hypotension and anaphylaxis. The treatment depends upon the nature and severity of the reaction. RhoGAM (rho(d) immune globulin (human)) and MICRhoGAM (rho(d) immune globulin (human)) contain a small quantity of IgA (less than 15 μg per dose).9 Although high doses of intravenous immunoglobulin containing IgA at levels of 270-720 μg/mL have been given without incident during treatment of patients with high-titered antibodies to IgA,17 the attending physician must weigh the benefit against the potential risks of hypersensitivity reactions. The presence of passively acquired anti-D in the maternal serum may cause a positive antibody screening test. This does not preclude further antepartum or postpartum prophylaxis. Some babies born of women given Rho(D) Immune Globulin (Human) antepartum have weakly positive direct antiglobulin (Coombs) tests at birth. Fetal-maternal hemorrhage may cause false blood typing results in the mother. Late in pregnancy or following delivery, there may be sufficient fetal Rh-positive red blood cells in the circulation of the Rh-negative mother to cause a positive antiglobulin test for weak D (Du). When there is any doubt as to the patient's Rh type, RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM (rho(d) immune globulin (human)) should be administered. Pregnancy Category C Animal reproduction studies have not been conducted with RhoGAM (rho(d) immune globulin (human)) or MICRhoGAM. The available evidence suggests that Rho(D) Immune Globulin (Human) does not harm the fetus or affect future pregnancies or the reproduction capacity of the maternal recipient.18,19 REFERENCES 4. Data on file at Ortho-Clinical Diagnostics, Inc. 9. Data on file at Ortho-Clinical Diagnostics, Inc. 17. Cunningham-Rundles C, Zhuo Z, Mankarious S, Courter S. Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J Clin Immunol 1993;13:272-78. 18. Zipursky A, Israels LG. The pathogenesis and prevention of Rh immunization. Can Med Assoc J 1967;97:1245-56. 19. Thornton JG, Page C, Foote G, Arthur GR, Tovey LAD, Scott JS. Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin. Brit Med J 1989;298:1671-73.