FDA label 1b2389ac-8403-4888-9221-0045996130b9

WARNING: INTRAVASCULAR HEMOLYSIS IN ITP This warning does not apply to Rh 0 (D)-negative patients treated for the suppression of Rh isoimmunization. Intravascular hemolysis leading to death has been reported in Rh 0 (D)-positive patients treated for immune thrombocytopenic purpura (ITP) with Rh 0 (D) Immune Globulin Intravenous (Human) products. 1 Intravascular hemolysis can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS). Serious complications, including severe anemia, acute renal insufficiency, renal failure, and disseminated intravascular coagulation (DIC), have also been reported. Closely monitor patients treated for ITP with Rhophylac in a healthcare setting for at least 8 hours after administration. Perform a dipstick urinalysis at baseline, 2 hours and 4 hours after administration, and prior to the end of the monitoring period. Alert patients to, and monitor them for, the signs and symptoms of intravascular hemolysis, including back pain, shaking chills, fever, and discolored urine or hematuria. Absence of these signs and/or symptoms within 8 hours does not indicate IVH cannot occur subsequently. If signs and/or symptoms of intravascular hemolysis are present or suspected after Rhophylac administration, perform post-treatment laboratory tests, including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). WARNING: INTRAVASCULAR HEMOLYSIS IN ITP See full prescribing information for complete boxed warning. This warning does not apply to Rh 0 (D)-negative patients treated for the suppression of Rh isoimmunization. Intravascular hemolysis leading to death has been reported in Rh 0 (D)-positive patients treated for immune thrombocytopenic purpura (ITP) withRh 0 (D) Immune Globulin Intravenous (Human) products . 1 Intravasular hemolysis can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS). Serious complications, including severe anemia, acute renal insufficiency, renal failure, and disseminated intravascular coagulation (DIC), have also been reported. Closely monitor patients treated for ITP with Rhophylac in a healthcare setting for at least 8 hours after administration.

5 WARNINGS AND PRECAUTIONS Both Indications ( 5.1 ) IgA deficient patients with known antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reactions ( 5.1.1 ). Rhophylac is made from human blood; therefore it may contain infectious agents; e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent ( 5.1.3 ). Suppression of Rh Isoimmunization ( 5.2 ) For postpartum use following an Rh-incompatible pregnancy, administer Rhophylac to the mother only. Do not administer to the newborn infant ( 5.2.1 ). ITP ( 5.3 ) Intravascular hemolysis has occurred in a clinical study; monitor patients for signs and symptoms and perform confirmatory laboratory tests ( 5.3.1 ). In ITP patients with pre-existing anemia, weigh the benefits of Rhophylac vs. the potential risk of increasing the severity of the anemia ( 5.3.2 ). 5.1 Both Indications 5.1.1 Hypersensitivity Severe hypersensitivity reactions may occur. If symptoms of allergic or early signs of hypersensitivity reactions (including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, discontinue Rhophylac administration immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Rhophylac contains trace amounts of IgA (less than 5 mcg/mL) (s ee Description [11] ). Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Rhophylac is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reactions ( see Contraindications [4] ). 5.1.2 Interference with Laboratory Tests The administration of Rh 0 (D) immune globulin may affect the results of blood typing, the antibody screening test, and the direct antiglobulin (Coombs') test. Antepartum administration of Rh 0 (D) immune globulin to the mother can also affect these tests in the newborn infant. Rhophylac can contain antibodies to other Rh antigens (e.g., anti-C antibodies), which might be detected by sensitive serological tests following administration. 5.1.3 Transmissible Infectious Agents Because Rhophylac is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of infectious agent transmission has been reduced by screening plasma donors for prior exposure to certain viruses, testing for the presence of certain current virus infections, and including virus inactivation/removal steps in the manufacturing process for Rhophylac. Report any infections thought to be possibly transmitted by Rhophylac to CSL Behring Pharmacovigilance at 1-866-915-6958. 5.2 Suppression of Rh Isoimmunization 5.2.1 Postpartum Use Following an Rh-incompatible Pregnancy Administer Rhophylac to the mother only. Do not administer to the newborn infant ( see Pediatric Use [8.4] ) . 5.3 ITP 5.3.1 Intravascular Hemolysis Intravascular hemolysis has occurred in a clinical study with Rhophylac. All cases resolved completely. However, as reported in the literature, some Rh 0 (D)-positive patients treated with Rh 0 (D) Immune Globulin Intravenous (Human) for ITP developed clinically compromising anemia, acute renal insufficiency, and, very rarely, disseminated intravascular coagulation (DIC) and death. 1 Note : This warning does not apply to Rh 0 (D)-negative patients treated for the suppression of Rh isoimmunization. Closely monitor patients in a healthcare setting for at least 8 hours after administration of Rhophylac. Perform a dipstick urinalysis at baseline, 2 hours and 4 hours after administration, and prior to the end of the monitoring period. Alert patients to, and monitor them for, the signs and symptoms of intravascular hemolysis, including back pain, shaking chills, fever, and discolored urine or hematuria. Absence of these signs and/or symptoms of intravascular hemolysis within 8 hours do not indicate intravascular hemolysis cannot occur subsequently. If signs and/or symptoms of intravascular hemolysis are present or suspected after Rhophylac administration, perform post-treatment laboratory tests, including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). DIC may be difficult to detect in the ITP population; the diagnosis is dependent mainly on laboratory testing. If patients who develop hemolysis with clinically compromising anemia after receiving Rhophylac are to be transfused, Rh 0 (D)-negative packed RBCs should be used to avoid exacerbating ongoing hemolysis. 5.3.2 Pre-existing Anemia The safety of Rhophylac in the treatment of ITP has not been established in patients with pre-existing anemia. The physician must weigh the benefits of Rhophylac against the potential risk of increasing the severity of the anemia.

6 ADVERSE REACTIONS The most serious adverse reactions in patients receiving Rh 0 (D) Immune Globulin Intravenous (Human) have been observed in the treatment of ITP and include intravascular hemolysis, clinically compromising anemia, acute renal insufficiency, and, very rarely, DIC and death ( see Boxed Warning , Warnings and Precautions [5.3.1] ). 1 The most common adverse reactions observed in the use of Rhophylac for suppression of Rh isoimmunization (≥0.5% of subjects) are nausea, dizziness, headache, injection-site pain, and malaise. The most common adverse reactions observed in the treatment of ITP (>14% of subjects) are chills, pyrexia/increased body temperature, and headache. Mild hemolysis (manifested by an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was also observed. Suppression of Rh Isoimmunization The most common adverse reactions, reported in ≥ 0.5% of subjects, are nausea, dizziness, headache, injection-site pain, and malaise ( 6.1 ). ITP The most common adverse reactions, reported in > 14% of subjects, are chills, pyrexia/increased body temperature, headache, and mild hemolysis (increased bilirubin, decreased hemoglobin, or decreased haptoglobin) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies Experience Because clinical studies are conducted under different protocols and widely varying conditions, adverse reaction rates observed cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. Suppression of Rh Isoimmunization In two clinical studies, 447 Rh 0 (D)-negative pregnant women received either an intravenous or intramuscular injection of Rhophylac 1500 IU (300 mcg) at Week 28 of gestation. A second 1500 IU (300 mcg) dose was administered to 267 (9 in Study 1 and 258 in Study 2) of these women within 72 hours of the birth of an Rh 0 (D)-positive baby. In addition, 30 women in Study 2 received at least one extra antepartum 1500 IU (300 mcg) dose due to obstetric complications ( see Clinical Studies [14.1] ). The most common adverse reactions in study subjects were nausea (0.7%), dizziness (0.5%), headache (0.5%), injection-site pain (0.5%), and malaise (0.5%). A laboratory finding of a transient positive anti-C antibody test was observed in 0.9% of subjects. ITP In a clinical study, 98 Rh 0 (D)-positive adult subjects with chronic ITP received an intravenous dose of Rhophylac 250 IU (50 mcg) per kg body weight ( see Clinical Studies [14.2] ). Premedication to alleviate infusion-related side effects was not used except in a single subject who received acetaminophen and diphenhydramine. Eighty-four (85.7%) subjects experienced 392 treatment-emergent adverse events (TEAEs). Sixty-nine (70.4%) subjects had 186 drug-related TEAEs (defined as TEAEs with a probable, possible, definite, or unknown relationship to the study drug). Within 24 hours of dosing, 73 (74.5%) subjects experienced 183 TEAEs, and 66 (67%) subjects experienced 156 drug-related TEAEs. Mild hemolysis (manifested as an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was observed. An increase in blood bilirubin was seen in 21% of subjects. The median decrease in hemoglobin was greatest (0.8 g/dL) at Day 6 and Day 8 following administration of Rhophylac. Table 2 shows the most common TEAEs observed in the clinical study. Table 2: Most Common Treatment-Emergent Adverse Events (TEAEs) in Subjects with ITP TEAE Number of Subjects (%) With a TEAE n=98 Number of Subjects (%) With a Drug-Related TEAE Defined as TEAEs with a possible, probable, definite, or unknown relationship to the study drug. n=98 Chills 34 (34.7%) 34 (34.7%) Pyrexia/ Increased body temperature 32 (32.6%) 30 (30.6%) Increased blood bilirubin 21 (21.4%) 21 (21.4%) Headache 14 (14.3%) 11 (11.2%) Serious adverse events (SAEs) were reported in 10 (10.2%) subjects. SAEs considered to be drug-related were intravascular hemolytic reaction (hypotension, nausea, chills and headache, and a decrease in haptoglobin and hemoglobin) in two subjects; headache, dizziness, nausea, pallor, shivering, and weakness requiring hospitalization in one subject; and an increase in blood pressure and severe headache in one subject. All four subjects recovered completely. 6.2 Postmarketing Experience Because postmarketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure . The following adverse reactions have been identified during post-approval use of Rhophylac: Suppression of Rh Isoimmunization Hypersensitivity reactions, including rare cases of anaphylactic shock or anaphylactoid reactions, headache, dizziness, vertigo, hypotension, tachycardia, dyspnea, nausea, vomiting, rash, erythema, pruritus, chills, pyrexia, malaise, diarrhea and back pain have been reported. Transient injection-site irritation and pain have been observed following intramuscular administration. ITP Transient hemoglobinuria has been reported in a patient being treated with Rhophylac for ITP.

<table width="80%"> <caption>Table 2: Most Common Treatment-Emergent Adverse Events (TEAEs) in Subjects with ITP</caption> <col align="left" width="34%" valign="top"/> <col align="center" width="33%" valign="top"/> <col align="center" width="33%" valign="top"/> <thead> <tr> <th styleCode="Lrule Rrule" align="center">TEAE</th> <th styleCode="Rrule">Number of Subjects (%) With a TEAE n=98</th> <th styleCode="Rrule">Number of Subjects (%) With a Drug-Related TEAE<footnote>Defined as TEAEs with a possible, probable, definite, or unknown relationship to the study drug.</footnote> n=98</th> </tr> </thead> <tbody> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Chills</td> <td styleCode="Rrule">34 (34.7%)</td> <td styleCode="Rrule">34 (34.7%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Pyrexia/ Increased body temperature</td> <td styleCode="Rrule">32 (32.6%)</td> <td styleCode="Rrule">30 (30.6%)</td> </tr> <tr styleCode="Botrule"> <td styleCode="Lrule Rrule">Increased blood bilirubin</td> <td styleCode="Rrule">21 (21.4%)</td> <td styleCode="Rrule">21 (21.4%)</td> </tr> <tr> <td styleCode="Lrule Rrule">Headache</td> <td styleCode="Rrule">14 (14.3%)</td> <td styleCode="Rrule">11 (11.2%)</td> </tr> </tbody> </table>