FDA label 7d002c1d-a0ba-6060-e053-2991aa0a55df

WARNING: INTRAVASCULAR HEMOLYSIS (IVH) This warning does not apply to Rh o (D)-negative patients treated for the suppression of Rh isoimmunization. Intravascular hemolysis (IVH) leading to death has been reported in patients treated with WinRho ® SDF for immune thrombocytopenic purpura (ITP). IVH 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 with WinRho ® SDF for ITP in a healthcare setting for at least eight hours after administration. A dipstick urinalysis to monitor for hematuria and hemoglobinuria is to be performed at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period. Alert patients and monitor the signs and symptoms of IVH including back pain, shaking chills, fever, and discolored urine or hemoglobinuria. Absence of these signs and/or symptoms of IVH within eight hours do not indicate IVH cannot occur subsequently. If signs and/or symptoms of IVH are present or suspected after WinRho ® SDF administration, post-treatment laboratory tests should be performed including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). WARNING: INTRAVASCULAR HEMOLYSIS (IVH) IN IMMUNE THROMBOCYTOPENIC PURPURA (ITP) See full prescribing information for complete boxed warning. This warning does not apply to Rh o (D)-negative patients treated for the suppression of Rh isoimmunization. Intravascular hemolysis (IVH) leading to death has been reported in patients treated for ITP with WinRho ® SDF. IVH 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 with WinRho ® SDF for ITP in a healthcare setting for at least eight hours after administration (5.2.1). Perform dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and 2 hours, 4 hours and prior to the end of the monitoring period. Alert patients and monitor the signs and symptoms of IVH including back pain, shaking chills, fever, and discolored urine or hematuria. Absence of these signs and/or symptoms of IVH within eight hours do not indicate IVH cannot occur subsequently.Perform post-treatment laboratory tests if signs and/or symptoms of IVH are present or suspected after WinRho ® SDF administration (5.2.1).

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) Risk of transmission of infectious agents: e.g., viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, from human plasma. (5.1.2) Interference with non-glucose-specific blood monitoring systems may result in elevated glucose readings that lead to untreated hypoglycemia or inappropriate insulin administration.(5.1.3) Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output in patients at risk of developing acute renal failure. (5.1.4) Monitor patients with known risk factors for thrombotic events; consider baseline assessment of blood viscosity for those at risk of hyperviscosity. (5.1.5) Passive transfer of antibodies may confound serologic testing. (5.1.6) Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury [TRALI]). (5.1.7) ITP ( 5.2 ) Risk of intravascular hemolysis (IVH) and its complications following administration of WinRho ® SDF. (5.2.1) Hemolytic anemia can develop subsequent to WinRho ® SDF therapy. Monitor patients for hemolysis and haemolytic anemi. (5.2.2) Suppression of Rh Isoimmunization ( 5.3 ) Do not administer to the newborn infant. 5.1 Both Indications 5.1.1 Hypersensitivity Severe hypersensitivity reactions may occur [see Contraindications (4) ] If symptoms of allergic or early signs of hypersensitivity reactions (including generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) occur, discontinue WinRho ® SDF infusion immediately and institute appropriate treatment. Have medications such as epinephrine available for immediate treatment of acute hypersensitivity reactions. WinRho ® SDF contains approximately 5 micrograms/mL IgA [see Description (11) ]. Patients with known antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. WinRho ® SDF is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction [see Contraindications (4) ]. 5.1.2 Transmissible Infectious Agents Because WinRho ® SDF is made from human plasma; it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. The risk of transmitting an infectious agent has been reduced by screening plasma donors for prior exposure to certain pathogens, testing for the presence of certain current viral infections, and including virus inactivation/removal steps in the manufacturing process [see Description (11) ] Report all infections thought to have been transmitted by WinRho ® SDF to Cangene Corporation at 1-800-768-2304. The physician should discuss the risks and benefits of this product with the patient. 5.1.3 Interference with Blood Glucose Testing: False High Blood Glucose Levels The liquid formulation of WinRho ® SDF contains maltose. Maltose in IGIV products has been shown to give falsely high blood glucose levels in certain types of blood glucose testing systems [for example, by systems based on glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods]. Due to the potential for falsely elevated glucose readings, only use testing systems that are glucose-specific to test or monitor blood glucose levels in patients receiving maltose-containing parenteral products, including WinRho ® SDF Liquid. Carefully review the product information of the blood glucose testing system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products. 5.1.4 Renal Dysfunction/Failure Acute renal dysfunction/failure, osmotic nephropathy, and death may occur upon use of Immune Globulin Intravenous (IGIV) products, including WinRho ® SDF. 2 Ensure that patients are not volume depleted before administering WinRho ® SDF. For patients at risk of renal dysfunction or failure, including those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or receiving known nephrotoxic drugs, administer WinRho ® SDF at the minimum infusion rate practicable. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of WinRho ® SDF. 5.1.5 Thromboembolic Events Thromboembolic events may occur during or following treatment with WinRho ® SDF and other IGIV products. 3,4 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/suspected hyperviscosity. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. For patients who are at risk of developing thromboembolic events, administer WinRho ® SDF at the minimum rate of infusion practicable. 5.1.6 Interference with Serological Testing After administration of WinRho ® SDF, a transitory increase of various passively transferred antibodies in the patient’s blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, C and E) and other blood group antibodies [for example, anti Duffy, anti Kidd (anti JKa) antibodies] 5 may cause a positive direct or indirect (Coombs’) test. A large fetomaternal hemorrhage late in pregnancy or following delivery may cause a weak mixed field positive D u test result. Assess such an individual for a large fetomaternal hemorrhage and adjust the dose of WinRho ® SDF accordingly. The presence of passively administered anti Rh o (D) in maternal or fetal blood can lead to a positive direct Coombs’ test. If there is an uncertainty about the father’s Rh group or immune status, administer WinRho ® SDF to the mother. 5.1.7 Transfusion-Related Acute Lung Injury (TRALI) Non-cardiogenic pulmonary edema may occur in patients following IGIV treatment, including WinRho ® SDF. 6 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically appear within 1 to 6 hours following administration of blood products. Monitor patients for pulmonary adverse reaction. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.1.8 Monitoring Laboratory Tests For all ITP patients, blood type, blood count, reticulocyte count, DAT and dipstick urinalysis are recommended before deciding to treat patients with WinRho ® SDF. In patients with evidence of hemolysis (reticulocytosis greater than 3%), or patients at risk of hemolysis (positive DAT not attributed to previous immune globulin administration) use other treatments. 1 Closely monitor patients administered WinRho ® SDF for at least 8 hours post administration and perform a dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period. If signs and/or symptoms of IVH and its complications are present after anti-D administration, perform appropriate confirmatory laboratory testing including, but not limited to, CBC (i.e. hemoglobin, platelet counts), haptoglobin, plasma hemoglobin, urine dipstick, assessment of renal function (i.e. BUN, serum creatinine), liver function (i.e. LDH, direct and indirect bilirubin) and DIC specific tests such as D-dimer or Fibrin Degradation Products (FDP) or Fibrin Split Products (FSP). Periodic monitoring of renal function and urine output in patients who are at increased risk of developing acute renal failure [see Warnings and Precautions (5.1.4)]. Assess renal function in these at-risk patients, including measurement of BUN and serum creatinine, before the initial infusion of WinRho ® SDF and at appropriate intervals thereafter. If TRALI is suspected in ITP patients, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient serum [see Warnings and Precautions (5.1.7)]. 5.2 Treatment of ITP 5.2.1 Intravascular Hemolysis (IVH) IVH leading to death has been reported in patients treated for ITP with WinRho ® SDF. IVH 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. 7,8 Closely monitor patients treated with WinRho ® SDF for ITP in a healthcare setting for at least eight hours after administration. Peform a dipstick urinalysis to monitor for hematuria and hemoglobinuria at baseline and then after administration at 2 hours, 4 hours and prior to the end of the monitoring period. Alert patients and monitor for signs and symptoms of IVH including back pain, shaking chills, fever, and discolored urine or hemoglobinuria. Absence of these signs and/or symptoms of IVH within eight hours do not indicate IVH cannot occur subsequently. If signs and/or symptoms of IVH are present or if IVH is suspected after WinRho ® SDF administration, perform post-treatment laboratory tests including plasma hemoglobin, haptoglobin, LDH, and plasma bilirubin (direct and indirect). 5.2.2 Hemolysis Although the mechanism of action of WinRho ® SDF in the treatment of ITP is not completely understood it is postulated that anti-D binds to the Rh o (D) RBC resulting in formation of antibody-coated RBC complexes. Immune-mediated clearance of the antibody-coated RBC complexes would spare the antibody-coated platelets because of the preferential destruction of antibody-coated RBC complexes by the macrophages located in the reticuloendothelial system. 9-11 The side effect of this action is a decrease in hemoglobin levels (extravascular hemolysis). 7 The pooled data from ITP clinical studies demonstrated a mean decrease from baseline in hemoglobin levels of 1.2 g/dL within 7 days after administration of WinRho ® SDF. If the patient has lower than normal hemoglobin levels (less than 10 g/dL), a reduced dose of 125 to 200 international unit/kg (25 to 40 mcg/kg) should be given to minimize the risk of increasing the severity of anemia in the patient. Alternative treatments should be used in patients with hemoglobin levels that are less than 8 g/dL due to the risk of increasing the severity of the anemia [see Dosage and Administration (2.2) ]. Significant anemia may present with pallor, hypotension, or tachycardia while acute renal insufficiency may present with oliguria or anuria, edema and dyspnea. Patients with IVH who develop DIC may exhibit signs and symptoms of increased bruising and prolongation of bleeding time and clotting time which may be difficult to detect in the ITP population. Consequently the diagnosis of this serious complication of IVH is dependent on laboratory testing [see Warnings and Precautions (5.1.7)]. Previous uneventful administration of WinRho ® SDF does not preclude the possibility of an occurrence of IVH and its complications following any subsequent administration of WinRho ® SDF. Have confirmatory laboratory testing on ITP patients presenting with signs and/or symptoms of IVH and its complications after anti-D administration [see Warnings and Precautions (5.1.7)]. If ITP patients are to be transfused, use Rh o (D)-negative red blood cells (PRBCs) so as not to exacerbate ongoing hemolysis. 5.3 Supression of Rh Isoimmunization Do not administer WinRho ® SDF to Rh o (D)-negative individuals who are Rh immunized as evidenced by an indirect antiglobulin (Coombs’) test revealing the presence of anti-Rh o (D) (anti-D) antibody. For postpartum use following an Rh-incompatible pregnancy administer WinRho ® SDF to the mother only. Do not administer to the newborn infant.

6 ADVERSE REACTIONS Serious adverse reactions, some of these cases resulted in fatal outcome, have been observed in patients receiving WinRho ® SDF for the treatment of ITP. These include: intravascular hemolysis (IVH), clinically compromising anemia, acute renal insufficiency and DIC [see Adverse Reactions, (6.2) ]. The most common adverse reactions observed for all indications are: headache, chills, fever, asthenia, pallor, diarrhea, nausea, vomiting, arthralgia, myalgia, dizziness, hyperkinesia, abdominal or back pain, hypotension, hypertension, increased LDH, somnolence, vasodilation, pruritus, rash and sweating. All adverse reactions listed occurred in ≤ 2% of WinRho ® doses administered in clinical trials. Adverse reactions observed in the use of WinRho ® SDF for Suppression of Rh Isoimmunization are <0.1% in Rh o (D)-negative individuals. The most common adverse reactions occurring in ≤ 2% of doses are headache, chills, fever, asthenia, pallor, diarrhea, nausea, vomiting, arthralgia, myalgia, dizziness, malaise, hyperkinesia, abdominal or back pain, hypotension, hypertension, increased LDH, somnolence, vasodilation, pruritus, rash and sweating. ( 6.1 ) errious adverse reactions, such as IVH, clinically compromising anemia, acute renal insufficiency and DIC have been observed in patients receiving WinRho ® SDF for treatment of ITP. Some of these cases resulted in fatal outcome. ( 6.2 ) To report SUSPECTED ADVERSE REACTIONS, contact Cangene Corporation at 1-800-768-2304 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experiences Because clinical studies are conducted under different protocols and widely varying conditions, adverse reaction rates observed in the clinical trials of a specific drug product cannot be directly compared to rates in clinical trials of another drug, and may not reflect rates observed in practice. Treatment of ITP The safety of WinRho SDF was evaluated in clinical trials (n=161) in children and adults with acute and chronic ITP and adults and children with ITP secondary to HIV. Overall, 417 adverse events were reported by 91 patients (57%). The most common adverse events were headache (14% of the patients), fever (11% of the patients) and asthenia (11% of the patients). A total of 117 adverse drug reactions were re ported by 46 patients (29%). Headache, chills, and fever were the most common related adverse events ( Table 4 ). With respect to safety profile per administration, 60/848 (7%) of WinRho ® infusions had at least one adverse reaction. The most common adverse reactions were headache (19 infusions; 2%), chills (14 infusions; < 2%), and fever (nine infusions; 1%). Table 4 Adverse drug Reaction s with an Incidence ≥5% of Patients Body System Adverse Event All Studies Children Adults # of Patients (%) Body as a Whole Headache 18 (11) 8 (11) 10 (12) Chills 13 (8) 4 (5) 9 (10) Fever 9 (6) 5 (7) 4 (5) Asthenia 6 (4) 2 (3) 4 (5) Infection 4 (3) 4 (5) 0 (0) Nervous System Dizziness 6 (4) 2 (3) 4 (5) In four clinical trials of patients treated with the recommended initial intravenous dose of 250 international unit/kg (50 mcg/kg), the mean maximum decrease in hemoglobin was 1.70 g/dL (range: +0.40 to -6.1g/dL). At a reduced dose, ranging from 125 to 200 international unit/kg (25 to 40 mcg/kg), the mean maximum decrease in hemoglobin was 0.81 g/dL (range: +0.65 to -1.9 g/dL). Only 5/137 (3.7%) of patients had a maximum decrease in hemoglobin of greater than 4 g/dL (range: -4.2 to -6.1 g/dL). Suppression of Rh Isoimmunization In the clinical trial of 1,186 Rh o (D)-negative pregnant women, no adverse reactions were reported to Rh o (D) IGIV. 6.2 Post-marketing Experience Because post-marketing 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 the post-approval use of WinRho ® SDF. Treatment of ITP These adverse reactions are classified by system organ class. Intravascular hemolysis (IVH) leading to death has been reported in patients treated with WinRho ® SDF for immune thrombocytopenic purpura (ITP). Serious complications including severe anemia, acute renal insufficiency, renal failure and disseminated intravascular coagulation (DIC) have also been reported. Infusion Reactions: Anaphylactic reaction, Hypersensitivity Hematologic: Intravascular hemolysis, Disseminated Intravascular Coagulation, Hemoglobinemia Cardiac: Cardiac arrest, Cardiac failure, Myocardial infarction, Tachycardia Gastrointestinal: Nausea General: Chest pain, Fatigue, Edema Hepatologic: Jaundice Musculoskeletal: Myalgia, Muscle spasm, Pain in extremities Renal: Renal failure, Renal impairment, Anuria, Chromaturia, Hemoglobinuria, Hematuria Respiratory: Acute respiratory distress syndrome, Transfusion related acute lung injury Integumentary: Hyperhidrosis Suppression of Rh Isoimmunization Infusion Reactions: Hypersensitivity, anaphylactic reaction, induration, pruritus or swelling at injection site Integumentary: Pruritus, Rash Healthcare professionals should report serious adverse reactions following the administration of WinRho ® SDF to Cangene Corporation at 1-800-768-2304 or FDA’s MedWatch reporting system by phone (1-800-FDA-1088).

<table border="single" width="442.000" ID="id_3d915738-664f-4ade-9abb-2e269c9d5425"> <caption ID="id_4d2fc194-09c7-4dd3-9453-e1d082a018b8">Table 4 Adverse drug Reaction s with an Incidence &#x2265;5% of Patients</caption> <col width="18.3%"/> <col width="20.8%"/> <col width="20.1%"/> <col width="20.8%"/> <col width="19.9%"/> <tbody> <tr ID="id_6fe55146-2217-4939-b47d-cf51d47237ce"> <td align="left" rowspan="2" styleCode="Botrule Toprule Rrule Lrule" valign="top"> <content styleCode="bold">Body System</content> </td> <td align="left" rowspan="2" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">Adverse Event</content> </td> <td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">All Studies</content> </td> <td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">Children</content> </td> <td align="left" styleCode="Botrule Rrule" valign="top"> <content styleCode="bold">Adults</content> </td> </tr> <tr ID="id_fd70e329-5601-44dc-86c1-4e8f0122587b"> <td align="left" colspan="3" styleCode="Lrule Botrule Rrule" valign="top"> <content styleCode="bold"># of Patients (%)</content> </td> </tr> <tr ID="id_ec19d2bd-b90d-4833-bd47-a9510a198ed0"> <td align="left" rowspan="5" styleCode="Lrule Botrule Rrule" valign="middle">Body as a Whole</td> <td align="left" styleCode="Botrule Rrule" valign="top">Headache</td> <td align="left" styleCode="Botrule Rrule" valign="top">18 (11)</td> <td align="left" styleCode="Botrule Rrule" valign="top">8 (11)</td> <td align="left" styleCode="Botrule Rrule" valign="top">10 (12)</td> </tr> <tr ID="id_6c43a48e-fc10-432e-98f2-60d474d1a20b"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">Chills</td> <td align="left" styleCode="Botrule Rrule" valign="top">13 (8)</td> <td align="left" styleCode="Botrule Rrule" valign="top">4 (5) </td> <td align="left" styleCode="Botrule Rrule" valign="top">9 (10)</td> </tr> <tr ID="id_2ceb894c-5dcb-41c2-84f6-629c19a93830"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">Fever </td> <td align="left" styleCode="Botrule Rrule" valign="top">9 (6)</td> <td align="left" styleCode="Botrule Rrule" valign="top">5 (7)</td> <td align="left" styleCode="Botrule Rrule" valign="top">4 (5)</td> </tr> <tr ID="id_d0abe7c5-62fa-478d-9eea-cd65528471c0"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">Asthenia</td> <td align="left" styleCode="Botrule Rrule" valign="top">6 (4)</td> <td align="left" styleCode="Botrule Rrule" valign="top">2 (3)</td> <td align="left" styleCode="Botrule Rrule" valign="top">4 (5)</td> </tr> <tr ID="id_83f9e511-73b0-47c9-9005-44e2919a65f4"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">Infection</td> <td align="left" styleCode="Botrule Rrule" valign="top">4 (3)</td> <td align="left" styleCode="Botrule Rrule" valign="top">4 (5)</td> <td align="left" styleCode="Botrule Rrule" valign="top">0 (0)</td> </tr> <tr ID="id_4cf4ac33-811f-47e9-8180-0756913add7f"> <td align="left" styleCode="Lrule Botrule Rrule" valign="top">Nervous System</td> <td align="left" styleCode="Rrule" valign="top">Dizziness</td> <td align="left" styleCode="Rrule" valign="top">6 (4)</td> <td align="left" styleCode="Rrule" valign="top">2 (3)</td> <td align="left" styleCode="Botrule Rrule" valign="top">4 (5)</td> </tr> </tbody> </table>