FDA label e650df09-753b-4dbe-bdf3-10cae76a7a6a

WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Patients predisposed renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, advanced age (above 65 years of age), volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose. GAMMAGARD LIQUID does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMMAGARD LIQUID at the minimum infusion rate practicable. Warning: RENAL DYSFUNCTION & ACUTE RENAL FAILURE See full prescribing information for complete boxed warning Renal dysfunction, acute renal failure, osmotic nephropathy, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction and acute failure occur more commonly in patients receiving IGIV products containing sucrose. GAMMAGARD LIQUID does not contain sucrose. For patients at risk of renal dysfunction or failure, administer GAMMAGARD LIQUID at the minimum rate of infusion practicable.

5 WARNINGS AND PRECAUTIONS IgA deficient patients with antibodies to IgA are at greater risk of developing severe hypersensitivity and anaphylactic reaction. ( 5.1 ) Monitor renal function, including blood urea nitrogen, serum creatinine, and urine output in patients at risk of acute renal failure. ( 5.2 ) Hyperproteinemia, increased serum viscosity and hyponatremia may occur. ( 5.3 ) Thrombotic events may occur. Monitor patients with known risk factors for thrombotic events; consider baseline assessment of blood viscosity for those at risk for hyperviscosity. ( 5.4 ) Aseptic Meningitis Syndrome (AMS) may occur. ( 5.5 ) Hemolytic anemia can develop. Monitor for clinical signs and symptoms of hemolysis and hemolytic anemia. ( 5.6 ) Monitor patients for pulmonary adverse reactions (transfusion-related acute lung injury, TRALI). ( 5.7 ) Product is made from human plasma and may contain infectious agents, e.g., viruses and theoretically, Creutzfeldt-Jacob disease (CJD) agent. ( 5.8 ) 5.1 Hypersensitivity Severe hypersensitivity reactions may occur, even in patients who had tolerated previous treatment with human normal immune globulin. In case of hypersensitivity, discontinue GAMMAGARD LIQUID infusion immediately and institute appropriate treatment. GAMMAGARD LIQUID contains trace amount of IgA (average concentration of 37μg/mL). Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. GAMMAGARD LIQUID is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction ( see CONTRAINDICATIONS [4 ] ) 5.2 Renal Dysfunction/Failure Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur upon use of IGIV treatment, especially those containing sucrose 3 . Acute renal dysfunction/failure has been reported in association with infusions of GAMMAGARD LIQUID. Assure that patients are not volume depleted prior to the initiation of infusion of GAMMAGARD LIQUID. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, etc.), administer GAMMAGARD LIQUID intravenously at the minimum rate of infusion practicable (not exceeding 3.3 mg IgG/kg/min (< 2 mL/kg/hr) (see DOSAGE AND ADMINISTRATION [ 2.3 ] ). Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of GAMMAGARD LIQUID and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMMAGARD LIQUID (see DOSAGE AND ADMINISTRATION[ 2 ]). 5.3 Hyperproteinemia, Increased Serum Viscosity, and Hyponatremia Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving GAMMAGARD LIQUID. It is critical to distinguish true hyponatremia from a pseudohyponatremia that is temporally or causally related to hyperproteinemia with concomitant decreased calculated serum osmolality or elevated osmolar gap; because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a predisposition to thromboembolic events 4 . 5.4 Thrombotic Events Thrombotic events, including myocardial infarction, cerebral vascular accident, deep vein thrombosis, and pulmonary embolism, have been reported in association with intravenous use of GAMMAGARD LIQUID ( see ADVERSE REACTIONS [ 6 ] ). Thrombotic events have also been reported with subcutaneous administration of immune globulin. Patients at risk for thrombotic events include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, coagulation disorders, prolonged periods of immobilization, obesity, diabetes mellitus, acquired or inherited thrombophilic disorder, a history of vascular disease, or a history of a previous thrombotic or thromboembolic event. 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 ( see WARNINGS AND PRECAUTIONS [ 5.9 ]). For patients judged to be at risk of developing thrombotic events, administer GAMMAGARD LIQUID intravenously at the minimum rate of infusion practicable, not exceeding 3.3 mg IgG/kg/min (< 2 mL/kg/hr) ( see DOSAGE AND ADMINISTRATION [ 2.3 ]) . When administering subcutaneously monitor the patients for signs and symptoms of thrombotic events. 5.5 Aseptic Meningitis Syndrome (AMS) AMS may occur with IGIV treatment, and has been reported with intravenous use of GAMMAGARD LIQUID. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following IGIV treatment. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. ( see PATIENT COUNSELING INFORMATION [ 17 ]). Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per mm 3 , predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently with high dose (2 g/kg) IGIV treatment and/or rapid infusion of IGIV. 5.6 Hemolysis GAMMAGARD LIQUID contains blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells (RBC) with immune globulin. These antibodies may cause a positive direct antiglobulin reaction and hemolysis 3,5 . Acute intravascular hemolysis has been reported, and delayed hemolytic anemia can develop due to enhanced RBC sequestration (see ADVERSE REACTIONS [ 6 ]). Monitor patients for clinical signs and symptoms of hemolysis ( see WARNINGS AND PRECAUTIONS [ 5.9 ]) . If signs and/or symptoms of hemolysis such as dark colored urine, swelling, fatigue or difficulty breathing, are present after GAMMAGARD LIQUID infusion, perform appropriate confirmatory laboratory testing ( see PATIENT COUNSELING INFORMATION [ 17 ]). 5.7 Transfusion-Related Acute Lung Injury (TRALI) Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following treatment with IGIV products, including GAMMAGARD LIQUID. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment. Monitor patients for pulmonary adverse reactions ( see PATIENT COUNSELING INFORMATION[ 17 ] ). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. 5.8 Transmittable Infectious Agents Because GAMMAGARD LIQUID is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent, and theoretically, the classic Creutzfeldt-Jakob disease agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or vCJD have been associated with GAMMAGARD LIQUID. ALL infections thought by a physician to possibly have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation, at 1-800-423-2862 (in the U.S.). 5.9 Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of GAMMAGARD LIQUID and at appropriate intervals thereafter. 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, because of the potentially increased risk of thrombosis 3 . If signs and/or symptoms of hemolysis are present after an infusion of GAMMAGARD LIQUID, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient’s serum. 5.10 Interference with Laboratory Tests After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient’s blood may yield false positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs’) test.

5.1 Hypersensitivity Severe hypersensitivity reactions may occur, even in patients who had tolerated previous treatment with human normal immune globulin. In case of hypersensitivity, discontinue GAMMAGARD LIQUID infusion immediately and institute appropriate treatment. GAMMAGARD LIQUID contains trace amount of IgA (average concentration of 37μg/mL). Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. GAMMAGARD LIQUID is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction ( see CONTRAINDICATIONS [4 ] )

5.2 Renal Dysfunction/Failure Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur upon use of IGIV treatment, especially those containing sucrose 3 . Acute renal dysfunction/failure has been reported in association with infusions of GAMMAGARD LIQUID. Assure that patients are not volume depleted prior to the initiation of infusion of GAMMAGARD LIQUID. In patients who are at risk of developing renal dysfunction, because of pre-existing renal insufficiency or predisposition to acute renal failure (such as diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs, etc.), administer GAMMAGARD LIQUID intravenously at the minimum rate of infusion practicable (not exceeding 3.3 mg IgG/kg/min (< 2 mL/kg/hr) (see DOSAGE AND ADMINISTRATION [ 2.3 ] ). Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk for developing acute renal failure. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of GAMMAGARD LIQUID and again at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of GAMMAGARD LIQUID (see DOSAGE AND ADMINISTRATION[ 2 ]).

5.7 Transfusion-Related Acute Lung Injury (TRALI) Non-cardiogenic pulmonary edema (TRALI) has been reported in patients following treatment with IGIV products, including GAMMAGARD LIQUID. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Symptoms typically occur within 1 to 6 hours after treatment. Monitor patients for pulmonary adverse reactions ( see PATIENT COUNSELING INFORMATION[ 17 ] ). If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support.

6 ADVERSE REACTIONS Intravenous : The most serious adverse reaction seen during intravenous treatment in the clinical trials was two episodes of aseptic meningitis in one subject. The most common adverse reactions (observed in ≥5% of subjects) were headache, pyrexia, fatigue, rigors, nausea, chills, dizziness, vomiting, migraine headache, pain in extremity, urticaria, cough, pruritus, rash and tachycardia. Subcutaneous : No serious adverse reactions were observed during the clinical trial of subcutaneous treatment. The most common adverse reactions during subcutaneous treatment (observed in ≥5% of subjects) were local infusion site reactions. The most common systemic reactions were headache, fever, fatigue, increased heart rate, increased systolic blood pressure, and upper abdominal pain. The most common adverse reactions observed in ≥5% of patients were ( 6.1 ): Intravenous Administration: headache, pyrexia, fatigue, rigors, nausea, chills, dizziness, vomiting, migraine headache, pain in extremity, urticaria, cough, pruritus, rash and tachycardia. Two serious adverse reactions occurred in the clinical trial with GAMMAGARD LIQUID: two episodes of aseptic meningitis in a single patient ( 6.1 ). Subcutaneous Administration - local infusion site reactions (e.g., swelling, redness, pain), headache, fever, fatigue, increased heart rate, increased systolic blood pressure, and upper abdominal pain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice . Intravenous Administration The safety of GAMMAGARD LIQUID intravenous infusion was evaluated in 61 subjects 6 . Of all adverse experiences, 15 events in 8 subjects were serious with two episodes of aseptic meningitis in one patient deemed to be possibly related to the infusion of GAMMAGARD LIQUID. Among the 896 non-serious adverse experiences, 258 were judged by the investigator to be possibly or probably related to the infusion of GAMMAGARD LIQUID. Of these, 136 were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 106 were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 16 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). All of the severe non-serious adverse experiences were transient, did not lead to hospitalization, and resolved without complication. One subject withdrew from the study due to a non-serious adverse experience (papular rash). Temporally associated adverse events are those occurring during or within 72 hours of completion of an infusion, regardless of causality. Of the 345 temporally related adverse events, those occurring in > 5% of subjects are shown in Table 5 Only one event, headache, occurred in association with more than 5% of infusions. Table 5. Adverse Events Excluding Infections , Regardless of Causality, that Occurred within 72 Hours of Infusion Event By Infusion N (%) By Subject N (%) Headache 57 (7%) 22(36%) Fever 19(2%) 13(21%) Fatigue 18(2%) 10(16%) Vomiting 10(1%) 9(15%) Chills 14(2%) 8(23%) Infusion site events 8(1%) 8(13%) Nausea 9(1%) 6(10%) Dizziness 7(1%) 6(10%) Pain in Extremity 7(1%) 5(8%) Diarrhea 7(1%) 5(8%) Cough 5(1%) 5(8%) Pruritus 5(1%) 4(7%) Pharyngeal Pain 5(1%) 4(7%) Table 6 lists the related adverse events occurring in 5% or more of the 61 subjects from the pivotal multicenter clinical study. Adverse drug reactions (ADR's) are those adverse events that were deemed by the investigators as causally related to the infusion of GAMMAGARD LIQUID. Table 6. Adverse Reactions Occurring in 5% or More of Subjects Event By Infusion N (%) By Subject N (%) Headache 90 (5%) 27 (44%) Pyrexia 23 (1%) 13 (21%) Fatigue 26 (1%) 10 (16%) Rigors 14 (1%) 8 (13%) Nausea 11 (1%) 8 (13%) Chills 13 (1%) 7 (12%) Dizziness 8 (0.4%) 5 (8%) Vomiting 6 (0.3%) 5 (8%) Migraine 16 (1%) 4 (7%) Pain in Extremity 10 (1%) 4 (7%) Urticaria 8 (0.4%) 4 (7%) Cough 4 (0.2%) 3 (5%) Pruritus 4 (0.2%) 3 (5%) Rash 4 (0.2%) 3 (5%) Tachycardia 3 (0.2%) 3 (5%) 31 of the 258 non-serious adverse events were not previously listed as associated with GAMMAGARD LIQUID and thus were considered unexpected. A total of 14 hospitalizations occurred during the study but none were related to infection. Subcutaneous Administration The safety of GAMMAGARD LIQUID subcutaneous infusion was evaluated in 47 subjects. The most common ADRs with subcutaneous infusion of GAMMAGARD LIQUID observed in ≥5% of study subjects in the clinical trial were local infusion site reactions (e.g., swelling, redness, pain), as well as systemic reactions of headache, fever, fatigue, increased heart rate, increased systolic blood pressure, and upper abdominal pain. Of the 632 non-serious AEs, the most frequent AEs, regardless of causality, and the most frequent temporally associated AEs, which occurred in ≥10% subjects, are shown in Table 7 . Table 7. Adverse Events Irrespective of Causality Excluding infections in ≥10% of Subjects Adverse Event All Adverse Events Adverse Events Occurring Within 72 Hours of subcutaneous Infusion Number (%) of Subjects (N= 47) Number (Rate Rate per subcutaneous infusions = total number of events divided by total number of subcutaneous infusions ) of Adverse Events (N= 2294 Infusions) Number (%) of Subjects (N= 47) Number (Rate ) of Adverse Events (N= 2294 Infusions) Local Reactions 21 (44.7) 56 (0.028) 21 (44.7) 53 (0.027) Headache 23 (48.9) 45 (0.020) 18 (38.3) 27 (0.012) Fever 14 (29.8) 22 (0.010) 9 (19.1) 11 (0.005) Nausea 8 (17.0) 20 (0.010) 3 (6.4) 6 (0.003) Vomiting 7 (14.9) 12 (0.005) 5 (10.6) 7 (0.003) Fatigue 7 (14.9) 11 (0.005) 6 (12.8) 10 (0.004) Diarrhea 5 (10.6) 13 (0.006) 3 (6.4) 3 (0.001) Asthma 6 (12.8) 9 (0.004) 4 (8.5) 6 (0.003) Oropharyngeal Pain 6 (12.8) 8 (0.003) 3 (6.4) 3 (0.001) Abdominal Pain Upper 5 (10.6) 12 (0.005) 5 (10.6) 9 (0.004) There were 150 AEs considered to be related to GAMMAGARD LIQUID use (ADRs), all of which were non-serious. Of these non-serious ADRs, 124 (83%) were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 24 (16%) were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 2 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae. Neither of the severe AEs required hospitalization or resulted in sequelae. The most frequent ADRs (AEs considered by the investigators to be at least possibly related to GAMMAGARD LIQUID) that occurred in 5% or more of subjects are shown in Table 8 . Table 8. Related Adverse Reactions Excluding infections Experienced by ≥ 5% of Subjects and Rate per Subcutaneous Infusion Adverse Reaction Number (%) of Subjects (N= 47) Number (Rate Rate per subcutaneous infusions= total number of events divided by total number of subcutaneous infusions ) of Adverse Reactions (N= 2294 subcutaneous Infusions) Local Reactions 21 (44.7) 53 (0.027) Headache 13 (27.7) 20 (0.009) Fever 6 (12.8) 7 (0.003) Fatigue 5 (10.6) 8 (0.003) Heart Rate Increased 3 (6.4) 9 (0.004) Blood Pressure Systolic Increased 3 (6.4) 6 (0.003) Abdominal Pain (Upper) 3 (6.4) 4 (0.002) Local AEs. The incidence of local AEs by MedDRA term during all GAMMAGARD LIQUID subcutaneous treatment is shown in Table 9 . Table 9. Local Adverse Events (> 1 Events) Excluding infections. N=2294 subcutaneous infusions in All Subjects Number (Rate) of subcutaneous Infusions Local Adverse Event Mild Mild: transient discomfort that resolves spontaneously or with minimal intervention Moderate Moderate: limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae. Severe Severe: marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae. Total Pain 14 (0.006) 8 (0.003) 0 (0.000) 22 (0.010) Hematoma 13 (0.006) 1 (<0.001) 0 (0.000) 14 (0.006) Pruritus 4 (0.002) 2 (0.001) 0 (0.000) 6 (0.003) Rash 4 (0.002) 0 (0.000) 0 (0.000) 4 (0.002) Erythema 3 (0.001) 0 (0.000) 0 (0.000) 3 (0.001) Edema 3 (0.001) 0 (0.000) 0 (0.000) 3 (0.001) Hemorrhage 2 (0.001) 0 (0.000) 0 (0.000) 2 (0.001) Irritation 2 (0.001) 0 (0.000) 0 (0.000) 2 (0.001) Swelling 1 (<0.001) 1 (<0.001) 0 (0.000) 2 (0.001) One subject withdrew from the study after 10 treatments with GAMMAGARD LIQUID subcutaneous infusion (2.5 months) due to increased fatigue and malaise. The overall rate of local AEs (excluding infections) during the subcutaneous treatment periods was 2.8% per infusion. In subcutaneous naïve patients, the incidence of local AEs (N = 1757 infusions) was 3.3% (2.6% mild and 0.7% moderate with no severe AEs). In the subjects who were subcutaneous experienced (N = 537 infusions), the incidence of local AEs was 1.1% (1.1% mild, and no moderate or severe AEs). In the clinical study after all subcutaneous doses were adjusted, all subjects but one reached their maximum rate allowed in the protocol, 20 mL/site/hour if weight was below 40 kg and 30/mL/hour for weight 40 kg and greater, for one or more of the infusions. 70% (31 of 44) of these subjects opted for the highest rate for all infusions. No subject restricted the rate due to an ADR. In the clinical study, median duration of each weekly infusion was 1.2 hours (range: 0.8 – 2.3 hours) after all subcutaneous doses were adjusted. The rate set on the pump was that rate per site multiplied by the number of sites, with no maximum. During all subcutaneous treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. The proportion of subjects who experienced local AEs (excluding infections) was highest immediately following the switch from intravenous to subcutaneous treatment in all age groups. Over subsequent subcutaneous infusions, there was a decrease of local AEs. The rate of all local AEs per infusion immediately after switching from intravenous to subcutaneous treatment was 4.9% (29/595), decreasing to 1.5% (8/538) by the end of the study and to 1.1% (10/893) in the Study Extension. Eight (17%) subjects experienced a local adverse reaction during the first infusion, but that decreased to 1 (2.1%) for the subsequent infusions, ranging from 0 to 4 (8.7%) during the first year of subcutaneous treatment. No subject reported a local adverse reaction from week 53 to end of study at week 68. 6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. Intravenous ADRs Hematologic Hemolysis, Leukopenia, positive direct Coombs test Infusion Reactions Hypersensitivity, anaphylactic shock, anaphylactic reaction Neurological Transient ischemic attack, tremor, burning sensation, cerebral vascular accident Cardiovascular Deep vein thrombosis, hypotension, phlebitis, hypertension, myocardial infarction, chest pain Respiratory Pulmonary embolism, pulmonary edema, dyspnea, oxygen saturation decreased, Transfusion-Related Acute Lung Injury (TRALI) Gastrointestinal Abdominal pain Integumentary Hyperhidrosis, allergic dermatitis Psychiatric Anxiety, insomnia General/Body as a Whole Edema Renal Acute renal dysfunction/failure In addition to the events listed above which were observed for GAMMAGARD LIQUID, the following events have been identified for IGIV products in general: Renal Osmotic nephropathy Respiratory Cyanosis, hypoxemia, bronchospasm, apnea, Acute Respiratory Distress Syndrome (ARDS) Integumentary Bullous dermatitis, epidermolysis, erythema multiforme, Stevens-Johnson Syndrome Cardiovascular Cardiac arrest, vascular collapse Neurological Coma, seizures, loss of consciousness, aseptic meningitis syndrome Hematologic Gastrointestinal Pancytopenia Hepatic dysfunction

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice . Intravenous Administration The safety of GAMMAGARD LIQUID intravenous infusion was evaluated in 61 subjects 6 . Of all adverse experiences, 15 events in 8 subjects were serious with two episodes of aseptic meningitis in one patient deemed to be possibly related to the infusion of GAMMAGARD LIQUID. Among the 896 non-serious adverse experiences, 258 were judged by the investigator to be possibly or probably related to the infusion of GAMMAGARD LIQUID. Of these, 136 were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 106 were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 16 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae). All of the severe non-serious adverse experiences were transient, did not lead to hospitalization, and resolved without complication. One subject withdrew from the study due to a non-serious adverse experience (papular rash). Temporally associated adverse events are those occurring during or within 72 hours of completion of an infusion, regardless of causality. Of the 345 temporally related adverse events, those occurring in > 5% of subjects are shown in Table 5 Only one event, headache, occurred in association with more than 5% of infusions. Table 5. Adverse Events Excluding Infections , Regardless of Causality, that Occurred within 72 Hours of Infusion Event By Infusion N (%) By Subject N (%) Headache 57 (7%) 22(36%) Fever 19(2%) 13(21%) Fatigue 18(2%) 10(16%) Vomiting 10(1%) 9(15%) Chills 14(2%) 8(23%) Infusion site events 8(1%) 8(13%) Nausea 9(1%) 6(10%) Dizziness 7(1%) 6(10%) Pain in Extremity 7(1%) 5(8%) Diarrhea 7(1%) 5(8%) Cough 5(1%) 5(8%) Pruritus 5(1%) 4(7%) Pharyngeal Pain 5(1%) 4(7%) Table 6 lists the related adverse events occurring in 5% or more of the 61 subjects from the pivotal multicenter clinical study. Adverse drug reactions (ADR's) are those adverse events that were deemed by the investigators as causally related to the infusion of GAMMAGARD LIQUID. Table 6. Adverse Reactions Occurring in 5% or More of Subjects Event By Infusion N (%) By Subject N (%) Headache 90 (5%) 27 (44%) Pyrexia 23 (1%) 13 (21%) Fatigue 26 (1%) 10 (16%) Rigors 14 (1%) 8 (13%) Nausea 11 (1%) 8 (13%) Chills 13 (1%) 7 (12%) Dizziness 8 (0.4%) 5 (8%) Vomiting 6 (0.3%) 5 (8%) Migraine 16 (1%) 4 (7%) Pain in Extremity 10 (1%) 4 (7%) Urticaria 8 (0.4%) 4 (7%) Cough 4 (0.2%) 3 (5%) Pruritus 4 (0.2%) 3 (5%) Rash 4 (0.2%) 3 (5%) Tachycardia 3 (0.2%) 3 (5%) 31 of the 258 non-serious adverse events were not previously listed as associated with GAMMAGARD LIQUID and thus were considered unexpected. A total of 14 hospitalizations occurred during the study but none were related to infection. Subcutaneous Administration The safety of GAMMAGARD LIQUID subcutaneous infusion was evaluated in 47 subjects. The most common ADRs with subcutaneous infusion of GAMMAGARD LIQUID observed in ≥5% of study subjects in the clinical trial were local infusion site reactions (e.g., swelling, redness, pain), as well as systemic reactions of headache, fever, fatigue, increased heart rate, increased systolic blood pressure, and upper abdominal pain. Of the 632 non-serious AEs, the most frequent AEs, regardless of causality, and the most frequent temporally associated AEs, which occurred in ≥10% subjects, are shown in Table 7 . Table 7. Adverse Events Irrespective of Causality Excluding infections in ≥10% of Subjects Adverse Event All Adverse Events Adverse Events Occurring Within 72 Hours of subcutaneous Infusion Number (%) of Subjects (N= 47) Number (Rate Rate per subcutaneous infusions = total number of events divided by total number of subcutaneous infusions ) of Adverse Events (N= 2294 Infusions) Number (%) of Subjects (N= 47) Number (Rate ) of Adverse Events (N= 2294 Infusions) Local Reactions 21 (44.7) 56 (0.028) 21 (44.7) 53 (0.027) Headache 23 (48.9) 45 (0.020) 18 (38.3) 27 (0.012) Fever 14 (29.8) 22 (0.010) 9 (19.1) 11 (0.005) Nausea 8 (17.0) 20 (0.010) 3 (6.4) 6 (0.003) Vomiting 7 (14.9) 12 (0.005) 5 (10.6) 7 (0.003) Fatigue 7 (14.9) 11 (0.005) 6 (12.8) 10 (0.004) Diarrhea 5 (10.6) 13 (0.006) 3 (6.4) 3 (0.001) Asthma 6 (12.8) 9 (0.004) 4 (8.5) 6 (0.003) Oropharyngeal Pain 6 (12.8) 8 (0.003) 3 (6.4) 3 (0.001) Abdominal Pain Upper 5 (10.6) 12 (0.005) 5 (10.6) 9 (0.004) There were 150 AEs considered to be related to GAMMAGARD LIQUID use (ADRs), all of which were non-serious. Of these non-serious ADRs, 124 (83%) were rated as mild (transient discomfort that resolves spontaneously or with minimal intervention), 24 (16%) were rated as moderate (limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae), and 2 were rated as severe (marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae. Neither of the severe AEs required hospitalization or resulted in sequelae. The most frequent ADRs (AEs considered by the investigators to be at least possibly related to GAMMAGARD LIQUID) that occurred in 5% or more of subjects are shown in Table 8 . Table 8. Related Adverse Reactions Excluding infections Experienced by ≥ 5% of Subjects and Rate per Subcutaneous Infusion Adverse Reaction Number (%) of Subjects (N= 47) Number (Rate Rate per subcutaneous infusions= total number of events divided by total number of subcutaneous infusions ) of Adverse Reactions (N= 2294 subcutaneous Infusions) Local Reactions 21 (44.7) 53 (0.027) Headache 13 (27.7) 20 (0.009) Fever 6 (12.8) 7 (0.003) Fatigue 5 (10.6) 8 (0.003) Heart Rate Increased 3 (6.4) 9 (0.004) Blood Pressure Systolic Increased 3 (6.4) 6 (0.003) Abdominal Pain (Upper) 3 (6.4) 4 (0.002) Local AEs. The incidence of local AEs by MedDRA term during all GAMMAGARD LIQUID subcutaneous treatment is shown in Table 9 . Table 9. Local Adverse Events (> 1 Events) Excluding infections. N=2294 subcutaneous infusions in All Subjects Number (Rate) of subcutaneous Infusions Local Adverse Event Mild Mild: transient discomfort that resolves spontaneously or with minimal intervention Moderate Moderate: limited impairment of function and resolves spontaneously or with minimal intervention with no sequelae. Severe Severe: marked impairment of function or can lead to temporary inability to resume normal life pattern; requires prolonged intervention or results in sequelae. Total Pain 14 (0.006) 8 (0.003) 0 (0.000) 22 (0.010) Hematoma 13 (0.006) 1 (<0.001) 0 (0.000) 14 (0.006) Pruritus 4 (0.002) 2 (0.001) 0 (0.000) 6 (0.003) Rash 4 (0.002) 0 (0.000) 0 (0.000) 4 (0.002) Erythema 3 (0.001) 0 (0.000) 0 (0.000) 3 (0.001) Edema 3 (0.001) 0 (0.000) 0 (0.000) 3 (0.001) Hemorrhage 2 (0.001) 0 (0.000) 0 (0.000) 2 (0.001) Irritation 2 (0.001) 0 (0.000) 0 (0.000) 2 (0.001) Swelling 1 (<0.001) 1 (<0.001) 0 (0.000) 2 (0.001) One subject withdrew from the study after 10 treatments with GAMMAGARD LIQUID subcutaneous infusion (2.5 months) due to increased fatigue and malaise. The overall rate of local AEs (excluding infections) during the subcutaneous treatment periods was 2.8% per infusion. In subcutaneous naïve patients, the incidence of local AEs (N = 1757 infusions) was 3.3% (2.6% mild and 0.7% moderate with no severe AEs). In the subjects who were subcutaneous experienced (N = 537 infusions), the incidence of local AEs was 1.1% (1.1% mild, and no moderate or severe AEs). In the clinical study after all subcutaneous doses were adjusted, all subjects but one reached their maximum rate allowed in the protocol, 20 mL/site/hour if weight was below 40 kg and 30/mL/hour for weight 40 kg and greater, for one or more of the infusions. 70% (31 of 44) of these subjects opted for the highest rate for all infusions. No subject restricted the rate due to an ADR. In the clinical study, median duration of each weekly infusion was 1.2 hours (range: 0.8 – 2.3 hours) after all subcutaneous doses were adjusted. The rate set on the pump was that rate per site multiplied by the number of sites, with no maximum. During all subcutaneous treatment periods, 99.8% of infusions were completed without a reduction, interruption, or discontinuation for tolerability reasons. The proportion of subjects who experienced local AEs (excluding infections) was highest immediately following the switch from intravenous to subcutaneous treatment in all age groups. Over subsequent subcutaneous infusions, there was a decrease of local AEs. The rate of all local AEs per infusion immediately after switching from intravenous to subcutaneous treatment was 4.9% (29/595), decreasing to 1.5% (8/538) by the end of the study and to 1.1% (10/893) in the Study Extension. Eight (17%) subjects experienced a local adverse reaction during the first infusion, but that decreased to 1 (2.1%) for the subsequent infusions, ranging from 0 to 4 (8.7%) during the first year of subcutaneous treatment. No subject reported a local adverse reaction from week 53 to end of study at week 68.

6.2 Postmarketing Experience Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure. Intravenous ADRs Hematologic Hemolysis, Leukopenia, positive direct Coombs test Infusion Reactions Hypersensitivity, anaphylactic shock, anaphylactic reaction Neurological Transient ischemic attack, tremor, burning sensation, cerebral vascular accident Cardiovascular Deep vein thrombosis, hypotension, phlebitis, hypertension, myocardial infarction, chest pain Respiratory Pulmonary embolism, pulmonary edema, dyspnea, oxygen saturation decreased, Transfusion-Related Acute Lung Injury (TRALI) Gastrointestinal Abdominal pain Integumentary Hyperhidrosis, allergic dermatitis Psychiatric Anxiety, insomnia General/Body as a Whole Edema Renal Acute renal dysfunction/failure In addition to the events listed above which were observed for GAMMAGARD LIQUID, the following events have been identified for IGIV products in general: Renal Osmotic nephropathy Respiratory Cyanosis, hypoxemia, bronchospasm, apnea, Acute Respiratory Distress Syndrome (ARDS) Integumentary Bullous dermatitis, epidermolysis, erythema multiforme, Stevens-Johnson Syndrome Cardiovascular Cardiac arrest, vascular collapse Neurological Coma, seizures, loss of consciousness, aseptic meningitis syndrome Hematologic Gastrointestinal Pancytopenia Hepatic dysfunction

<table ID="id_ce5f8686-89f1-477f-96fc-8ba571a278b4" width="440"> <caption ID="id_8401f8ef-4966-4ace-a771-0393ff651794">Table 5. Adverse Events<footnote ID="id-92c89909-b185-4cbe-9e53-07c5e36ae710">Excluding Infections</footnote>, Regardless of Causality, that Occurred within 72 Hours of Infusion</caption> <col width="35.0%"/> <col width="21.1%"/> <col width="43.9%"/> <tbody> <tr ID="id_9b3842b8-45fb-4303-8ef3-58cd00ccb068" styleCode="Toprule"> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">Event</content> </td> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">By Infusion N (%)</content> </td> <td align="center" styleCode="Botrule" valign="top"> <content styleCode="bold">By Subject N (%)</content> </td> </tr> <tr ID="id_1ccfc1f5-4f58-40de-8e2b-dfbeeaadd5ac"> <td align="left" valign="top">Headache</td> <td align="center" valign="top">57 (7%)</td> <td align="center" valign="top">22(36%)</td> </tr> <tr ID="id_2f58346a-9c5b-402a-9141-7f3d08ee913d"> <td align="left" valign="top">Fever</td> <td align="center" valign="top">19(2%)</td> <td align="center" valign="top">13(21%)</td> </tr> <tr ID="id_34b569df-f73b-49e2-a6b2-1009ce65ad3a"> <td align="left" valign="top">Fatigue</td> <td align="center" valign="top">18(2%)</td> <td align="center" valign="top">10(16%)</td> </tr> <tr ID="id_18120fc4-8044-452c-abdf-8632833a522b"> <td align="left" valign="top">Vomiting</td> <td align="center" valign="top">10(1%)</td> <td align="center" valign="top">9(15%)</td> </tr> <tr ID="id_460159f0-455b-46d0-a333-2f2e2cab18ca"> <td align="left" valign="top">Chills</td> <td align="center" valign="top">14(2%)</td> <td align="center" valign="top">8(23%)</td> </tr> <tr ID="id_76a0342a-2d63-464e-a459-fb8bc186e190"> <td align="left" valign="top">Infusion site events</td> <td align="center" valign="top">8(1%)</td> <td align="center" valign="top">8(13%)</td> </tr> <tr ID="id_1e2ef923-2cec-4981-8ca6-c08b335a3140"> <td align="left" valign="top">Nausea</td> <td align="center" valign="top">9(1%)</td> <td align="center" valign="top">6(10%)</td> </tr> <tr ID="id_0c766e62-5a83-4e7e-bc9a-d55b15dd8eb2"> <td align="left" valign="top">Dizziness</td> <td align="center" valign="top">7(1%)</td> <td align="center" valign="top">6(10%)</td> </tr> <tr ID="id_4a344212-87a7-4742-b059-9e9d329d16cc"> <td align="left" valign="top">Pain in Extremity</td> <td align="center" valign="top">7(1%)</td> <td align="center" valign="top">5(8%)</td> </tr> <tr ID="id_2c25fedb-f282-4379-bdc3-496471c2d49a"> <td align="left" valign="top">Diarrhea</td> <td align="center" valign="top">7(1%)</td> <td align="center" valign="top">5(8%)</td> </tr> <tr ID="id_0bed1b18-f07c-4386-a6ad-8f5da2f15c95"> <td align="left" valign="top">Cough</td> <td align="center" valign="top">5(1%)</td> <td align="center" valign="top">5(8%)</td> </tr> <tr ID="id_c5f92782-ed39-459a-bcb4-757294275dfd"> <td align="left" valign="top">Pruritus</td> <td align="center" valign="top">5(1%)</td> <td align="center" valign="top">4(7%)</td> </tr> <tr ID="id_37afb5db-b058-4c8f-b9c6-bee986f35fb6" styleCode="Botrule"> <td align="left" valign="top">Pharyngeal Pain</td> <td align="center" valign="top">5(1%)</td> <td align="center" valign="top">4(7%)</td> </tr> </tbody> </table>