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CLINICAL PHARMACOLOGY Mechanism Of Action Treatment Of Primary Humoral Immunodeficiency Privigen is a replacement therapy for primary humoral immunodeficiency, and supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacterial, viral, parasitic and mycoplasma agents and their toxins. The mechanism of action in PI has not been fully elucidated. Treatment Of Chronic Immune Thrombocytopenic Purpura The mechanism of action of high doses of immunoglobulins in the treatment of chronic ITP has not been fully elucidated. Pharmacokinetics Treatment Of Primary Humoral Immunodeficiency In the clinical study (pivotal study) assessing the efficacy and safety of Privigen in 80 subjects with PI [see Clinical Studies], serum concentrations of total IgG and IgG subclasses were measured in 25 subjects (ages 13 to 69) following the 7th infusion for the 3 subjects on the 3-week dosing interval and following the 5th infusion for the 22 subjects on the 4-week dosing interval. The dose of Privigen used in these subjects ranged from 200.0 mg/kg to 714.3 mg/kg. After the infusion, blood samples were taken until Day 21 and Day 28 for the 3-week and 4-week dosing intervals, respectively. Table 6 summarizes the pharmacokinetic parameters of Privigen, based on serum concentrations of total IgG. Table 6: PI Pivotal Study - Pharmacokinetic Parameters of Privigen in Subjects Parameter 3-Week Dosing Interval (n=3) 4-Week Dosing Interval (n=22) Mean (SD) Median (Range) Mean (SD) Median (Range) Cmax (peak, mg/dL) 2,550 (400) 2,340 (2,290-3,010) 2,260 (530) 2,340 (1,040-3,460) Cmin (trough, mg/dL) 1,230 (230) 1,200 (1,020-1,470) 1,000 (200) 1,000 (580-1,360) t½ (days) 27.6 (5.9) 27.8 (21.6-33.4) 45.4 (18.5) 37.3 (20.6-96.6) AUC0-t (day x mg/dL)* 32,820 (6,260) 29,860 (28,580- 40,010) 36,390 (5,950) 36,670 (19,680- 44,340) * /dL g/ m x TO (d S C0 U A 79,315 (20,170) 78,748 (59,435- 99,762) 104,627 (33,581) 98,521 (64,803- 178,600) Clearance (mL/day/kg)* 1.3 (0.1) 1.3 (1.1-1.4) 1.3 (0.3) 1.3 (0.9-2.1) Mean residence time (days)* 38.6 (8.1) 39.5 (30.1-46.2) 65.2 (24.7) 59.0 (33.2-129.6) Volume of distribution at steady state (mL/kg)* 50 (13) 44 (40-65) 84 (35) 87 (40-207) Cmax, maximum serum concentration; Cmin, trough (minimum level) serum concentration; t½, elimination half-life; AUC0-t, area under the curve from 0 hour to last sampling time; AUC0-∞, area under the curve from 0 hour to infinite time. * Calculated by log-linear trapezoidal rule. The median half-life of Privigen was 36.6 days for the 25 subjects in the pharmacokinetic subgroup. Although no systematic study was conducted to evaluate the effect of gender and age on the pharmacokinetics of Privigen, based on the small sample size (11 males and 14 females) it appears that clearance of Privigen is comparable in males (1.27 ± 0.35 mL/day/ kg) and females (1.34 ± 0.22 mL/day/kg). In six subjects between 13 and 15 years of age, the clearance of Privigen (1.35 ± 0.44 mL/day/kg) is comparable to that observed in 19 adult subjects 19 years of age or older (1.29 ± 0.22 mL/day/kg). The IgG subclass levels observed in the pharmacokinetic study were consistent with a physiologic distribution pattern (mean trough values): IgG1, 564.91 mg/dL; IgG2, 394.15 mg/dL; IgG3, 30.16 mg/dL; IgG4, 10.88 mg/dL. Treatment Of Chronic Immune Thrombocytopenic Purpura Pharmacokinetic studies with Privigen were not performed in subjects with chronic ITP. Clinical Studies Treatment Of Primary Humoral Immunodeficiency A prospective, open-label, single-arm, multicenter study (pivotal study) assessed the efficacy, safety, and pharmacokinetics of Privigen in adult and pediatric subjects with PI, who were treated for 12 months at a 3-week or 4-week dosing interval. Subjects ranged in age from 3 to 69; 46 (57.5%) were male and 34 (42.5%) were female; 77.5% were Caucasian, 15% were Hispanic, and 7.5% were African-American. All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. The efficacy analysis included 80 subjects, 16 (20%) on the 3-week dosing interval and 64 (80%) on the 4-week dosing interval. Doses ranged from 200 mg/kg to 888 mg/kg per infusion. The median dose for the 3-week interval was 428.3 mg/kg per infusion; the median dose for the 4-week interval was 440.6 mg/kg per infusion. Subjects received a total of 1038 infusions of Privigen, 272 for the 3-week dosing regimen and 766 for the 4-week dosing regimen. The maximum infusion rate allowed during this study was 8 mg/ kg/min with 715 (69%) of the infusions administered at a rate of 7 mg/kg/min or greater. The primary analysis for efficacy was based on the annual rate of acute serious bacterial infections (aSBIs), defined as pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess, per subject per year. Secondary analyses were based on the annual rate of other infections, antibiotic use, days out of work/school/ day care or unable to perform normal activities due to illness, and days of hospitalization. During the 12-month study period, the aSBI rate was 0.08 (with an upper 1-sided 99% confidence interval of 0.203), which met the predefined success rate of less than one aSBI per subject per year. Six subjects experienced an aSBI, including three cases of pneumonia and one case each of septic arthritis, osteomyelitis, and visceral abscess. All six subjects completed the study. The rate of other infections was 3.55 infections per subject per year. The infections that occurred most frequently were sinusitis (31.3%), nasopharyngitis (22.5%), upper respiratory tract infection (18.8%), bronchitis (13.8%), and rhinitis (13.8%). Among the 255 infections, 16 (6.3%) occurring in 10 subjects were considered severe. Table 7 summarizes the efficacy results for all 80 subjects. Table 7: PI Pivotal Study – Summary of Efficacy Results in Subjects Number of Subjects 80 Results from Case Report Forms Total Number of Subject Days 26,198 Infections Annual rate of confirmed aSBIs* 0.08 aSBIs/subject year† Annual rate of other infections 3.55 infections/subject year Antibiotic use Number of subjects (%) 64 (80%) Annual rate 87.4 days/subject year Results from Subject Diaries Total Number of Diary Days 24,059 Out of work/school/day care or unable to perform normal activities due to illness Number of days (%) 570 (2.37%) Annual rate 8.65 days/subject year Hospitalization Number of days (%) 166 (0.69%) Annual rate 2.52 days/subject year * Defined as pneumonia, bacterial meningitis, bacteremia/septicemia, osteomyelitis/septic arthritis, and visceral abscess. † Upper 1-sided 99% confidence interval: 0.203. Treatment Of Chronic Immune Thrombocytopenic Purpura A prospective, open-label, single-arm, multicenter study assessed the efficacy, safety, and tolerability of Privigen in 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less. Subjects ranged in age from 15 to 69; 23 (40.4%) were male and 34 (59.6%) were female; all were Caucasian. Subjects received a 2 g/kg dosage of Privigen administered as 1 g/kg (10 mL/kg) intravenous infusion daily for 2 consecutive days, and were observed for 29 days. Fifty-three (93%) subjects received Privigen at the maximum infusion rate allowed (4 mg/kg/min [0.04 mL/kg/min]). The primary analysis was based on the response rate defined as the percentage of subjects with an increase in platelet counts to at least 50 x 109/L within 7 days after the first infusion (responders). Secondary analyses were based on the increase in platelet counts and the time to reach a platelet count of at least 50 x 109/L at any point within the study period, the duration of that response, and the regression (decrease in the severity) of hemorrhage in subjects who had bleeding at baseline. Platelet counts were measured on Days 1, 2, 4, 6, 8, 15, 22, and 29. Additional measurements on Days 57 and 85 occurred in subjects with a platelet count of at least 50 x 109/L at the previous visit. Of the 57 subjects in the efficacy analysis, 46 (80.7%) responded to Privigen with a rise in platelet counts to at least 50 x 109/L within 7 days after the first infusion. The lower bound of the 95% confidence interval for the response rate (69.2%) is above the predefined response rate of 50%. The highest median increase in platelet counts was seen 7 days after the first infusion (123 x 109/L). The median maximum platelet count achieved was 154 x 109/L. The median time to reach a platelet response of more than 50 x 109/L was 2.5 days after the first infusion. Twenty-five (43%) of the 57 subjects reached this response by Day 2 prior to the second infusion and 43 (75%) subjects reached this response by Day 6. The duration of platelet response was analyzed for the 48 subjects who achieved a response any time after the first infusion. The median duration of platelet response in these subjects was 15.4 days (range: 1 to > 82 days). Thirty-six (75%) of the 48 subjects maintained the response for at least 8.8 days and 12 (25%) of them for at least 21.9 days. Five (9%) subjects maintained a response up to Day 29 and two (4%) up to Day 85. A decrease in the severity of hemorrhage from baseline was observed in the following bleeding locations: skin (31 of 36 subjects), oral cavity (11 of 11 subjects), and genitourinary tract (7 of 9 subjects). This decrease was not sustained in all subjects up to the end of the 29-day study period.

CLINICAL PHARMACOLOGY Mechanism Of Action Suppression Of Rh Isoimmunization The mechanism by which Rh0(D) immune globulin suppresses immunization to Rh0(D)- positive RBCs is not completely known. In a clinical study of Rh0(D)-negative healthy male volunteers, both the intravenous and intramuscular administration of a 1500 IU (300 mcg) dose of Rhophylac 24 hours after injection of 15 mL of Rh0(D)-positive RBCs resulted in an effective clearance of Rh0(D)- positive RBCs. On average, 99% of injected RBCs were cleared within 12 hours following intravenous administration and within 144 hours following intramuscular administration. ITP Rhophylac has been shown to increase platelet counts and to reduce bleeding in nonsplenectomized Rh0(D)-positive subjects with chronic ITP. The mechanism of action is thought to involve the formation of Rh0(D) immune globulin RBC complexes, which are preferentially removed by the reticuloendothelial system, particularly the spleen. This results in Fc receptor blockade, thus sparing antibody-coated platelets.7 Pharmacokinetics Suppression Of Rh Isoimmunization In a clinical study comparing the pharmacokinetics of intravenous versus intramuscular administration, 15 Rh0(D)-negative pregnant women received a single 1500 IU (300 mcg) dose of Rhophylac at Week 28 of gestation.8 Following intravenous administration, peak serum levels of Rh0(D) immune globulin ranged from 62 to 84 ng/mL after 1 day (i.e., the time the first blood sample was taken following the antepartum dose). Mean systemic clearance was 0.20 ± 0.03 mL/min, and half-life was 16 ± 4 days. Following intramuscular administration, peak serum levels ranged from 7 to 46 ng/ mL and were achieved between 2 and 7 days. Mean apparent clearance was 0.29 ± 0.12 mL/min, and half-life was 18 ± 5 days. The absolute bioavailability of Rhophylac was 69%. Regardless of the route of administration, Rh0(D) immune globulin titers were detected in all women up to at least 9 weeks following administration of Rhophylac. ITP Pharmacokinetic studies with Rhophylac were not performed in Rh0(D)-positive subjects with ITP. Rh0(D) immune globulin binds rapidly to Rh0(D)-positive erythrocytes.9 Clinical Studies Suppression Of Rh Isoimmunization In two clinical studies, 447 Rh0(D)-negative pregnant women received a 1500 IU (300 mcg) dose of Rhophylac during Week 28 of gestation. The women who gave birth to an Rh0(D)-positive baby received a second 1500 IU (300 mcg) dose within 72 hours of birth. Study 1 (Pharmacokinetic Study) – Eight of the women who participated in the pharmacokinetic study [see CLINICAL PHARMACOLOGY] gave birth to an Rh0(D)-positive baby and received the postpartum dose of 1500 IU (300 mcg) of Rhophylac.8 Antibody tests performed 6 to 8 months later were negative for all women. This suggests that no Rh0(D) immunization occurred. Study 2 (Pivotal Study) – In an open-label, single-arm clinical study at 22 centers in the US and United Kingdom, 432 pregnant women received the antepartum dose of 1500 IU (300 mcg) of Rhophylac either as an intravenous or intramuscular injection (two randomized groups of 216 women each).10 Subjects received an additional 1500 IU (300 mcg) dose if an obstetric complication occurred between the routine antepartum dose and birth or if extensive fetomaternal hemorrhage was measured after birth. Of the 270 women who gave birth to an Rh0(D)-positive baby, 248 women were evaluated for Rh0(D) immunization 6 to 11.5 months postpartum. None of these women developed antibodies against the Rh0(D) antigen. ITP In an open-label, single-arm, multicenter study, 98 Rh0(D)-positive adult subjects with chronic ITP and a platelet count of 30 x 109/L or less were treated with Rhophylac. Subjects received a single intravenous dose of 250 IU (50 mcg) per kg body weight. The primary efficacy endpoint was the response rate defined as achieving a platelet count of ≥ 30 x 109/L as well as an increase of > 20 x 109/L within 15 days after treatment with Rhophylac. Secondary efficacy endpoints included the response rate defined as an increase in platelet counts to ≥ 50 x 109/L within 15 days after treatment and, in subjects who had bleeding at baseline, the regression of hemorrhage defined as any decrease from baseline in the severity of overall bleeding status. Table 4 presents the primary response rates for the intent-to-treat (ITT) and per-protocol (PP) populations. Table 4: Primary Response Rates (ITT and PP Populations) Analysis Population No. Subjects No. Responders Primary Response Rate at Day 15 % Responders 95% Confidence Interval (CI) ITT 98 65 66.3% 56.5%, 74.9% PP 92 62 67.4% 57.3%, 76.1% The primary efficacy response rate (ITT population) demonstrated a clinically relevant response to treatment, i.e., the lower bound of the 95% confidence interval (CI) was greater than the predefined response rate of 50%. The median time to platelet response was 3 days, and the median duration of platelet response was 22 days. Table 5 presents the response rates by baseline platelet count for subjects in the ITT population. Table 5: Response Rates By Baseline Platelet Count (ITT Population) Baseline Platelet count (x 109/L) Total No. Subjects Response Rates at Day 15 No. (%) Subjects Achieving a Platelet Count of ≥ 30 x 109/L and an Increase of > 20 x 109/L No. (%) Subjects With an Increase in Platelet Counts to ≥ 50 x 109/L ≤ 10 38 15 (39.5) 10 (26.3) > 10 to 20 28 22 (78.6) 17 (60.7) > 20 to 30 27 24 (88.9) 22 (81.5) > 30* 5 4 (80.0) 5 (100.0) Overall (all subjects) 98 65 (66.3) 54 (55.1) * Reflects subjects with a platelet count of ≤ 30 × 109/L at screening but > 30 × 109/L immediately before treatment. During the study, an overall regression of hemorrhage was seen in 44 (88%, 95% CI: 76% to 94%) of the 50 subjects with bleeding at baseline. The percentage of subjects showing a regression of hemorrhage increased from 20% at Day 2 to 64% at Day 15. There was no evidence of an association between the overall hemorrhage regression rate and baseline platelet count. Approximately half of the 98 subjects in the ITT population had evidence of bleeding at baseline. Post-baseline, the percentage of subjects without bleeding increased to a maximum of 70.4% at Day 8. REFERENCES 7. Lazarus AH, Crow AR. Mechanism of action of IVIG and anti-D in ITP. Transfus Apher Sci. 2003;28:249-255. 8. Bichler J, Schöndorfer G, Pabst G, Andresen I. Pharmacokinetics of anti-D IgG in pregnant RhD-negative women. BJOG. 2003;110:39-45. 9. Ware RE, Zimmerman SA. Anti-D: mechanisms of action. Semin Hematol. 1998;35:14-22. 10. MacKenzie IZ, Bichler J, Mason GC, et al. Efficacy and safety of a new, chromatographically purified rhesus (D) immunoglobulin. Eur J Obstetr Gynecol Reprod Biol. 2004;117:154-161.

CLINICAL PHARMACOLOGY Carimune® NF contains a broad spectrum of antibody specificities against bacterial, viral, parasitic, and mycoplasma antigens, that are capable of both opsonization and neutralization of microbes and toxins. The 3 week half-life of Carimune® NF corresponds to that of Immune Globulin (Human) for intramuscular use, although individual variations in half-life have been observed.27,28 Appropriate doses of Carimune® NF restore abnormally low immunoglobulin G levels to the normal range. One hundred percent of the infused dose of IGIV-products is available in the recipient's circulation immediately after infusion. After approximately 6 days, equilibrium is reached between the intra- and extravascular compartments, with immunoglobulin G being distributed approximately 50% intravascular and 50% extravascular. In comparison, after the intramuscular injection of immune globulin, the IgG requires 2–5 days to reach its maximum concentration in the intravascular compartment. This concentration corresponds to about 40% of the injected dose.28 While Carimune® NF has been shown to be effective in some cases of Immune Thrombocytopenic Purpura (ITP) (see INDICATIONS AND USAGE), the mechanism of action in ITP has not been fully elucidated. Toxicity from overdose has not been observed on regimens of 0.4 g/kg body weight each day for 5 days.29–31 Sucrose is added to Carimune® NF for reasons of stability and solubility. Since sucrose is excreted unchanged in the urine when given intravenously, Carimune® NF may be given to diabetics without compensatory changes in insulin dosage regimen. Please see WARNINGS section. REFERENCES 27. Morell A, and Skvaril F: Struktur und biologische Eigenschaften von Immunglobulinen und g-Globulin-Präparaten. II. Eigenschaften von g-Globulin-Präparaten. Schweiz Med Wochenschr 1980; 110:80. 28. Morell A, Schürch B, Ryser D, et al: In vivo behaviour of gamma globulin preparations. Vox Sang 1980; 38:272. 29. Imbach P, Barandun S, d'Apuzzo V, et al: High-dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; 1:1228. 30. Barandun S, Morell A, Skvaril F: Clinical experiences with immunoglobulin for intravenous use, in Alving BM, Finlayson JS (eds): Immunoglobulins: Characteristics and Uses of Intravenous Preparations. DHHS Publication No. (FDA)-80-9005. US Government Printing Office, 1980, pp 31–35. 31. Schiff R, Sedlak D, Buckley R: Rapid infusion of Sandoglobulin™ in patients with primary humoral immunodeficiency. J Allergy Clin Immunol 88:61, 1991.

CLINICAL PHARMACOLOGY Mechanism of Action Treatment of Primary Humoral Immunodeficiency GAMUNEX (immune globulin intravenous (human) 10%) supplies a broad spectrum of opsonic and neutralizing IgG antibodies against bacteria or their toxins. The mechanism of action in PI has not been fully elucidated. Treatment of Idiopathic Thrombocytopenic Purpura The mechanism of action of high doses of immunoglobulins in the treatment of Idiopathic Thrombocytopenic Purpura (ITP) has not been fully elucidated. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy The precise mechanism of action in CIDP has not been fully elucidated. Pharmacokinetics Two randomized pharmacokinetic crossover trials were carried out with GAMUNEX (immune globulin intravenous (human) 10%) in 38 subjects with Primary Humoral Immunodeficiencies given 3 infusions 3 or 4 weeks apart of test product at a dose of 100-600 mg/kg body weight per infusion. One trial compared the pharmacokinetic characteristics of GAMUNEX (immune globulin intravenous (human) 10%) to GAMIMUNE N 10%, Immune Globulin Intravenous (Human), 10%, (study 100152) and the other trial compared the pharmacokinetics of GAMUNEX (immune globulin intravenous (human) 10%) (10% strength) with a 5% concentration of this product (study 100174). The ratio of the geometric least square means for dose-normalized IgG peak levels of GAMUNEX (immune globulin intravenous (human) 10%) and GAMIMUNE N was 0.996. The corresponding value for the dose-normalized area under the curve (AUC) of IgG levels was 0.990. The results of both PK parameters were within the pre-established limits of 0.080 and 1.25. Similar results were obtained in the comparison of GAMUNEX (immune globulin intravenous (human) 10%) 10% to a 5% concentration of GAMUNEX (immune globulin intravenous (human) 10%) . [3, 4] The main pharmacokinetic parameters of GAMUNEX (immune globulin intravenous (human) 10%) , measured as total IgG in study 100152 are displayed below: Table 13: PK Parameters of GAMUNEX (immune globulin intravenous (human) 10%) and GAMIMUNE N 10% (Study 100152) GAMUNEX GAMIMUNEN 10% N Mean SD Median N Mean SD Median Cmax (mg/mL) 17 19.04 3.06 19.71 17 19.31 4.17 19.30 Cmax-norm (kg/mL) 17 0.047 0.007 0.046 17 0.047 0.008 0.047 AUC(0-tn)a (mg*hr/mL) 17 6746.48 1348.13 6949.47 17 6854.17 1425.08 7119.86 AUC(0-tn)norma (kg*hr/mL) 17 16.51 1.83 16.95 17 16.69 2.04 16.99 T1/2b (days) 16 35.74 8.69 33.09 16 34.27 9.28 31.88 aPartial AUC: defined as pre-dose concentration to the last concentration common across both treatment periods in the same patient. bonly 15 subjects were valid for the analysis of T1/2 The two pharmacokinetic trials with GAMUNEX (immune globulin intravenous (human) 10%) show the IgG concentration/time curve follows a biphasic slope with a distribution phase of about 5 days characterized by a fall in serum IgG levels to about 65-75% of the peak levels achieved immediately post-infusion. This phase is followed by the elimination phase with a half-life of approximately 35 days [3, 4]. IgG trough levels were measured over nine months in the therapeutic equivalence trial (100175). Mean trough levels were 7.8 +/- 1.9 mg/mL for the GAMUNEX (immune globulin intravenous (human) 10%) treatment group and 8.2 +/- 2.0 mg/mL for the GAMIMUNE N, 10% control group [1]. Clinical Studies Treatment of Primary Immunodeficiency In a randomized, double-blind, parallel group clinical trial with 172 subjects with primary humoral immunodeficiencies (study 100175) GAMUNEX (immune globulin intravenous (human) 10%) was demonstrated to be at least as efficacious as GAMIMUNE N, Immune Globulin Intravenous (Human), in the prevention of any infection, i.e. validated plus clinically defined, non-validated infections of any organ system, during a nine month treatment period. Twenty six subjects were excluded from the Per Protocol analysis (2 due to non-compliance and 24 due to protocol violations). The endpoint was the proportion of subjects with at least one of the following validated infections: pneumonia, acute sinusitis and acute exacerbations of chronic sinusitis. Table 14: Primary Endpoint Per Protocol Analysis (Study 100175) GAMUNE (n=73) No. of subjects with at least one infection GAMIMUNE N (n=73) No. of subjects with at least one infection Mean Difference (90% confidence interval) p-Value Validated Infections 9 (12%) 17 (23%) -0.117 (-0.220, -0.015) 0.06 Acute Sinusitis 4 (5%) 10 (14%) Exacerbati on of Chronic 5 (7%) 6 (8%) Sinusitis Pneumonia 0 (0%) 2 (3%) Any Infection (Validated plus Clinically defined non-validated Infections) 56 (77%) 57(78%) -0.020 (-0.135, 0.096) 0.78 The annual rate of validated infections (Number of Infection/year/subject) was 0.18 in the group treated with GAMUNEX (immune globulin intravenous (human) 10%) and 0.43 in the group treated with GAMIMUNE N, 10% (p=0.023). The annual rates for any infection (validated plus clinically-defined, non-validated infections of any organ system) were 2.88 and 3.38, respectively (p=0.300). [1, 2] Treatment of Idiopathic Thrombocytopenic Purpura A double-blind, randomized, parallel group clinical trial with 97 ITP subjects was carried out to prove the hypothesis that GAMUNEX (immune globulin intravenous (human) 10%) was at least as effective as GAMIMUNE N, 10% in raising platelet counts from less than or equal to 20 x109/L to more than 50 x109/L within 7 days after treatment with 2 g/kg IGIV (study 100176). Twenty-four percent of the subjects were less than or equal to 16 years of age. GAMUNEX (immune globulin intravenous (human) 10%) was demonstrated to be at least as effective as GAMIMUNE N, 10% in the treatment of adults and children with acute or chronic ITP. [11] Table 15: Platelet Response of Per Protocol Analysis (Study 100176) GAMUNEX (n=39) GAMIMUNE N (n=42) Mean Difference (90% confidence interval) By Day 7 35 (90%) 35 (83%) 0.075 (-0.037, 0.186) By Day 23 35 (90%) 36 (86%) 0.051 (-0.058, 0.160) Sustained for 7 days 29 (74%) 25 (60%) 0.164 (0.003, 0.330) A trial was conducted to evaluate the clinical response to rapid infusion of GAMUNEX (immune globulin intravenous (human) 10%) in patients with ITP. The study involved 28 chronic ITP subjects, wherein the subjects received 1 g/kg GAMUNEX (immune globulin intravenous (human) 10%) on three occasions for treatment of relapses. The infusion rate was randomly assigned to 0.08, 0.11, or 0.14 mL/kg/min (8, 11 or 14 mg/kg/min). Pre-medication with corticosteroids to alleviate infusion-related intolerability was not permitted. Pre-treatment with antihistamines, anti-pyretics and analgesics was permitted. The average dose was approximately 1 g/kg body weight at all three prescribed rates of infusion (0.08, 0.11 and 0.14 mL/kg/min). All patients were administered each of the three planned infusions except seven subjects. Based on 21 patients per treatment group, the a posteriori power to detect twice as many drug-related adverse events between groups was 23%. Of the seven subjects that did not complete the study, five did not require additional treatment, one withdrew because he refused to participate without concomitant medication (prednisone) and one experienced an adverse event (hives); however, this was at the lowest dose rate level (0.08 mL/kg/min). Treatment of Chronic Inflammatory Demyelinating Polyneuropathy A multi-center, randomized, double-blind, Placebo-controlled trial (study 100538, The Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified CIDP Efficacy or ICE study) was conducted with GAMUNEX (immune globulin intravenous (human) 10%) .[43] This study included two separately randomized periods to assess whether GAMUNEX (immune globulin intravenous (human) 10%) was more effective than Placebo for the treatment of CIDP (assessed in the Efficacy Period for up to 24 weeks) and whether long-term administration of GAMUNEX (immune globulin intravenous (human) 10%) could maintain long-term benefit (assessed in the 24 week Randomized Withdrawal Period). In the Efficacy Period, there was a requirement for Rescue (crossover) to the alternate study drug if the subject did not improve and maintain this improvement until the end of the 24 week treatment period. Subjects entering the Rescue phase followed the same dosing and schedule as in the Efficacy period. Any subject who was rescued (crossed over) and did not improve and maintain this improvement was withdrawn from the study. Subjects who completed 24 weeks treatment in the Efficacy period or Rescue phase and responded to therapy were eligible for entry into a double-blind Randomized Withdrawal Period. Eligible subjects were re-randomized to GAMUNEX (immune globulin intravenous (human) 10%) or Placebo. Any subject who relapsed was withdrawn from the study. The Efficacy Period and the Rescue treatment started with a loading dose of 2 g/kg bw of GAMUNEX (immune globulin intravenous (human) 10%) or equal volume of Placebo given over 2-4 consecutive days. All other infusions (including the first infusion of the Randomized Withdrawal Period) were given as maintenance doses of 1 g/kg bw (or equivalent volume of Placebo) every three weeks. The Responder rates of the GAMUNEX (immune globulin intravenous (human) 10%) and Placebo treatment groups as measured by the INCAT score. The INCAT (Inflammatory Neuropathy Cause and Treatment) scale is used to assess functional disability of both upper and lower extremities in demyelinating polyneuropathy. The INCAT scale has upper and lower extremity components (maximum of 5 points for upper (arm disability) and maximum of 5 points for lower (leg disability)) that add up to a maximum of 10-points (0 is normal and 10 is severely incapacitated). [44] At the start of the efficacy portion of the study, the INCAT scores were as follows: Upper Extremity mean was 2.2 ± 1.0, and median was 2.0 with a range of 0 to 5; Lower Extremity mean was 1.9 ± 0.9, and median was 2.0 with a range of 1 to 5; Total Overall Score mean was 4.2 ± 1.4, and median was 4.0 with a range of 2 to 9. A Responder was defined as a subject with at least 1-point improvement from baseline in the adjusted INCAT score that was maintained through 24 weeks. Significantly more subjects with CIDP responded to GAMUNEX (immune globulin intravenous (human) 10%) : 28 of 59 subjects (47.5%) responded to GAMUNEX (immune globulin intravenous (human) 10%) compared with 13 of 58 subjects (22.4%) administered Placebo (25% difference; 95% CI 7%-43%]; p=0.006). The study included both subjects who were IGIV naive and subjects who had previous IGIV experience. The outcome was influenced by the group of subjects who experienced prior therapy with IGIV, as shown by the outcomes table, below. Time to relapse for the subset of 57 subjects who previously responded to GAMUNEX (immune globulin intravenous (human) 10%) was evaluated: 31 were randomly reassigned to continue to receive GAMUNEX (immune globulin intravenous (human) 10%) and 26 subjects were randomly reassigned to Placebo in the Randomized Withdrawal Period. Subjects who continued to receive GAMUNEX (immune globulin intravenous (human) 10%) experienced a significantly longer time to relapse versus subjects treated with Placebo (p=0.011). The probability of relapse was 13% with GAMUNEX (immune globulin intravenous (human) 10%) versus 45% with Placebo (hazard ratio, 0.19 [95% confidence interval, 0.05, 0.70]). Table 16: Outcomes in Intent-to-Treat Population Efficacy Period Efficacy Period GAMUNEX Placebo p-valuea Responder Non-Responder Responder Non-Responder All Subjects 28/59 (47.5%) 31/59 (52.5%) 13/58 (22.4%) 45/58 (77.6%) 0.006 IGIV Naïve Subjects 17/39 (43.6%) 22/39 (56.4%) 13/46 (28.3%) 33/46 (71.7%) 0.174 IGIV Experienced Subjects 11/20 (55.0%) 9/20 (45.0%) 0/12 (0%) 12/12 (100%) 0.002 ap-value based on Fisher's exact method The following table shows outcomes for the Rescue Phase (which are supportive data): Table 17: Outcomes in Rescue Phase Rescue Phase GAMUNEX Placebo p-valuea Success Failure Success Failure All Subjects 25/45 (55.6%) 20/45 (44.4%) 6/23 (26.1%) 17/23 (73.9%) 0.038 IGIV Naïve Subjects 19/33(57. 6%) 14/33 (42.4%) 6/18 (33.3%) 12/18 (66.7%) 0.144 IGIV Experienced Subjects 6/12 (50%) 6/12 (50%) 0/5 (0%) 5/5 (100%) 0.102 ap-value based on Fisher's exact method The following Kaplan-Meier curves show the outcomes for the Randomized Withdrawal Period: Figure 1: Outcome for Randomized Withdrawal Period REFERENCES 1. Kelleher J, F.G., Cyrus P, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune Deficiency (PID), 2000. Report on file. 2. Data on File. 3. Bayever E, M.F., Sundaresan P, Collins S, Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999. 4. Lathia C, E.B., Sundaresan PR, Schwartz L, A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100174). 2000. 43. Hughes RAC, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate/chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomized Placebo-controlled trial. Lancet Neurol 2008. 7:136-144. 44. Hughes R, Bensa S, Willison H, Van den BP, Comi G, Illa I, et al. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol 2001 Aug;50(2):195-201.

CLINICAL PHARMACOLOGY Clinical Efficacy Use of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) in patients with Primary Immunodeficiency is supported by the Phase 3 clinical study of subjects who were treated with 300 to 600 mg/kg every 21 to 28 days for 12 months. The 61 subjects in this study were between 6 to 72 years of age, 54% female and 46% male, and 93% Caucasian, 5% African-American, and 2% Asian. Three subjects were excluded from the per-protocol analysis due to non-study product related reasons. The primary efficacy endpoint was the annualized rate of specified acute serious bacterial infections, i.e., the mean number of specified acute serious bacterial infections per subject per year (see Table 2). Table 2: Summary of Validated Acute Serious Bacterial Infections for the Per-Protocol Analysis Number of Events Validated Infections a Bacteremia/Sepsis 0 Bacterial Meningitis 0 Osteomyelitis/Septic Arthritis 0 Bacterial Pneumonia 0 Visceral Abscess 0 Total 0 Hospitalizations Secondary to Infection 0 Mean Number of Validated Infections per Subject per Year 0 p-value b p < 0.0001 95% Confidence Interval b (0.000, 0.064) a Serious acute bacterial infections were defined by FDA and met specific diagnostic requirements. b The rate of validated infections was compared with a rate of 1 per subject per year, in accordance with recommendations by the FDA Blood Products Advisory Committee.10 The secondary efficacy endpoints in this study were the annualized rate of other specified validated bacterial infections (see Table 3), and the number of hospitalizations secondary to all validated infectious complications (see Table 2 and Table 3). Table 3: Summary of Validated Other Bacterial Infections Number of Events Validated Infections a Urinary Tract Infection 1 Gastroenteritis 1 Lower Respiratory Tract Infection: Tracheobronchitis, Bronchiolitis Without Evidence of Pneumonia 0 Lower Respiratory Tract Infection: Other Infections (e.g., Lung Abscess, Empyema) 0 Otitis Media 2 Total 4 Hospitalizations Secondary to Infection 0 Mean Number of Validated Infections per Subject per Year 0.07 95% Confidence Interval (0.018, 0.168) a Other bacterial infections that met specific diagnostic requirements. In this study, there were no validated acute serious bacterial infections in any of the treated subjects. The annualized rate of acute serious bacterial infections was significantly less than (p < 0.0001) the rate of one infection per year, in accordance with recommendations by the FDA Blood Products Advisory Committee.10 Four of the 61 subjects reported a total of 4 other specified validated bacterial infections. None were serious or severe, none resulted in hospitalization, and all resolved completely. The rate of all clinically-defined but non-validated infections was 3.4 infections per patient per year. These consisted primarily of recurrent episodes of commonly observed infections in this patient population - sinusitis, bronchitis, nasopharyngitis, urinary tract infections, and upper respiratory infections. Pharmacokinetics The overall pharmacokinetic characteristics of Immune Globulin Intravenous (Human) [IGIV] products are well-described in the literature.11,12 Following infusion, IGIV products show a biphasic decay curve. The initial (a) phase is characterized by an immediate post-infusion peak in serum IgG and is followed by rapid decay due to equilibration between the plasma and extravascular fluid compartments. The second (p) phase is characterized by a slower and constant rate of decay The commonly cited "normal" half life of 18 to 25 days is based on studies in which tiny quantities of radiolabeled IgG are injected into healthy individuals.13,14 When radiolabeled IgG was injected into patients with hypogammaglobulinemia or agammaglobulinemia, highly variable half-lives ranging from 12 to 40 days were observed.13,14 In other radiolabeled studies, high serum concentrations of IgG, and hypermetabolism associated with fever and infection, have been seen to coincide with a shortened half-life of IgG.14,15,16,17 In contrast, however, pharmacokinetic studies in immunodeficient patients are based on the decline of IgG concentrations following infusions of large quantities of gammaglobulin. In such trials, investigators have reported uniformly prolonged half-lives of 26 - 35 days.16,18,19,20,21,22 Pharmacokinetic parameters for GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) were determined from total IgG levels following the fourth infusion. A total of 61 subjects were enrolled and treated. Of these, 57 had sufficient pharmacokinetic data to be included in the dataset. Pharmacokinetic parameters are presented in Table 4. Table 4: Summary of Pharmacokinetic Parameters in 57 Subjects Parameter Median 95% Confidence Interval Elimination Half-Life ( T ½ days) 35 (31, 42) AUC0-21d (mg-days/dL) 29139 (27494, 30490) Cmax (Peak, mg/dL) 2050 (1980, 2200) Cmin (Trough, mg/dL) 1030 (939, 1110) Incremental recovery (mg/dL)/(mg/kg) 2.3 (2.2, 2.6) Abbreviations: AUC= area under the curve; Cmax=maximum concentration; Cmin= minimum concentration Median IgG trough levels were maintained between 960-1120 mg/dL. These dosing regimens maintained serum trough IgG levels considerably above 450 mg/dL, which is consistent with levels considered to be effective in the treatment of patients with Primary Immunodeficiency.23,24 The elimination half-life of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) of 35 days was similar to the half-lives reported for other IGIV products.13,14,15,17,25,26 REFERENCES 11. Schiff RI. Intraveneous immunoglobulins for treatment of antibody deficiencies. In: Good RA, Lindenlaub E, eds. The Nature, Cellular, and Biochemical Basis and Management of Immunodeficiencies. Symposium Vernried, West Germany. 21-25 September. Stuttgart: F. K. Schattauer Verlag; 1986:523-541. 12. Morell A. Pharmacokinetics of intravenous immunoglobulin preparations. In: Lee ML, Strand V, eds. Intravenous Immunoglobulins in Clinical Practice. New York: M. Dekker, Inc.; 1997:1-18. 13. Morell A, Skvaril F. Structure and Biological Properties of Immunoglobulins and y-Globulin Preparations. II. Properties of y-Globulin Preparations, Schweizerishche Medizinische Wochenschrift 1980; 110:80-85. 14. Waldmann TA, Strober W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1-110. 15. Stiehm ER. Standard and special human immune serum globulins as therapeutic agents. Pediatrics. 1979;63:301-319. 16. Lee ML, Mankarious S, Ochs H, Fischer S, Wedgwood RJ. The pharmacokinetics of total IgG, IgG subclasses, and type specific antibodies in immunodeficient patients. Immunol Invest. 1991;20:193-198. 17. Buckley RH. Immunoglobulin replacement therapy: indications and contraindications for use and variable IgG levels achieved. In: Alving BM, Finlayson JS, eds. Immunoglobulins: characteristics and use of intravenous preparations. Washington, D.C.: US Department of Health and Human Services; 1979:3-8. 18. Mankarious S, Lee M, Fischer S, et al. The half-lives of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med. 1988;112:634-640. 19. Pirofsky B. Safety and toxicity of a new serum immunoglobulin G intravenous preparation, IGIV pH 4.25. Rev Infect Dis. 1986;8 Suppl 4:S457-63. 20. Pirofsky B. Clinical use of a new pH 4.25 intravenous immunoglobulin preparation (Gamimune-N). J Infect. 1987;15 Suppl 1:29-37. 21. Schiff RI. Half-life and clearance of pH 6.8 and pH 4.25 immunoglobulin G intravenous preparations in patients with primary disorders of humoral immunity. Rev Infect Dis. 1986;8 Suppl 4:S449-56. 22. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy with intravenous gamma-globulin in 16 patients with severe primary humoral immunodeficiency. J Clin Immunol. 1986;6:256-264. 23. Eijkhout HW, Der Meer JW, Kallenberg CG, et al. The effect of two different dosages of intravenous immunoglobulin on the incidence of recurrent infections in patients with primary hypogammaglobulinemia. A randomized, double-blind, multicenter crossover trial. Ann Intern Med. 2001;135:165-174. 24. Roifman CM, Gelfand EW. Replacement therapy with high dose intravenous gamma-globulin improves chronic sinopulmonary disease in patients with hypogammaglobulinemia. Pediatr Infect Dis J. 1988;7:S92-S96. 25. Ballow M, Berger M, Bonilla FA, et al. Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%). Vox Sang. 2003;84:202-210. 26. Ochs HD, Pinciaro PJ, The Octagam Study Group. Octagam((R)) 5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J Clin Immunol. 2004;24:309-314.

Find Lowest Prices on Privigen®, Immune Globulin Intravenous (Human), 10% Liquid WARNING THROMBOSIS, RENAL DYSFUNCTION AND ACUTE RENAL FAILURE Thrombosis may occur with immune globulin products1-3, including Privigen. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors [see WARNINGS AND PRECAUTIONS, PATIENT INFORMATION]. Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Patients predisposed to renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, 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.4 Privigen does not contain sucrose. For patients at risk of thrombosis, renal dysfunction or failure, administer Privigen at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity [see DOSAGE AND ADMINISTRATION, WARNINGS AND PRECAUTIONS]. DESCRIPTION Privigen is a ready-to-use, sterile, 10% protein liquid preparation of polyvalent human immunoglobulin G (IgG) for intravenous administration. Privigen has a purity of at least 98% IgG, consisting primarily of monomers. The balance consists of IgG dimers ( ≤ 12%), small amounts of fragments and polymers, and albumin. Privigen contains ≤ 25 mcg/mL IgA. The IgG subclass distribution (approximate mean values) is IgG1, 67.8%; IgG2, 28.7%; IgG3, 2.3%; and IgG4, 1.2%. Privigen has an osmolality of approximately 320 mOsmol/kg (range: 240 to 440) and a pH of 4.8 (range: 4.6 to 5.0). Privigen contains approximately 250 mmol/L (range: 210 to 290) of L-proline (a nonessential amino acid) as a stabilizer and trace amounts of sodium. Privigen contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative. Privigen is prepared from large pools of human plasma by a combination of cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography. The IgG proteins are not subjected to heating or to chemical or enzymatic modification. The Fc and Fab functions of the IgG molecule are retained. Fab functions tested include antigen binding capacities, and Fc functions tested include complement activation and Fc-receptormediated leukocyte activation (determined with complexed IgG). Privigen does not activate the complement system or prekallikrein in an unspecific manner. All plasma units used in the manufacture of Privigen have been tested and approved for manufacture using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to HCV and HIV-½ as well as FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV and HIV-1 and found to be nonreactive (negative). In addition, the plasma has been tested for B19 virus (B19V) DNA by NAT. Only plasma that passed virus screening is used for production, and the limit for B19V in the fractionation pool is set not to exceed 104 IU of B19V DNA per mL. The manufacturing process for Privigen includes three steps to reduce the risk of virus transmission. Two of these are dedicated virus clearance steps: pH 4 incubation to inactivate enveloped viruses and virus filtration to remove, by size exclusion, both enveloped and nonenveloped viruses as small as approximately 20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity. These steps have been independently validated in a series of in vitro experiments for their capacity to inactivate and/or remove both enveloped and non-enveloped viruses. Table 5 shows the virus clearance during the manufacturing process for Privigen, expressed as the mean log10 reduction factor (LRF). Table 5: Virus Inactivation/Removal in Privigen* HIV-1 PRV BVDV WNV EMCV MVM Virus property Genome RNA DNA RNA RNA RNA DNA Envelope Yes Yes Yes Yes No No Size (nm) 80-100 120-200 50-70 50-70 25-30 18-24 Manufacturing step Mean LRF pH 4 incubation ≥ 5.4 ≥ 5.9 4.6 ≥ 7.8 nt nt Depth filtration ≥ 5.3 ≥ 6.3 2.1 3.0 4.2 2.3 Virus filtration ≥ 5.3 ≥ 5 ≥ 5.1 ≥ 5.9 ≥ 5.4 ≥ 5.5 Overall reduction (log10 units) ≥ 16.0 ≥ 17.7 ≥ 11.8 ≥ 16.7 ≥ 9.6 ≥ 7.8 HIV-1, human immunodeficiency virus type 1, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a nonspecific model for large enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for hepatitis C virus; WNV, West Nile virus; EMCV, encephalomyocarditis virus, a model for hepatitis A virus; MVM, minute virus of mice, a model for a small highly resistant non-enveloped DNA virus (e.g., parvovirus); LRF, log10 reduction factor; nt, not tested. * The virus clearance of human parvovirus B19 was investigated experimentally at the pH 4 incubation step. The estimated LRF obtained was ≥ 5.3. The manufacturing process was also investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered a model for CJD and its variant vCJD.18 Several of the production steps have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include octanoic acid fractionation ( ≥ 6.4 log10), depth filtration (2.6 log10), and virus filtration ( ≥ 5.8 log10). These studies provide reasonable assurance that low levels of vCJD/CJD agent infectivity, if present in the starting material, would be removed. REFERENCES 1. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226. 2. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218. 3. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34. 18. Gregori L, Maring J-A, MacAuley C, Stühler A, Löwer J, Blümel J. Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals 2004;32:1-10.

Find Lowest Prices on RHOPHYLAC Rh0(D) Immune Globulin Intravenous (Human) 1500 IU (300 mcg) Solution for Intravenous (IV) or Intramuscular (IM) Injection (Human) WARNING INTRAVASCULAR HEMOLYSIS IN ITP This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization. Intravascular hemolysis leading to death has been reported in Rh0(D)- positive patients treated for immune thrombocytopenic purpura (ITP) with Rh0(D) Immune Globulin Intravenous (Human) products. Intravascular hemolysis can lead to clinically compromising anemia and multi-system organ failure including acute respiratory distress syndrome (ARDS); acute renal insufficiency, renal failure, and disseminated intravascular coagulation (DIC) have been reported. Monitor patients treated for signs and symptoms of hemolysis 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 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). DESCRIPTION Rhophylac is a sterile Rh0(D) Immune Globulin Intravenous (Human) (anti-D) solution in a ready-to-use prefilled glass syringe for intravenous or intramuscular injection. One syringe contains at least 1500 IU (300 mcg) of IgG antibodies to Rh0(D) in a 2 mL solution, sufficient to suppress the immune response to at least 15 mL of Rh-positive RBCs.2 The product potency is expressed in IUs by comparison to the World Health Organization (WHO) standard, which is also the US and the European Pharmacopoeia standard. Plasma is obtained from healthy Rh0(D)-negative donors who have been immunized with Rh0(D)-positive RBCs. The donors are screened carefully to reduce the risk of receiving donations containing blood-borne pathogens. Each plasma donation used in the manufacture of Rhophylac is tested for the presence of HBV surface antigen (HBsAg), HIV-½, and HCV antibodies. In addition, plasma used in the manufacture of Rhophylac is tested by FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV, and HIV-1 and found to be negative. The credit plasma is also tested by NAT for hepatitis A virus (HAV) and B19 virus (B19V). Rhophylac is produced by an ion-exchange chromatography isolation procedure4, using pooled plasma obtained by plasmapheresis of immunized Rh0(D)-negative US donors. The manufacturing process includes a solvent/detergent treatment step (using tri-n-butyl phosphate and Triton™ X-100) that is effective in inactivating enveloped viruses such as HIV, HCV, and HBV.5,6 Rhophylac is filtered using a Planova® 15 nanometer (nm) virus filter that has been validated to be effective in removing both enveloped and nonenveloped viruses. Table 3 presents viral clearance and inactivation data from validation studies, expressed as the mean log10 reduction factor (LRF). Table 3: Virus Inactivation and Removal in Rhophylac HIV PRV BVDV MVM Virus property Genome RNA DNA RNA DNA Envelope Yes Yes Yes No Size (nm) 80-100 120-200 40-70 18-24 Manufacturing step Mean LRF Solvent/detergent treatment ≥ 6.0 ≥ 5.6 ≥ 5.4 Not tested Chromatographic process steps 4.5 ≥ 3.9 1.6 ≥ 2.6 Virus filtration ≥ 6.3 ≥ 5.6 ≥ 5.5 3.4 Overall reduction ≥ 16.8 ≥ 15.1 ≥ 12.5 ≥ 6.0 HIV, a model for HIV-1 and HIV-2; PRV, pseudorabies virus, a model for large, enveloped DNA viruses (e.g., herpes virus); BVDV, bovine viral diarrhea virus, a model for HCV and West Nile virus; MVM, minute virus of mice, a model for B19V and other small, non-enveloped DNA viruses. Rhophylac contains a maximum of 30 mg/mL of human plasma proteins, 10 mg/mL of which is human albumin added as a stabilizer. Prior to the addition of the stabilizer, Rhophylac has a purity greater than 95% IgG. Rhophylac contains less than 5 mcg/mL of IgA, which is the limit of detection. Additional excipients are approximately 20 mg/ mL of glycine and up to 0.25 M of sodium chloride. Rhophylac contains no preservative.  Human albumin is manufactured from pooled plasma of US donors by cold ethanol fractionation, followed by pasteurization. REFERENCES 2. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh0(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005;106:1532- 1537. 4. Stucki M, Moudry R, Kempf C, Omar A, Schlegel A, Lerch PG. Characterisation of a chromatographically produced anti-D immunoglobulin product. J Chromatogr B. 1997;700:241-248. 5. Horowitz B, Chin S, Prince AM, Brotman B, Pascual D, Williams B. Preparation and characterization of S/D-FFP, a virus sterilized “fresh frozen plasma”. J Thromb Haemost. 1991;65:1163. 6. Horowitz B, Bonomo R, Prince AM, Chin S, Brotman B, Shulman RW. Solvent/ detergent-treated plasma: a virus-inactivated substitute for fresh frozen plasma. Blood. 1992;79:826-831.

Carimune® NF [Immune Globulin Intravenous (Human), Nanofiltered] Lyophilized Preparation WARNING THROMBOSIS, RENAL DYSFUNCTION, or ACUTE RENAL FAILURE Thrombosis may occur with immune globulin products1-8, including Carimune NF. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors (see PRECAUTIONS: Thrombosis, PATIENT INFORMATION). Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur in predisposed patients with immune globulin intravenous (IGIV) products9–14, including Carimune NF. Patients predisposed to renal dysfunction include those with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, 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. Carimune NF contains sucrose. For patients at risk of thrombosis, renal dysfunction or acute renal failure, administer Carimune NF at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity (see DOSAGE AND ADMINISTRATION, and PRECAUTIONS: Thrombosis). DESCRIPTION Carimune® NF, Nanofiltered, Immune Globulin Intravenous (Human), is a sterile, highly purified polyvalent antibody product containing in concentrated form all the IgG antibodies which regularly occur in the donor population.15 This immunoglobulin preparation is produced by cold alcohol fractionation from the plasma of US donors. Part of the fractionation may be performed by another US-licensed manufacturer. Carimune® NF is made suitable for intravenous use by treatment at acid pH in the presence of trace amounts of pepsin.16,17 The manufacturing process by which Carimune® NF is prepared from plasma consists of fractionation and purification steps that comprise filtrations in the presence of filter aids. Four of these steps were validated for virus elimination of both enveloped and non-enveloped viruses. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents.18 To complement the existing virus elimination / inactivation mechanism in the Carimune® NF manufacturing process, nanofiltration (removing viruses via size-exclusion) was introduced as an additional virus removal step into the manufacturing process.19,20 Nanofiltration is performed prior to the viral inactivation step (pH 4 in presence of pepsin) in order to reduce the potential viral load before inactivation is performed. Treatment with pepsin at pH 4 rapidly inactivates enveloped viruses.21 The Carimune® NF manufacturing process provides a significant virus reduction capacity as shown in in vitro studies. The results, summarized in Table 1, demonstrate virus clearance during Carimune® NF manufacturing using model viruses for lipid enveloped and nonenveloped viruses. Table 1: Virus Elimination and Inactivation Virus HIV BVDV PRV SFV SV BEV Genome RNA RNA DNA RNA RNA RNA Envelope Yes Yes Yes Yes Yes No Size (nm) 80-100 40-60 120-200 50-70 50-70 28-30 Fractionation & Depth filtration 15.5 nt 16.0 9.3 12.4 14.1 pH 4 / pepsin ≥ 6.1 ≥ 4.4 ≥ 5.3 ≥ 6.8 nt nt Nanofiltration ≥ 4.9 ≥ 4.5 ≥ 4.4 nt ≥ 7.5 ≥ 5.1 Overall reduction ≥ 26 ≥ 9 ≥ 25 ≥ 16 ≥ 19 ≥ 19 HIV: Human immunodeficiency virus, model for HIV 1 and HIV 2 BVDV: Bovine viral diarrhea virus, model for HCV (Hepatitis C virus) PRV: Pseudorabies virus, model for large, enveloped DNA viruses (e.g., herpes virus) SFV: Semliki Forest virus, model for HCV SV: Sindbis virus, model for HCV BEV: Bovine enterovirus, model for HAV (Hepatitis A virus) nt: not tested PRV and the two model viruses for HCV, BVDV and SFV, were inactivated within 1/10, and HIV within ½ of the incubation time (pH 4/pepsin treatment) used during production of Carimune® NF. Several of the individual production steps in the Carimune® NF manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include precipitation (3.5 logs), depth filtrations (7.3 logs), and nanofiltration (4.4 logs).  These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. The preparation contains at least 96% of IgG and after reconstitution with a neutral unbuffered diluent has a pH of 6.6 ± 0.2. Most of the immunoglobulins are monomeric (7 S) IgG; the remainder consists of dimeric IgG and a small amount of polymeric IgG, traces of IgA and IgM and immunoglobulin fragments.22 The distribution of the IgG subclasses corresponds to that of normal serum.23–26 Final container lyophilized units are prepared so as to contain 3, 6, or 12 g protein with 1.67 g sucrose and less than 20 mg NaCl per gram of protein. The lyophilized preparation contains no preservative and may be reconstituted with sterile water, 5% dextrose or 0.9% saline to a solution with protein concentrations ranging from 3% to 12% (see Table 4). See Table 2 for calculated Carimune® NF osmolality (mOsm/kg) at each protein concentration. The patient's fluid, electrolyte, caloric requirements and renal function should be considered in selecting an appropriate diluent and concentration. Table 2: Calculated Carimune® NF Osmolality (mOsm/kg) Diluent Concentration 3% 6% 9% 12% 0.9% NaCI 498 690 882 1074 5% Dextrose 444 636 828 1020 Sterile Water 192 384 576 768 REFERENCES 1. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223–226. 2. Caress JB, Cartwright MS, Donofrio PD, Peacock JE: The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 2003; 60:1822–1824. 3. Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; 2:217–218. 4. Jordan S, Cunningham-Rundles C, McEwan R: Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transplant 2003; 3:653–664. 5. Wolberg AS, Kon RH, Monroe DM, Hoffman M: Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30–34. 6. Zaidan R, Al Moallem M, Wani BA, Shameena AR, Al Tahan AR, Daif AK, Al Rajeh S: Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurology 2003; 10:367–372. 7. Okuda D, Flaster M, Frey J, Sivakumar, K: Arterial thrombosis induced by IVIg and its treatment with tPA. Neurology 2003; 60:1825–1826. 8. Dalakas MC, Clark WM: Strokes, thromboembolic events, and IVIg. Rare incidents blemish an excellent safety record. Neurology 2003; 60:1736–1737. 9. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: Review of the literature and case report. Pharmacotherapy 1995; 15:765–772. 10. Cantú TG, Hoehn-Saric EW, Burgess KM, Racusen L, Scheel P: Acute renal failure associated with immunoglobulin therapy. Am J Kidney Dis 1995; 25:228–234.11. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Amer Soc Nephrology 1997; 8:1788–1793. 12. Rault R, Piraino B, Johnston JR, Oral A: Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol 1991, 36:83–86. 13. Michail S, Nakopoulou L, Stravrianopoulos I, Stamatiadis D, Avdikou K, Vaiopoulos G, Stathakis C: Acute renal failure associated with immunoglobulin administration. Nephrol Dial Transplant 1997; 12:1497–99. 14. Ashan N, Wiegand LA, Abendroth CS, Manning EC: Acute renal failure following immunoglobulin therapy. Am J Nephrol 1996; 16:532–6. 15. Gardi A: Quality control in the production of an immunoglobulin for intravenous use. Blut 1984; 48:337–344. 16. Römer J, Morgenthaler JJ, Scherz R, et al: Characterization of various immunoglobulinpreparations for intravenous application. I. Protein composition and antibody content. Vox Sang 1982; 42:62–73. 17. Römer J, Späth PJ, Skvaril F, et al: Characterization of various immunoglobulin preparations for intravenous application. II. Complement activation and binding to Staphylococcus protein A. Vox Sang 1982; 42:74–80. 18. Gregori L, Maring JA, MacAuley C et al: Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals 2004; 32:1–10. 19. Omar A, and Kempf C: Removal of neutralized model Parvoviruses and Enteroviruses in human IgG solutions by nanofiltration. Transfusion 2002; 42:1005–1010. 20. Späth P, Kempf C, and Gold R: Herstellung, Verträglichkeit und Virussicherheit von intravenösem Immunglobulin. In “Immunglobuline in der Neurobiologie” (P. Berlit, ed.), Steinkopff Verlag, Darmstadt, BRD 2001, pp 1–42. 21. Kempf C, Morgenthaler JJ, Rentsch M, and Omar A: Viral safety and manufacturing of an intravenous immunoglobulin. In “Intravenous Immunoglobulin Research and Therapy” Kazatchkine and Morell, eds. Parthenon Publishing Group. 1996, pp 11–18. 22. Römer J, Späth PJ: Molecular composition of immunoglobulin preparations and its relation to complement activation, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press 1981, pp 123–130. 23. Skvaril F, Roth-Wicky B, and Barandun S: IgG subclasses in human-g-globulin preparations for intravenous use and their reactivity with Staphylococcus protein A. Vox Sang 1980; 38:147. 24. Skvaril F: Qualitative and quantitative aspects of IgG subclasses in i.v. immunoglobulin preparations, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 113–122. 25. Skvaril F, and Barandun S: In vitro characterization of immunoglobulins for intravenous use, in Alving BM, Finlayson JS (eds): Immunoglobulins: Characteristics and Uses of Intravenous Preparations, DHHS Publication No. (FDA)-80-9005. US Government Printing Office, 1980, pp 201–206. 26. Burckhardt JJ, Gardi A, Oxelius V, et al: Immunoglobulin G subclass distribution in three human intravenous immunoglobulin preparations. Vox Sang 1989; 57:10–14.

Gamunex® Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified 10% Liquid Preparation WARNING: ACUTE RENAL DYSFUNCTION AND ACUTE RENAL FAILURE Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis and death. [24] Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. GAMUNEX (immune globulin intravenous human 10%) does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer. (See DOSAGE AND ADMINISTRATION and WARNINGS and PRECAUTIONS for important information intended to reduce the risk of acute renal failure.) DESCRIPTION Immune Globulin Intravenous (Human), 10% Caprylate/Chromatography Purified (GAMUNEX) is a ready-to-use sterile solution of human immune globulin protein for intravenous administration. GAMUNEX (immune globulin intravenous human 10%) consists of 9%–11% protein in 0.16–0.24 M glycine. Not less than 98% of the protein has the electrophoretic mobility of gamma globulin. GAMUNEX (immune globulin intravenous human 10%) contains trace levels of fragments, IgA (average 0.046 mg/mL), and IgM. The distribution of IgG subclasses is similar to that found in normal serum. GAMUNEX (immune globulin intravenous human 10%) doses of 1 g/kg correspond to a glycine dose of 0.15 g/kg. While toxic effects of glycine administration have been reported [12], the doses and rates of administration were 3 – 4 fold greater than those for GAMUNEX (immune globulin intravenous human 10%) . In another study it was demonstrated that intravenous bolus doses of 0.44 g/kg glycine were not associated with serious adverse effects [13] Caprylate is a saturated medium-chain (C8) fatty acid of plant origin. Medium chain fatty acids are considered to be essentially non-toxic. Human subjects receiving medium chain fatty acids parenterally have tolerated doses of 3.0 to 9.0 g/kg/day for periods of several months without adverse effects [14]. Residual caprylate concentrations in the final container are no more than 0.216 g/L (1.3 mmol/L).The measured buffer capacity is 35 mEq/L and the osmolality is 258 mOsmol/kg solvent, which is close to physiological osmolality (285-295 mOsmol/kg). The pH of GAMUNEX (immune globulin intravenous human 10%) is 4.0 – 4.5. GAMUNEX (immune globulin intravenous human 10%) contains no preservative and is latex-free. GAMUNEX is made from large pools of human plasma by a combination of cold ethanol fractionation, caprylate precipitation and filtration, and anion-exchange chromatography. Isotonicity is achieved by the addition of glycine. GAMUNEX (immune globulin intravenous human 10%) is incubated in the final container (at the low pH of 4.0 – 4.3), for a minimum of 21 days at 23° to 27°C. The product is intended for intravenous administration. The capacity of the manufacturing process to remove and/or inactivate enveloped and non-enveloped viruses has been validated by laboratory spiking studies on a scaled down process model, using the following enveloped and non-enveloped viruses: human immunodeficiency virus, type I (HIV-1) as the relevant virus for HIV-1 and HIV–2; bovine viral diarrhea virus (BVDV) as a model for hepatitis C virus; pseudorabies virus (PRV) as a model for large DNA viruses (e.g. herpes viruses); Reo virus type 3 (Reo) as a model for non-enveloped viruses and for its resistance to physical and chemical inactivation; hepatitis A virus (HAV) as relevant non-enveloped virus, and porcine parvovirus (PPV) as a model for human parvovirus B19. Overall virus reduction was calculated only from steps that were mechanistically independent from each other and truly additive. In addition, each step was verified to provide robust virus reduction across the production range for key operating parameters. Table 12: Log10 Virus Reduction Process Step Log10 Virus Reduction Enveloped Viruses Non-enveloped Viruses HIV PRV BVDV Reo HAV PPV Caprylate Precipitation/Depth Filtration C/Ia C/I 2.7 ≥ 3.5 ≥ 3.6 4.0 Caprylate Incubation ≥ 4.5 ≥ 4.6 ≥ 4.5 NAb NA NA Depth Filtrationd CAPc CAP CAP ≥ 4.3 ≥ 2.0 3.3 Column Chromatography ≥ 3.0 ≥ 3.3 4.0 ≥ 4.0 ≥ 1.4 4.2 Low pH Incubation (21 days) ≥ 6.5 ≥ 4.3 ≥ 5.1 NA NA NA Global Reduction ≥ 14.0 ≥ 12.2 ≥ 16.3 ≥ 7.5 ≥ 5.0 8.2 a C/I - Interference by caprylate precluded determination of virus reduction for this step. Although removal of viruses is likely to occur at the caprylate precipitation/depth filtration step, BVDV is the only enveloped virus for which reduction is claimed. The presence of caprylate prevents detection of other, less resistant enveloped viruses and therefore their removal cannot be assessed. b Not Applicable – This step has no effect on non-enveloped viruses. c CAP - The presence of caprylate in the process at this step prevents detection of enveloped viruses, and their removal cannot be assessed. d Some mechanistic overlap occurs between depth filtration and other steps. Therefore, Talecris Biotherapeutics, Inc. has chosen to exclude this step from the global virus reduction calculations. Additionally, the manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents [38-42 ]. Several of the individual production steps in the GAMUNEX (immune globulin intravenous human 10%) manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps include two depth filtrations (in sequence, a total of ≥ 6.6 logs). These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed. REFERENCE 12. Hahn, R.G., H.P. Stalberg, and S.A. Gustafsson, Intravenous infusion of irrigating fluids containing glycine or mannitol with and without ethanol. J Urol, 1989. 142(4): p. 1102-5. 13. Tai VM, M.E., Lee-Brotherton V, Manley JJ, Nestmann ER, Daniels JM. Safety Evaluation of Intravenous Glycine in Formulation Development. in J Pharm Pharmaceut Sci. 2000. 14. Traul, K.A., et al., Review of the toxicologic properties of medium-chain triglycerides. Food Chem Toxicol, 2000. 38(1): p. 79-98. 38. Stenland CJ, Lee DC, Brown P, et al. Partitioning of human and sheep forms of the pathogenic prion protein during the purification of therapeutic proteins from human plasma. Transfusion 2002. 42(11):1497-500. 39. Lee DC, Stenland CJ, Miller, JL, et al. A direct relationship between the partitioning of the pathogenic prion protein and transmissible spongiform encephalopathy infectivity during the purification of plasma proteins. Transfusion 2001. 41(4):449-55. 40. Lee DC, Stenland CJ, Hartwell, RC, et al. Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein. J Virol Methods 2000. 84(1):77-89. 41. Cai K, Miller JL, Stenland, CJ, et al. Solvent-dependent precipitation of prion protein. Biochim Biophys Acta 2002. 1597(1):28-35. 42. Trejo SR, Hotta JA, Lebing W, et al. Evaluation of virus and prion reduction in a new intravenous immunoglobulin manufacturing process. Vox Sang 2003. 84(3):176-87.

Find Lowest Prices on GAMMAGARD LIQUID [Immune Globulin Intravenous (Human)] 10% DESCRIPTION GAMMAGARD LIQUID Immune Globulin Intravenous (Human), 10% is a ready-for-use sterile, liquid preparation of highly purified and concentrated immunoglobulin G (IgG) antibodies. The distribution of the IgG subclasses is similar to that of normal plasma.1,2 The Fc and Fab functions are maintained in GAMMAGARD LIQUID. Pre-kallikrein activator activity is not detectable. GAMMAGARD LIQUID (immune globulin intravenous human 10%) contains 100 mg/mL protein. At least 98% of the protein is gammaglobulin, the average immunoglobulin A (IgA) concentration is 37µg/mL, and immunoglobulin M is present in trace amounts. GAMMAGARD LIQUID (immune globulin intravenous human 10%) contains a broad spectrum of IgG antibodies against bacterial and viral agents. Glycine (0.25M) serves as a stabilizing and buffering agent, and there are no added sugars, sodium or preservatives. The pH is 4.6 to 5.1. The osmolality is 240-300 mOsmol/kg, which is similar to physiological osmolality (285 to 295 mOsmol/kg).3 GAMMAGARD LIQUID is manufactured from large pools of human plasma. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collection and plasma preparation. Each individual plasma donation used in the manufacture of GAMMAGARD LIQUID (immune globulin intravenous human 10%) is collected only at FDA approved blood establishments and is tested by FDA licensed serological tests for Hepatitis B Surface Antigen (HBsAg), and for antibodies to Human Immunodeficiency Virus (HIV-1/HIV-2) and Hepatitis C Virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of the plasma are tested for the presence of HIV-1 and HCV by FDA licensed Nucleic Acid Testing (NAT) and found negative. IgGs are purified from plasma pools using a modified Cohn-Oncley cold ethanol fractionation process, as well as cation and anion exchange chromatography. To further improve the margin of safety, three dedicated, independent and effective virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely solvent/detergent (S/D) treatment,4,5 35 nm nanofiltration,6,7 and a low pH incubation at elevated temperature.8,9 The S/D process includes treatment with an organic mixture of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80 at 18°C to 25°C for a minimum of 60 minutes. In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed under extreme conditions (e.g., at minimum S/D concentrations, incubation time and temperature for the S/D treatment). Virus clearance studies for GAMMAGARD LIQUID (immune globulin intravenous human 10%) performed in accordance with good laboratory practices (Table 1) have demonstrated that: S/D treatment inactivates the lipid-enveloped viruses investigated to below detection limits within minutes. 35 nm nanofiltration removes lipid-enveloped viruses to below detection limits and reduces the non-lipid enveloped viruses HAV and B19V As determined by a polymerase chain reaction assay nanofiltration reduced B19V by a mean log10 reduction factor of 4.8 genome equivalents. Treatment with low pH at elevated temperature of 30°C to 32°C inactivates lipid-enveloped viruses and encephalomyocarditis virus (EMCV, model for HAV) to below detection limits, and reduces mice minute virus (MMV, model for B19V). Table 1: Three Dedicated Independent Virus Inactivation/Removal Steps Mean Log10 Reduction Factors a (RFs) For Each Virus and Manufacturing Step Virus type Family Enveloped RNA Enveloped DNA Non-enveloped RNA Non-enveloped DNA Retroviridae Flaviviridae Herpesviridae Picornaviridae Parvoviridae Virus HIV-1 BVDV WNV PRV HAV EMCV MMV SD treatment > 4.5 > 6.2 n.a. > 4.8 n.d. n.d. n.d. 35 nm nanofiltration > 4.5 > 5.1 > 6.2 > 5.6 5.7 1.4 2.0 Low pH treatment > 5.8 > 5.5 > 6.0 > 6.5 n.d.b > 6.3 3.1 Overall log reduction factor (ORF) > 14.8 > 16.8 > 12.2 > 16.9 5.7 b > 7.7 5.1 Abbreviations: HIV-1, Human Immunodeficiency Virus Type 1; BVDV, Bovine Viral Diarrhea Virus (model for Hepatitis C Virus and other lipid enveloped RNA viruses); WNV, West Nile Virus; PRV, Pseudorabies Virus (model for ipid enveloped DNA viruses, including Hepatitis B Virus); EMCV, Encephalomyocarditis Virus (model for non-lipid enveloped RNA viruses, including Hepatitis A virus [HAV]); MMV, Mice Minute Virus (model for non-lipid enveloped DNA viruses, including B19 virus [B19V]); n.d. (not done), n.a. (not applicable). a For the calculation of these RF data from virus clearance study reports, applicable manufacturing conditions were used. Log10 RFs on the order of 4 or more are considered effective for virus clearance in accordance with the Committee for Medicinal Products for Human Use (CHMP, formerly CPMP) guidelines. b No RF obtained due to immediate neutralization of HAV by the anti-HAV antibodies present in the product. REFERENCES 1. Skvaril F. Qualitative and quantitative aspects of IgG subclasses in i.v. immunoglobulin preparations. In: Nydegger UE, ed. Immunotherapy. London: Academic Press; 1981:118-122. 2. French M. Serum IgG subclasses in normal adults. Monogr Allergy. 1986;19:100-107. 3. Lacy CF, Armstrong LL, Goldman MP, Lance LL. Appendix: Abbreviations and Measurements. Drug Information Handbook. Lexi-Comp; 1999:1254. 4. Horowitz B, Prince AM, Hamman J, Watklevicz C. Viral safety of solvent/detergent-treated blood products. Blood Coagul Fibrinolysis. 1994;5 Suppl 3:S21-S28. 5. Kreil TR, Berting A, Kistner O, Kindermann J. West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data. Transfusion. 2003;43:1023-1028. 6. Hamamoto Y, Harada S, Kobayashi S, et al. A novel method for removal of human immunodeficiency virus: filtration with porous polymeric membranes. Vox Sang. 1989;56:230-236. 7. Yuasa T, Ishikawa G, Manabe S, Sekiguchi S, Takeuchi K, Miyamura T. The particle size of hepatitis C virus estimated by filtration through microporous regenerated cellulose fibre. J Gen Virol. 1991 ;72 (Pt 8):2021 -2024. 8. Kempf C, Jentsch P, Poirier B, et al. Virus inactivation during production of intravenous immunoglobulin. Transfusion. 1991;31:423-427. 9. Louie RE, Galloway CJ, Dumas ML, Wong MF, Mitra G. Inactivation of hepatitis C virus in low pH intravenous immunoglobulin. Biologicals. 1994;22:13-19.

INDICATIONS Privigen is an Immune Globulin Intravenous (Human), 10% Liquid indicated for the treatment of the following conditions. Primary Humoral Immunodeficiency Privigen is indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency (CVID), X-linked agammaglobulinemia, Wiskott- Aldrich syndrome, and severe combined immunodeficiencies. Chronic Immune Thrombocytopenic Purpura Privigen is indicated for the treatment of patients with chronic immune thrombocytopenic purpura (ITP) to raise platelet counts. DOSAGE AND ADMINISTRATION Table 1: Recommended Dosage and Administration for Privigen Indication Dose Initial infusion rate Maintenance infusion rate (as tolerated) Primary Immunodeficiency 200-800 mg/kg (2-8 mL/kg) every 3-4 weeks 0.5 mg/kg/min (0.005 mL/kg/min) Increase to 8 mg/kg/min (0.08 mL/kg/min) Chronic Immune Thrombocytopenic Purpura 1 g/kg (10 mL/kg) for 2 consecutive days 0.5 mg/kg/min (0.005 mL/kg/min) Increase to 4 mg/kg/min (0.04 mL/kg/min) Dosage For Primary Humoral Immunodeficiency (PI) As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The recommended dose of Privigen for patients with PI is 200 to 800 mg/kg (2 to 8 mL/ kg), administered every 3 to 4 weeks. If a patient misses a dose, administer the missed dose as soon as possible, and then resume scheduled treatments every 3 or 4 weeks, as applicable. Adjust the dosage over time to achieve the desired serum IgG trough levels and clinical responses. No randomized, controlled trial data are available to determine an optimal trough level in patients receiving immune globulin therapy. Dosage For Chronic Immune Thrombocytopenic Purpura (ITP) The recommended dose of Privigen for patients with chronic ITP is 1 g/kg (10 mL/kg) administered daily for 2 consecutive days, resulting in a total dosage of 2 g/kg. Carefully consider the relative risks and benefits before prescribing the high dose regimen (e.g., 1 g/kg/day for 2 days) in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload [see WARNINGS AND PRECAUTIONS]. Preparation And Handling Privigen is a clear or slightly opalescent, colorless to pale yellow solution. Inspect parenteral drug products visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the solution is cloudy, turbid, or if it contains particulate matter. DO NOT SHAKE. Do not freeze. Do not use if Privigen has been frozen. Privigen should be at room temperature (up to 25°C [77°F]) at the time of administration. Do not use Privigen beyond the expiration date on the product label. The Privigen vial is for single-use only. Promptly use any vial that has been entered. Privigen contains no preservative. Discard partially used vials or unused product in accordance with local requirements. Infuse Privigen using a separate infusion line. Prior to use, the infusion line may be flushed with Dextrose Injection, USP (D5W) or 0.9% Sodium Chloride for Injection, USP. Do not mix Privigen with other IGIV products or other intravenous medications. However, Privigen may be diluted with Dextrose Injection, USP (D5W). An infusion pump may be used to control the rate of administration. If large doses of Privigen are to be administered, several vials may be pooled using aseptic technique. Begin infusion within 8 hours of pooling. Administration Privigen is for intravenous administration only. Monitor the patient's vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient. Ensure that patients with pre-existing renal insufficiency are not volume depleted. For patients judged to be at risk for renal dysfunction or thrombosis, administer Privigen at the minimum dose and infusion rate practicable, and discontinue Privigen administration if renal function deteriorates [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. The following patients may be at risk of developing systemic reactions (mimicking symptoms of an inflammatory response or infection) on rapid infusion of Privigen (greater than 4 mg/kg/min [0.04 mL/kg/min]): 1) those who have never received Privigen or another IgG product or who have not received it within the past 8 weeks, and 2) those who are switching from another IgG product. These patients should be started at a slow rate of infusion (e.g., 0.5 mg/kg/min [0.005 mL/kg/min] or less) and gradually increase as tolerated. HOW SUPPLIED Dosage Forms And Strengths Privigen is a liquid solution containing 10% IgG (0.1 g/mL) for intravenous infusion. Privigen is supplied in a single-use, tamper-evident vial containing the labeled amount of functionally active IgG. Each product presentation includes a package insert and the following components: Presentation Carton NDC Number Components 50 mL 44206-436-05 Vial containing 5 grams of protein (NDC 44206-436-90) 100 mL 44206-437-10 Vial containing 10 grams of protein (NDC 44206-437-91) 200 mL 44206-438-20 Vial containing 20 grams of protein (NDC 44206-438-92) 400 mL 44206-439-40 Vial containing 40 grams of protein (NDC 44206-439-93) Storage And Handling Keep Privigen in its original carton to protect it from light. Each vial has an integral suspension band and a label with two peel-off strips showing the product name, lot number, and expiration date. When stored at room temperature (up to 25°C [77°F]), Privigen is stable for up to 36 months, as indicated by the expiration date printed on the outer carton and vial label. Do not freeze. The Privigen packaging components are not made with natural rubber latex. Manufactured by: CSL Behring AG, Bern, Switzerland. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: Nov 2013

INDICATIONS Rhophylac is an Rh0(D) Immune Globulin Intravenous (Human) (anti-D) product that is indicated for the suppression of Rh isoimmunization in non-sensitized Rh0(D)-negative patients and for the treatment of immune thrombocytopenic purpura (ITP) in Rh0(D)- positive patients. Suppression Of Rh Isoimmunization Pregnancy And Obstetric Conditions Rhophylac is indicated for suppression of rhesus (Rh) isoimmunization in non-sensitized Rh0(D)-negative women with an Rh-incompatible pregnancy, including: Routine antepartum and postpartum Rh prophylaxis Rh prophylaxis in cases of: Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage) Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma) An Rh-incompatible pregnancy is assumed if the fetus/baby is either Rh0(D)-positive or Rh0(D)-unknown or if the father is either Rh0(D)-positive or Rh0(D)-unknown. Incompatible Transfusions Rhophylac is indicated for the suppression of Rh isoimmunization in Rh0(D)-negative individuals transfused with Rh0(D)-positive red blood cells (RBCs) or blood components containing Rh0(D)-positive RBCs. Treatment can be given without a preceding exchange transfusion when the transfused blood represents less than 20% of the total circulating RBCs. If the volume exceeds 20%, an exchange transfusion should be considered prior to administering Rhophylac. ITP Rhophylac is indicated in Rh0(D)-positive, non-splenectomized adult patients with chronic ITP to raise platelet counts. DOSAGE AND ADMINISTRATION As with all blood products, patients should be observed for at least 20 minutes following administration of Rhophylac. Preparation And Handling Rhophylac is a clear or slightly opalescent, colorless to pale yellow solution. Inspect Rhophylac visually for particulate matter and discoloration prior to administration.  Do not use if the solution is cloudy or contains particulates. Prior to intravenous use, ensure that the needle-free intravenous administration system is compatible with the tip of the Rhophylac glass syringe. Do not freeze. Bring Rhophylac to room temperature before use. Rhophylac is for single use only. Dispose of any unused product or waste material in accordance with local requirements. Suppression Of Rh Isoimmunization Rhophylac should be administered by intravenous or intramuscular injection. If large doses (greater than 5 mL) are required and intramuscular injection is chosen, it is advisable to administer Rhophylac in divided doses at different sites. Ensure the site of administration will allow the injection to reach the muscle if Rhophylac is administered intramuscularly. Consider intravenous administration if reaching the muscle is of concern [see Postmarketing Experience]. Do not administer Rhophylac subcutaneously into the fatty tissue. Table 1 provides dosing guidelines based on the condition being treated. Table 1: Dosing Guidelines for Suppression of Rh Isoimmunization Indication Timing of Administration Dose* (Administer by Intravenous or Intramuscular Injection) Rh-incompatible pregnancy Routine antepartum prophylaxis At Week 28-30 of gestation 1500 IU (300 mcg) Postpartum prophylaxis (required only if the newborn is Rh0(D)-positive) Within 72 hours of birth 1500 IU (300 mcg)† Obstetric complications (e.g., miscarriage, abortion, threatened abortion, ectopic pregnancy or hydatidiform mole, transplacental hemorrhage resulting from antepartum hemorrhage) Within 72 hours of complication 1500 IU (300 mcg)† Invasive procedures during pregnancy (e.g., amniocentesis, chorionic biopsy) or obstetric manipulative procedures (e.g., external version, abdominal trauma) Within 72 hours of procedure 1500 IU (300 mcg)† Excessive fetomaternal hemorrhage ( > 15 mL) Within 72 hours of complication 1500 IU (300 mcg) plus: 100 IU (20 mcg) per mL fetal RBCs in excess of 15 mL if excess transplacental bleeding is quantified or An additional 1500 IU (300 mcg) dose if excess transplacental bleeding cannot be quantified Incompatible transfusions Within 72 hours of exposure 100 IU (20 mcg) per 2 mL transfused blood or per 1 mL erythrocyte concentrate IU, international units; mcg, micrograms. * A 1500 IU (300 mcg) dose of Rhophylac will suppress the immunizing potential of ≤ 15 mL of Rh0(D)-positive RBCs. † The dose of Rhophylac must be increased if the patient is exposed to > 15 mL of Rh0(D)-positive RBCs; in this case, follow the dosing guidelines for excessive fetomaternal hemorrhage. ITP For treatment of ITP, ADMINISTER RHOPHYLAC BY THE INTRAVENOUS ROUTE ONLY [see Preparation and Handling]. Do not administer intramuscularly. A 250 IU (50 mcg) per kg body weight dose of Rhophylac is recommended for patients with ITP. The following formula can be used to calculate the recommended amount of Rhophylac to administer: Dose (IU) x body weight (kg) = Total IU / 1500 IU per syringe = Number of syringes Rhophylac should be administered at a rate of 2 mL per 15 to 60 seconds. HOW SUPPLIED Dosage Forms And Strengths 1500 IU (300 mcg) per 2 mL prefilled, ready-to-use, glass syringe for IV or IM use. Rhophylac 1500 IU (300 mcg) is supplied in packages of one or ten (10) prefilled, ready-to-use, glass syringe(s), each containing 2 mL liquid for injection. Each syringe is accompanied by a SafetyGlide™ needle for intravenous or intramuscular use. Each product presentation includes a package insert and the following components: Presentation Carton NDC Number Components 1500 IU (300 mcg) 44206-300-01 Single-use, prefilled 2 mL syringe (NDC 44206300-90) SafetyGlide needle 1500 IU (300 mcg) Multipack 44206-300-10 Ten single-use, prefilled 2 mL syringes (NDC 44206-300-90) Ten SafetyGlide needles Storage And Handling DO NOT FREEZE. Rhophylac contains no preservatives; do not store at room temperature. Store at 2 to 8°C (36 to 46°F) for a shelf life of 36 months from the date of manufacture, as indicated by the expiration date printed on the outer carton and syringe label. Keep Rhophylac in its original carton to protect it from light. The prefilled Rhophylac syringe is not made with natural rubber latex. Manufactured by: CSL Behring AG, Bern, Switzerland, US License No. 1766. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: May 2015

INDICATIONS Immunodeficiency Carimune® NF is indicated for the maintenance treatment of patients with primary immunodeficiencies (PID), e.g., common variable immunodeficiency, X-linked agammaglobulinemia, severe combined immunodeficiency.30,32-34 Carimune® NF is preferable to intramuscular Immune Globulin (Human) preparations in treating patients who require an immediate and large increase in the intravascular immunoglobulin level28, in patients with limited muscle mass, and in patients with bleeding tendencies for whom intramuscular injections are contraindicated. The infusions must be repeated at regular intervals. Please see DOSAGE AND ADMINISTRATION section. Immune Thrombocytopenic Purpura (ITP) Acute A controlled study was performed in children in which Carimune® was compared with steroids for the treatment of acute (defined as less than 6 months duration) ITP. In this study sequential platelet levels of 30,000, 100,000, and 150,000/μL were all achieved faster with Carimune® than with steroids and without any of the side effects associated with steroids.29,35 However, it should be noted that many cases of acute ITP in childhood resolve spontaneously within weeks to months. Carimune® has been used with good results in the treatment of acute ITP in adult patients.36–38 In a study involving 10 adults with ITP of less than 16 weeks duration, Carimune® therapy raised the platelet count to the normal range after a 5 day course. This effect lasted a mean of over 173 days, ranging from 30 to 372 days.39 Chronic Children and adults with chronic (defined as greater than 6 months duration) ITP have also shown an increase (sometimes temporary) in platelet counts upon administration of Carimune®.35,39-43 Therefore, in situations that require a rapid rise in platelet count, for example prior to surgery or to control excessive bleeding, use of Carimune® should be considered. In children with chronic ITP, Carimune® therapy resulted in a mean rise in platelet count of 312,000/μL with a duration of increase ranging from 2 to 6 months.40,43 Carimune® therapy may be considered as a means to defer or avoid splenectomy.42–44 In adults, Carimune® therapy has been shown to be effective in maintaining the platelet count in an acceptable range with or without periodic booster therapy. The mean rise in platelet count was 93,000/μL and the average duration of the increase was 20–24 days.39,40 However, it should be noted that not all patients will respond. Even in those patients who do respond, this treatment should not be considered to be curative. DOSAGE AND ADMINISTRATION It is generally advisable not to dilute plasma derivatives with other infusable drugs. Carimune® NF should be given by a separate infusion line. No other medications or fluids should be mixed with Carimune® NF preparation. Carimune® NF should be used with caution in patients with pre-existing renal insufficiency and in patients judged to be at increased risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs). In these cases especially it is important to assure that patients are not volume depleted prior to Carimune® NF infusion. No prospective data are presently available to identify a maximum safe dose, concentration, and rate of infusion in patients determined to be at increased risk of acute renal failure. In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum practicable. For patients judged to be at risk for developing renal dysfunction, Carimune® NF should be infused at a rate less than 2 mg/kg/min. For patients judged to be at an increased risk for thrombosis, a maximum infusion rate of less than 2 mg/kg/min for patients is recommended (see PRECAUTIONS: Thrombosis). If side effects occur, the infusion should be stopped or slowed until the symptoms subside. Adult And Child Substitution Therapy The recommended dose of Carimune® NF in primary immunodeficiency is 0.4 to 0.8 g/kg of body weight administered once every three to four weeks by intravenous infusion. The first infusion of Carimune® NF in previously untreated agammaglobulinemic or hypogammaglobulinemic patients must be given as a 3% immunoglobulin solution (see Reconstitution). Subsequent infusions may be administered at a higher concentration if the patient shows good tolerance. An initial infusion rate of 0.5 mg/kg/min is recommended. If tolerated, after 30 minutes, the rate may be increased to 1 mg/kg/min for the next 30 minutes. Thereafter, the rate may be gradually increased in a stepwise manner up to a maximum of 3 mg/kg/min as tolerated. Refer to Table 3 for the corresponding infusion rates in mg/kg/min or mL/kg/min for all product concentrations. The first infusion of Carimune® NF in previously untreated agammaglobulinemic and hypogammaglobulinemic patients may lead to systemic side effects. The nature of these effects has not been fully elucidated. Some of them may be due to the release of proinflammatory cytokines by activated macrophages in immunodeficient recipients.67,68  Subsequent administration of Carimune® NF to immunodeficient patients as well as to normal individuals usually does not cause further untoward side effects. Therapy of Idiopathic Thrombocytopenic Purpura (ITP) Induction The recommended dose of Carimune® NF for the treatment of ITP is 0.4 g/kg of body weight on 2–5 consecutive days. An immunoglobulin solution of 6% (see Reconstitution) is recommended for use in ITP. The recommended initial infusion rate for the treatment of ITP is 0.5 mg/kg/min. If tolerated, after 30 minutes, the rate may be increased to 1 mg/kg/min for the next 30 minutes. Thereafter, the rate may be gradually increased in a stepwise manner up to a maximum of 3 mg/kg/min as tolerated. Refer to Table 3 for the corresponding infusion rates in mg/kg/ min or mL/kg/min for all product concentrations. Acute ITP – Childhood In acute ITP of childhood, if an initial platelet count response to the first two doses is adequate (30–50,000/μL), therapy may be discontinued after the second day of the 5 day course.35 Maintenance – Chronic ITP In adults and children, if after induction therapy the platelet count falls to less than 30,000/ μL and/or the patient manifests clinically significant bleeding, 0.4 g/kg of body weight may be given as a single infusion. If an adequate response does not result, the dose can be increased to 0.8–1 g/kg of body weight given as a single infusion.36,69,70 Table 3: Infusion Rates for Carimune® NF Concentrations Concentration (%) Initial Infusion Rate: 0.5 mg/kg/min 1 mg/kg/min 2 mg/kg/min* Maximum Infusion Rate†: 3 mg/kg/min 3% 0.0167 mL/kg/min 0.033 mL/kg/min 0.067 mL/kg/min 0.10 mL/kg/min 6% 0.008 mL/kg/min 0.016/ mL/kg/ min 0.033 mL/kg/min 0.050 mL/kg/min 9% 0.006 mL/kg/min 0.011 mL/kg/min 0.022 mL/kg/min 0.033 mL/kg/min 12% 0.004 mL/kg/min 0.008 mL/kg/min 0.016 mL/kg/min 0.025 mL/kg/min * Maximum infusion rate for patients at risk of renal dysfunction or thromboembolic events. † For patients not at risk of renal dysfunction of thromboembolic events. Reconstitution (see also pictures next page) 1. Remove the protective plastic caps from the lyophilisate (LYO) and diluents bottles and disinfect both rubber stoppers with alcohol. Remove the protective cover from one end of the transfer set and insert the exposed needle through the rubber stopper into the bottle containing the diluent (picture 1). 2a. and 2b. Remove the second protective cover from the other end of the transfer set. Grasp both bottles as shown in picture 2a, quickly plunge the diluent bottle onto the lyophilisate bottle and bring the bottles into an upright position. Only if this is done quickly and the bottles are immediately brought into an upright position can the vacuum in the lyophilisate bottle be maintained, thus speeding up reconstitution and facilitating the transfer. Allow the diluent to flow into the lyophilisate bottle (picture 2b). 3. Once the appropriate amount of diluent is transferred (see Table 4), lift the diluent bottle off the spike to release the vacuum (picture 3). This will reduce foaming and facilitate dissolution. Remove the spike. 4. Swirl vigorously but do not shake, otherwise a foam will form which is very slow to subside (picture 4). The lyophilisate dissolves within a few minutes. To reconstitute Carimune® NF from the individual vial package, or when using other diluents or higher concentrations, Table 4 indicates the volume of sterile diluent required. Observing aseptic technique, this volume should be drawn into a sterile hypodermic syringe and needle. The diluent is then injected into the corresponding Carimune® NF vial size. Table 4: Required Diluent Volume* Target 3 g 6 g 12 g Concentration Vial Vial Vial 3% 100 mL 200 mL † 6% 50 mL 100 mL 200 mL 9% 33 mL 66 mL 132 mL 12% 25 mL 50 mL 100 mL * In patients judged to be at increased risk of developing renal insufficiency and thromboembolic events, the concentration and infusion rate of Carimune® NF should be the minimum practicable. † Container not large enough to permit this concentration. If large doses of Carimune® NF are to be administered, several reconstituted vials of identical concentration and diluent may be pooled in an empty sterile glass or plastic i.v. infusion container using aseptic technique. Carimune® NF normally dissolves within a few minutes, though in exceptional cases it may take up to 20 minutes. DO NOT SHAKE! Excessive shaking will cause foaming. Any undissolved particles should respond to careful rotation of the bottle. Avoid foaming. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Filtering of Carimune® NF is acceptable but not required. Pore sizes of 15 microns or larger will be less likely to slow infusion, especially with higher Carimune® NF concentrations. Antibacterial filters (0.2 microns) may be used. When reconstitution of Carimune® NF occurs outside of sterile laminar air flow conditions, administration must begin promptly with partially used vials discarded. When reconstitution is carried out in a sterile laminar flow hood using aseptic technique, administration may begin within 24 hours provided the solution has been refrigerated during that time. Do not freeze Carimune® NF solution. PROCEED WITH INFUSION ONLY IF SOLUTION IS CLEAR AND AT APPROXIMATELY ROOM TEMPERATURE. HOW SUPPLIED Carimune® NF is available as a white lyophilized powder in 3, 6 and 12 g size vials. The only diluents which may be used to reconstitute the product are sterile (0.9%) Sodium Chloride Injection USP, 5% Dextrose, or Sterile Water. Each product presentation includes a package insert and the following components: Presentation Carton NDC Number Components 3 g 44206-416-03 Carimune NF in a single-use vial [NDC 44206-416-90] One double-ended transfer spike for reconstitution 6 g 44206-417-06 Carimune NF in a single-use vial [NDC 44206-417-91] One double-ended transfer spike for reconstitution 12 g 44206-418-12 Carimune NF in a single-use vial [NDC 44206-418-92] One double-ended transfer spike for reconstitution Storage And Handling Carimune® NF should be stored at room temperature not exceeding 30°C (86°F). The preparation should not be used after the expiration date printed on the label. REFERENCES 28. Morell A, Schürch B, Ryser D, et al: In vivo behaviour of gamma globulin preparations. Vox Sang 1980; 38:272. 29. Imbach P, Barandun S, d'Apuzzo V, et al: High-dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; 1:1228. 30. Barandun S, Morell A, Skvaril F: Clinical experiences with immunoglobulin for intravenous use, in Alving BM, Finlayson JS (eds): Immunoglobulins: Characteristics and Uses of Intravenous Preparations. DHHS Publication No. (FDA)-80-9005. US Government Printing Office, 1980, pp 31–35. 32. Joller PW, Barandun S, Hitzig WH: Neue Möglichkeiten der Immunglobulin- Ersatztherapie bei Antikörpermangel-Syndrom. Schweiz Med Wochenschr 1980; 110:1451. 33. Barandun S, Imbach P, Morell A, et al: Clinical indications for immunoglobulin infusion, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 275–282. 34. Cunningham-Rundles C, Smithwick EM, Siegal FP, et al: Treatment of primary humoral immunodeficiency disease with intravenous (pH 4.0 treated) gamma globulin, in Nydegger UE (ed): Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 283–290. 35. Imbach P, Wagner HP, Berchtold W, et al: Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet 1985; 2:464. 36. Fehr J, Hofmann V, Kappeler U: Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med 1982; 306:1254. 37. Müller-Eckhardt C, Küenzlen E, Thilo-Körner D, et al: High-dose intravenous immunoglobulin for posttransfusion purpura. N Engl J Med 1983; 308:287. 38. Wenske G, Gaedicke G, Küenzlen E, et al: Treatment of idiopathic thrombocytopenic purpura in pregnancy by high-dose intravenous immunoglobulin. Blut 1983; 46:347–353. 39. Newland AC, Treleaven JG, Minchinton B, et al: High-dose intravenous IgG in adults with autoimmune thrombocytopenia. Lancet 1983; 1:84–87. 40. Bussel JB, Kimberly RP, Inman RD, et al: Intravenous gammaglobulin for chronic idiopathic thrombocytopenic purpura. Blood 1983; 62:480–486. 41. Abe T, Matsuda J, Kawasugi K, et al: Clinical effect of intravenous immunoglobulin in chronic idiopathic thrombocytopenic purpura. Blut 1983; 47:69–75. 42. Bussel JB, Schulman I, Hilgartner MW, et al: Intravenous use of gamma globulin in the treatment of chronic immune thrombocytopenic purpura as a means to defer splenectomy. J Pediatr 1983; 103:651–654. 43. Imholz B, et al: Intravenous immunoglobulin (i.v. IgG) for previously treated acute or for chronic idiopathic thrombocytopenic purpura (ITP) in childhood: A prospective multicenter study. Blut 1988; 56:63–68. 44. Lusher JM, and Warrier I: Use of intravenous gamma globulin in children with idiopathic thrombocytopenic purpura and other immune thrombocytopenias. Am J Med 1987; 83 (suppl 4A):10–16. 69. Bussel JB, Pham LC, Hilgartner MW, et al: Long-term maintenance of adults with ITP using intravenous gamma globulin. Abstract, American Society of Hematology. New Orleans, December, 1985. 70. Imbach PA, Kühne T, Holländer G: Immunologic aspects in the pathogenesis and treatment of immune thrombocytopenic purpura in children. Current opinion in Pediatrics 1997; 9:35–40. Manufactured by: CSL Behring AG, Bern, Switzerland. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: September 2013

INDICATIONS Gamunex is an immune globulin intravenous (human) 10% liquid indicated for the treatment of: Primary Humoral Immunodeficiency (PI) GAMUNEX (immune globulin intravenous (human) 10%) is indicated as replacement therapy of primary humoral immunodeficiency This includes, but is not limited to, congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies [16-23]. Idiopathic Thrombocytopenic Purpura (ITP) GAMUNEX (immune globulin intravenous (human) 10%) is indicated in Idiopathic Thrombocytopenic Purpura to rapidly raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery [5-10]. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) GAMUNEX (immune globulin intravenous (human) 10%) is indicated for the treatment of CIDP to improve neuromuscular disability and impairment and for maintenance therapy to prevent relapse. DOSAGE AND ADMINISTRATION For intravenous use only GAMUNEX (immune globulin intravenous (human) 10%) consists of 9%–11% protein in 0.16–0.24 M glycine. The buffering capacity of GAMUNEX (immune globulin intravenous (human) 10%) is 35.0 mEq/L (0.35 mEq/g protein). A dose of 1 g/kg body weight therefore represents an acid load of 0.35 mEq/kg body weight. The total buffering capacity of whole blood in a normal individual is 45–50 mEq/L of blood, or 3.6 mEq/kg body weight [15]. Thus, the acid load delivered with a dose of 1 g/kg of GAMUNEX (immune globulin intravenous (human) 10%) would be neutralized by the buffering capacity of whole blood alone, even if the dose was infused instantaneously. Preparation and Handling GAMUNEX (immune globulin intravenous (human) 10%) should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid. Do not freeze. Solutions that have been frozen should not be used. The GAMUNEX (immune globulin intravenous (human) 10%) vial is for single use only. GAMUNEX (immune globulin intravenous (human) 10%) contains no preservative. Any vial that has been entered should be used promptly. Partially used vials should be discarded. GAMUNEX (immune globulin intravenous (human) 10%) should be infused using a separate line by itself, without mixing with other intravenous fluids or medications the subject might be receiving. GAMUNEX (immune globulin intravenous (human) 10%) is not compatible with saline. If dilution is required, GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated. Content of vials may be pooled under aseptic conditions into sterile infusion bags and infused within 8 hours after pooling. Do not mix with immune globulin intravenous (IGIV) products from other manufacturers. Do not use after expiration date. Treatment of Primary Humoral Immunodeficiency As there are significant differences in the half-life of IgG among patients with primary immunodeficiencies, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The dose of GAMUNEX (immune globulin intravenous (human) 10%) for replacement therapy in primary immune deficiency diseases is 300 to 600 mg/kg body weight (3-6 mL/kg) administered every 3 to 4 weeks. The dosage may be adjusted over time to achieve the desired trough levels and clinical responses. Treatment of Idiopathic Thrombocytopenic Purpura GAMUNEX (immune globulin intravenous (human) 10%) may be administered at a total dose of 2 g/kg, divided in two doses of 1 g/kg (10 mL/kg) given on two consecutive days or into five doses of 0.4 g/kg (4 mL/kg) given on five consecutive days. If after administration of the first of two daily 1 g/kg (10 mL/kg) doses, an adequate increase in the platelet count is observed at 24 hours, the second dose of 1g/kg (10 mL/kg) body weight may be withheld. Forty-eight ITP subjects were treated with 2 g/kg GAMUNEX (immune globulin intravenous (human) 10%) , divided in two 1 g/kg doses (10 mL/kg) given on two successive days. With this dose regimen 35/39 subjects (90%) responded with a platelet count from less than or equal to 20 x109/L to more than or equal to 50 x109/L within 7 days after treatment. [11] The high dose regimen (1 g/kg × 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy GAMUNEX (immune globulin intravenous (human) 10%) may be initially administered as a total loading dose of 2 g/kg (20 mL/kg) given in divided doses over two to four consecutive days. GAMUNEX (immune globulin intravenous (human) 10%) may be administered as a maintenance infusion of 1 g/kg (10 mL/kg) administered over 1 day or divided into two doses of 0.5 g/kg (5 mL/kg) given on two consecutive days, every 3 weeks. Administration GAMUNEX (immune globulin intravenous (human) 10%) should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if turbid and/or if discoloration is observed. Only administer intravenously. GAMUNEX (immune globulin intravenous (human) 10%) should be at room temperature during administration. Only 18 gauge needles should be used to penetrate the stopper for dispensing product from the 10 mL vial; 16 gauge needles or dispensing pins should only be used with 25 mL vial sizes and larger. Needles or dispensing pins should only be inserted once and be within the stopper area delineated by the raised ring. The stopper should be penetrated perpendicular to the plane of the stopper within the ring. GAMUNEX vial size Gauge of needle to penetrate stopper 10 mL 18 gauge 25, 50, 100, 200 mL 16 gauge Any vial that has been opened should be used promptly. Partially used vials should be discarded. If dilution is required, GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W). Rate of Administration It is recommended that GAMUNEX (immune globulin intravenous (human) 10%) should initially be infused at a rate of 0.01 mL/kg per minute (1 mg/kg per minute) for the first 30 minutes. If well-tolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg per minute (8 mg/kg per minute). Indication Initial Infusion rate (first 30 minutes) Maximum infusion rate (if tolerated) PI 1 mg/kg/min 8 mg/kg/min ITP 1 mg/kg/min 8 mg/kg/min CIDP 2 mg/kg/min 8 mg/kg/min Certain severe adverse drug reactions may be related to the rate of infusion. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. Ensure that patients with pre-existing renal insufficiency are not volume depleted; discontinue GAMUNEX (immune globulin intravenous (human) 10%) if renal function deteriorates. For patients at risk of renal dysfunction or thromboembolic events, administer GAMUNEX (immune globulin intravenous (human) 10%) at the minimum infusion rate practicable. Incompatibilities GAMUNEX (immune globulin intravenous (human) 10%) is not compatible with saline. If dilution is required, GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W). No other drug interactions or compatibilities have been evaluated. Shelf Life GAMUNEX (immune globulin intravenous (human) 10%) may be stored for 36 months at 2-8ºC (36-46ºF) from the date of manufacture AND product may be stored at temperatures not to exceed 25ºC (77º F) for up to 6 months any time during the 36 month shelf life , after which the product must be immediately discarded. Special Precautions for Storage Do not freeze. Frozen product should not be used. Do not use after expiration date HOW SUPPLIED Dosage Forms and Strength GAMUNEX (immune globulin intravenous (human) 10%) is supplied in 1.0 g, 2.5 g, 5 g, 10 g, or 20 g single use bottles. 1 g in 10 mL solution 2.5 g in 25 mL solution 5 g in 50 mL solution 10 g in 100 mL solution 20 g in 200 mL solution GAMUNEX (immune globulin intravenous (human) 10%) is supplied in single-use, tamper evident vials (shrink band) containing the labeled amount of functionally active IgG. The three larger vial size labels incorporate integrated hangers. The components used in the packaging for GAMUNEX (immune globulin intravenous (human) 10%) are latex-free. GAMUNEX (immune globulin intravenous (human) 10%) is supplied in the following sizes: NDC Number Size Grams Protein 13533-645-12 10 mL 1.0 13533-645-15 25 mL 2.5 13533-645-20 50 mL 5.0 13533-645-71 100 mL 10.0 13533-645-24 200 mL 20.0 GAMUNEX (immune globulin intravenous (human) 10%) may be stored for 36 months at 2 - 8°C (36 - 46°F), AND product may be stored at temperatures not to exceed 25°C (77°F) for up to 6 months anytime during the 36 month shelf life, after which the product must be immediately used or discarded. Do not freeze. Do not use after expiration date. REFERENCES 5. Blanchette, V.S., M.A. Kirby, and C. Turner, Role of intravenous immunoglobulin G in autoimmune hematologic disorders. Semin Hematol, 1992. 29(3 Suppl 2): p. 72-82. 6. Lazarus, A.H., J. Freedman, and J.W. Semple, Intravenous immunoglobulin and anti-D in idiopathic thrombocytopenic purpura (ITP): mechanisms of action. Transfus Sci, 1998. 19(3): p. 289-94. 7. Semple, J.W., A.H. Lazarus, and J. Freedman, The cellular immunology associated with autoimmune thrombocytopenic purpura: an update. Transfus Sci, 1998. 19(3): p. 245-51. 8. Imbach, P.A., Harmful and beneficial antibodies in immune thrombocytopenic purpura. Clin Exp Immunol, 1994. 97(Suppl 1): p. 25-30. 9. Bussel, J.B., Fc receptor blockade and immune thrombocytopenic purpura. Semin Hematol, 2000. 37(3): p. 261-6. 10. Imbach, P., et al., Immunthrombocytopenic purpura as a model for pathogenesis and treatment of autoimmunity. Eur J Pediatr, 1995. 154(9 Suppl 4): p. S60-4. 11. Cyrus P, F.G., Kelleher J, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2000. Report on file. 15. Guyton, A., Textbook of Medical Physiology. 5th Edition. 1976, Philadelphia: W.B. Saunders. 499-500. 16. Ammann, A.J., et al., Use of intravenous gamma-globulin in antibody immunodeficiency: results of a multicenter controlled trial. Clin Immunol Immunopathol, 1982. 22(1): p. 60-7. 17. Buckley, R.H. and R.I. Schiff, The use of intravenous immune globulin in immunodeficiency diseases. N Engl J Med, 1991. 325(2): p. 110-7. 18. Cunningham-Rundles, C. and C. Bodian, Common variable immunodeficiency: clinical and immunological features of 248 patients. Clin Immunol, 1999. 92(1): p. 34-48. 19. Nolte, M.T., et al., Intravenous immunoglobulin therapy for antibody deficiency. Clin Exp Immunol, 1979. 36(2): p. 237-43. 20. Pruzanski, W., et al., Relationship of the dose of intravenous gammaglobulin to the prevention of infections in adults with common variable immunodeficiency. Inflammation, 1996. 20(4): p. 353-9. 21. Roifman, C.M., H. Levison, and E.W. Gelfand, High-dose versus low-dose intravenous immunoglobulin in hypogammaglobulinaemia and chronic lung disease. Lancet, 1987. 1(8541): p. 1075-7. 22. Sorensen, R.U. and S.H. Polmar, Efficacy and safety of high-dose intravenous immune globulin therapy for antibody deficiency syndromes. Am J Med, 1984. 76(3A): p. 83-90. 23. Stephan, J.L., et al., Severe combined immunodeficiency: a retrospective single-center study of clinical presentation and outcome in 117 patients. J Pediatr, 1993. 123(4): p. 564-72. 24. Cayco, A.V., M.A. Perazella, and J.P. Hayslett, Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol, 1997. 8(11): p. 1788-94. Manufactured by: Talecris Biotherapeutics, Inc. Research Triangle Park, NC 27709 USA. September 2008. FDA Rev date: 9/12/2008

INDICATIONS Primary Immunodeficiency GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) is indicated for the treatment of primary immunodeficiency disorders associated with defects in humoral immunity. These include but are not limited to congenital X-linked agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.15,22 DOSAGE AND ADMINISTRATION GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) should be at room temperature during administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use if particulate matter and/or discoloration is observed. Only clear or slightly opalescent and colorless or pale yellow solutions are to be administered. GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) should only be administered intravenously. Other routes of administration have not been evaluated. The use of an in-line filter is optional. For patients with Primary Immunodeficiency, monthly doses of approximately 300 - 600 mg/kg infused at 3 to 4 week intervals are commonly used.23,24 As there are significant differences in the half-life of IgG among patients with Primary Immunodeficiency, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The minimum serum concentration of IgG necessary for protection varies among patients and has not been established by controlled clinical studies. Rate of Administration During the first infusion of the Phase 3 clinical study, GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) was infused at an initial rate of 0.5 mL/kg/hr (0.8 mg/kg/min). The rate was gradually increased every 30 minutes to a rate of 5.0 mL/kg/hr (8.9 mg/kg/min) if it was well tolerated. However, some patients completed the infusion before the maximum rate could be obtained. During subsequent infusions the initial rate and the rate of escalation were based on their previous infusion history; however, the maximum rate attained during the first infusion was used throughout the remainder of the study. The mean rate attained by all patients was 4.3 mL/kg/hr. Fifty-eight subjects (95%) achieved a maximum rate of 4.0 mL/kg/hr or greater and of these, 16 subjects (26%) attained a rate of 5.0 mL/kg/hr. In general, it is recommended that patients beginning therapy with IGIV or switching from one IGIV product to another be started at the lower rates and then advanced to the maximal rate if they have tolerated several infusions at intermediate rates of infusion. It is important to individualize rates for each patient. As noted in the WARNINGS section, patients who have underlying renal disease or who are judged to be at risk of developing thrombotic events should not be infused rapidly with any IGIV product. Although there are no prospective studies demonstrating that any concentration or rate of infusion is completely safe, it is believed that risk is decreased at lower rates of infusion.46 Therefore, as a guideline, it is recommended that these patients who are judged to be at risk of renal dysfunction or thrombotic complications be gradually titrated up to a more conservative maximal rate of less than 3.3 mgIgG/kg/min ( < 2mL/kg/hr). A rate of administration that is too rapid may cause flushing and changes in pulse rate and blood pressure. Slowing or stopping the infusion usually results in the prompt disappearance of signs. The infusion may then be resumed at a rate that is comfortable for the patient. Drug Interactions Antibodies in IGIV products may interfere with patient responses to live vaccines, such as those for measles, mumps and rubella.47,48,49 The immunizing physician should be informed of recent therapy with IGIV products so that appropriate precautions can be taken. Admixtures of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) with other drugs and intravenous solutions have not been evaluated. It is recommended that GAMMAGARD LIQUID be administered separately from other drugs or medications that the patient may be receiving. The product should not be mixed with IGIV products from other manufacturers. Normal saline should not be used as a diluent. If dilution is preferred, GAMMAGARD LIQUID may be diluted with 5% dextrose in water (D5W).50 No other drug interactions or compatibilities have been evaluated. HOW SUPPLIED GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) is supplied in single use bottles as follows: NDC Number Volume Grams 0944-2700-02 10 mL 1.0 0944-2700-03 25 mL 2.5 0944-2700-04 50 mL 5.0 0944-2700-05 100 mL 10.0 0944-2700-06 200 mL 20.0 Storage Refrigeration: 36 months storage at refrigerated temperature 2° to 8°C (36°-46°F). Do not freeze. Room Temperature: 9 months storage at room temperature 25°C, (77°F) within the first 24 months of the date of manufacture. See below for detailed storage information. The total storage time of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) depends on the point of time the vial is transferred to room temperature. Examples for total storage times are illustrated in Figure 1. The new expiration date must be recorded on the package when the product is transferred to room temperature. Figure 1: Storage Guidelines Months from Date of Manufacture Storage Details: Example 1: If the product is taken out of the refrigerator after 3 months from date of manufacture, it can be stored for 9 months at room temperature. Total storage time is 12 months. Example 2: If the product is taken out of the refrigerator after 21 months from the date of manufacture, it can be stored for 3 additional months at room temperature. Total storage time is 24 months. After 24 months from date of manufacture, product cannot be stored at room temperature. REFERENCES 15. Stiehm ER. Standard and special human immune serum globulins as therapeutic agents. Pediatrics. 1979;63:301-319. 22. Schiff RI, Rudd C. Alterations in the half-life and clearance of IgG during therapy with intravenous gamma-globulin in 16 patients with severe primary humoral immunodeficiency. J Clin Immunol. 1986;6:256-264. 46. Tan E, Hajinazarian M, Bay W, Neff J, Mendell JR. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol. 1993;50:137-139. 47. Morbidity and Mortality Weekly Report. Measles, Mumps, and Rubella; Vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps. Recommendations for the Advisory Committee on Immunization Practices (ACIP). 98 A.D.;47. 48. Peter G. Summary of major changes in the 1994 Red Book: American Academy of Pediatrics. Report of the Committee on Infectious Disease. Pediatrics. 1994;93:1000-1002. 49. Siber GR, Werner BG, Halsey NA, et al. Interference of immune globulin with measles and rubella immunization. J Pediatr. 1993;122:204-211. 50. Data on file, Baxter Healthcare Corporation. To enroll in the confi dential, industry-wide Patient Notifi cation System, call 1-888-UPDATE U (1-888-873-2838). Baxter Healthcare Corporation, Westlake Village, CA 91362 USA. april 2005. FDA rev date: n/a

PATIENT INFORMATION Inform patients of the early signs of hypersensitivity reactions to Privigen (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis), and advise them to notify their physician if they experience any of these symptoms. Inform patients to immediately report the following signs and symptoms to their physician: Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath, which may suggest kidney problems Instruct patients to immediately report symptoms of thrombosis. These symptoms may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body. Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting, which may suggest aseptic meningitis syndrome Fatigue, increased heart rate, yellowing of skin or eyes, and dark-colored urine, which may suggest hemolysis Severe breathing problems, lightheadedness, drops in blood pressure, and fever, which may suggest TRALI (a condition typically occurring within 1 to 6 hours following transfusion) Inform patients that Privigen is made from human blood and may contain infectious agents that can cause disease (e.g., viruses and, theoretically the CJD agent). Explain that the risk that Privigen may transmit an infectious agent has been reduced by screening the plasma donors, by testing donated plasma for certain virus infections, and by inactivating or removing certain viruses during manufacturing, and counsel patients to report any symptoms that concern them. Inform patients that administration of IgG may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella), and instruct them to notify their immunizing physician of recent therapy with Privigen.

PATIENT INFORMATION (See Boxed Warning and WARNINGS and PRECAUTIONS Sections) Inform patients to immediately report the following to their physician: signs and symptoms of renal failures, such as decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath signs and symptoms of aseptic meningitis, such as headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting signs and symptoms of hemolysis, such as fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine signs and symptoms of TRALI, such as severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. TRALI typically occurs within 1 to 6 hours following transfusion Inform patients that GAMUNEX is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses, and, theoretically, the CJD agent). Inform patients that the risk GAMUNEX (immune globulin intravenous (human) 10%) may transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing the donated plasma for certain virus infections and by inactivating and/or removing certain viruses during manufacturing.. Inform patients that administration of IgG may interfere with the response to live viral vaccines such as measles, mumps and rubella. Inform patients to notify their immunizing physician of therapy with GAMUNEX (immune globulin intravenous (human) 10%) .

PATIENT INFORMATION Patients should be instructed to immediately report symptoms of decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (which may suggest kidney damage) to their physicians.

OVERDOSE No information provided. CONTRAINDICATIONS Carimune® NF is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin. Individuals with IgA deficiency, especially those who have known antibody against IgA, or hypersensitivity to immunoglobulins should only receive Carimune® NF with utmost caution due to the risk of severe immediate hypersensitivity reactions including anaphylaxis.

OVERDOSE No information provided. CONTRAINDICATIONS GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) is contraindicated in patients with known anaphylactic or severe hypersensitivity responses to Immune Globulin (Human). Patients with severe selective IgA deficiency (IgA < 0.05 g/L) may develop anti-IgA antibodies that can result in a severe anaphylactic reaction. Anaphylaxis can occur using GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) even though it contains low amounts of IgA (average concentration of 37µg/mL). These patients should be treated only if their IgA deficiency is associated with an immune deficiency for which therapy with intravenous immune globulin is clearly indicated. Such patients should only receive intravenous immune globulin with utmost caution and in a setting where supportive care is available for treating life-threatening reactions.

SIDE EFFECTS Adverse reactions (ARs), as presented below and in Clinical Trials Experience (6.1), are defined as adverse events at least possibly related or events occurring during or within 72 hours of a Privigen infusion or treatment cycle (for ITP). Primary Humoral Immunodeficiency The most serious adverse reaction observed in clinical study subjects receiving Privigen for PI was hypersensitivity in one subject [see WARNINGS AND PRECAUTIONS]. The most common adverse reactions observed in > 5% of clinical study subjects with PI were headache, fatigue, nausea, chills, vomiting, back pain, pain, elevated body temperature, abdominal pain, diarrhea, cough, stomach discomfort, chest pain, joint swelling/effusion, influenza-like illness, pharyngolaryngeal pain, urticaria, and dizziness. Chronic Immune Thrombocytopenic Purpura The most serious adverse reactions observed in clinical study subjects receiving Privigen for chronic ITP were aseptic meningitis syndrome in one subject and hemolysis in two subjects [see WARNINGS AND PRECAUTIONS]. A total of 8 subjects (14%) in the ITP study experienced hemolysis as documented from clinical laboratory data. The most common adverse reactions observed in > 5% of clinical study subjects with chronic ITP were headache, elevated body temperature, positive DAT, anemia, nausea, epistaxis, vomiting, blood bilirubin unconjugated increased, blood bilirubin conjugated increased, blood total bilirubin increased, hematocrit decreased, and blood lactate dehydrogenase increased. Clinical Trials Experience Because different 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. Treatment Of Primary Humoral Immunodeficiency In a prospective, open-label, single-arm, multicenter clinical study (pivotal study), 80 subjects with PI (with a diagnosis of XLA or CVID) received Privigen every 3 or 4 weeks for up to 12 months [see Clinical Studies]. All subjects had been on regular IGIV replacement therapy for at least 6 months prior to participating in the study. Subjects ranged in age from 3 to 69; 46 (57.5%) were male and 34 (42.5%) were female. The safety analysis included all 80 subjects, 16 (20%) on the 3-week schedule and 64 (80%) on the 4-week schedule. The median dose of Privigen administered was 428.3 mg/ kg (3-week schedule) or 440.6 mg/kg (4-week schedule) and ranged from 200 to 888 mg/ kg. A total of 1038 infusions of Privigen were administered, 272 in the 3-week schedule and 766 in the 4-week schedule. Routine premedication was not allowed. However, subjects who experienced two consecutive infusion-related ARs that were likely to be prevented by premedication were permitted to receive antipyretics, antihistamines, NSAIDs, or antiemetic agents. During the study, 8 (10%) subjects received premedication prior to 51 (4.9%) of the 1038 infusions administered. Table 2 summarizes the most frequent ARs (defined as adverse events at least possibly related or events occurring during or within 72 hours of a Privigen infusion) that occurred in > 5% of subjects. Table 2: PI Pivotal Study – ARs* Occurring in > 5% of Subjects AR Number (%) of Subjects [n=80] Number (Rate) of Infusions with AR [n=1038] Headache 36 (45.0) 100 (0.096) Fatigue 13 (16.3) 29 (0.028) Nausea 11 (13.8) 23 (0.022) Chills 9 (11.3) 15 (0.014) Vomiting 9 (11.3) 15 (0.014) Back pain 8 (10.0) 15 (0.014) Pain 7 (8.8) 14 (0.013) Elevated body temperature 7 (8.8) 12 (0.012) Diarrhea 6 (7.5) 6 (0.006) Cough 5 (6.3) 5 (0.005) Stomach discomfort 5 (6.3) 5 (0.005) * Excluding infections. Of the 192 ARs reported (including 5 serious, severe ARs described below) 91 were mild (awareness of sign, symptom or event, but easily tolerated), 81 were moderate (discomfort enough to cause interference with usual activity and may have warranted intervention), 19 were severe (incapacitating with inability to do usual activities or significantly affected clinical status, and warranted intervention), and 1 was of unknown severity. The five serious ARs (hypersensitivity, chills, fatigue, dizziness, and increased body temperature, all severe) were related to Privigen, occurred in one subject, and resulted in the subject's withdrawal from the study. Two other subjects withdrew from the study due to ARs (chills and headache in one subject; vomiting in the other). Seventy-seven of the 80 subjects enrolled in this study had a negative DAT at baseline. Of these 77 subjects, 36 (46.8%) developed a positive DAT at some time during the study. However, no subjects showed evidence of hemolytic anemia. During this study, no subjects tested positive for infection due to human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), or B19 virus (B19V). An extension of the pivotal study was conducted in 55 adult and pediatric subjects with PI to collect additional efficacy, safety, and tolerability data. This study included 45 subjects from the pivotal study who were receiving Privigen and 10 new subjects who were receiving another IGIV product prior to enrolling in the extension study. Subjects ranged in age from 4 to 81 years; 26 (47.3%) were male and 29 (52.7%) were female. Subjects were treated with Privigen at median doses ranging from 286 to 832 mg/kg per infusion over a treatment period ranging from 1 to 27 months. Twelve (21.8%) subjects were on a 3¬week treatment schedule with the number of infusions per subject ranging from 4 to 38 (median: 8 infusions); 43 (78.2%) subjects were on a 4-week schedule with the number of infusions ranging from 1 to 31 (median: 15 infusions). A total of 771 infusions were administered in this study. In this study, subjects who continued from the pivotal study were permitted to receive infusions of Privigen at a rate up to 12 mg/kg/min (as opposed to the maximum of 8 mg/ kg/min allowed in the pivotal study) at the discretion of the investigator based on individual tolerability. Twenty¬three (51%) of the 45 subjects from the pivotal study (41.8% of the 55 subjects in the extension study) received 265 (38.4%) infusions at a maximum rate greater than the recommended rate of 8 mg/kg/min [see Administration]. The median of the maximum infusion rate in this subset was 12 mg/kg/min. However, because the study was not designed to compare infusion rates, no definitive conclusions regarding tolerability could be drawn for infusion rates higher than the recommended rate of 8 mg/kg/min. Table 3 summarizes the ARs that occurred in > 5% of subjects. Table 3: PI Extension Study – ARs* Occurring in > 5% of Subjects AR* Number (%) of Subjects [n=55] Number (Rate) of Infusions with AR [n=771] Headache 18 (32.7) 76 (0.099) Nausea 6 (10.9) 10 (0.013) Elevated body temperature 4 (7.3) 12 (0.016) Abdominal pain† 4 (7.3) 7 (0.009) Chest pain 3 (5.5) 4 (0.005) Chills 3 (5.5) 7 (0.009) Joint swelling/effusion 3 (5.5) 7 (0.009) Pain 3 (5.5) 6 (0.008) Fatigue 3 (5.5) 5 (0.006) Influenza-like illness 3 (5.5) 5 (0.006) Pharyngolaryngeal pain 3 (5.5) 4 (0.005) Urticaria 3 (5.5) 4 (0.005) Dizziness 3 (5.5) 3 (0.004) Note: The AR rates in this study cannot be compared directly to the rates in other IGIV studies, including the original pivotal study described earlier in this section, because (1) the extension study used an enriched population and (2) the selective use of higher infusion rates at the investigators' discretion in a subset of subjects may have introduced bias. * Excluding infections. † Includes abdominal pain, abdominal pain upper, and abdominal pain lower. Of the 125 reported ARs, 76 were mild (does not interfere with routine activities), 40 were moderate (interferes somewhat with routine activities), and 9 were severe (impossible to perform routine activities). Three subjects experienced ARs that were considered to be at least possibly related to Privigen: dyspnea and pancytopenia in one subject, a transient ischemic attack 16 days after the infusion in one subject, and mild urticaria in one subject, resulting in the subject's withdrawal from the study. Treatment Of Chronic Immune Thrombocytopenic Purpura In a prospective, open-label, single-arm, multicenter clinical study, 57 subjects with chronic ITP and a platelet count of 20 x 109/L or less received a total of 2 g/kg dose of Privigen administered as 1 g/kg infusions daily for 2 consecutive days [see Clinical Studies]. Subjects ranged in age from 15 to 69; 23 (40.4%) were male and 34 (59.6%) were female. Concomitant medications affecting platelets or other treatments for chronic ITP were not allowed. Thirty-two (56.1%) subjects received premedication with acetaminophen and/or an antihistamine. Table 4 summarizes the most frequent ARs (adverse events at least possibly related or events occurring during or within 72 hours after the end of a treatment cycle [two consecutive infusions]) that occurred in > 5% of subjects with chronic ITP. Table 4: Chronic ITP Study – ARs Occurring in > 5% of Subjects AR Number (%) of Subjects [n=57] Number (Rate) of Infusions with AR [n=114] Headache 37 (64.9) 52 (0.456) Elevated body temperature 21 (36.8) 23 (0.202) Positive DAT 7 (12.3) 8 (0.070) Anemia 6 (10.5) 6 (0.053) Nausea 6 (10.5) 8 (0.070) Epistaxis 6 (10.5) 8 (0.070) Vomiting 6 (10.5) 7 (0.061) Blood bilirubin unconjugated increased 6 (10.5) 6 (0.053) Blood bilirubin conjugated increased 5 (8.8) 5 (0.044) Blood total bilirubin increased 3 (5.3) 3 (0.026) Hematocrit decreased 3 (5.3) 3 (0.026) Blood lactate dehydrogenase increased 3 (5.3) 3 (0.026) Of the 149 non-serious ARs, 103 were mild (awareness of sign, symptom or event, but easily tolerated), 37 were moderate (discomfort enough to cause interference with usual activity and may have warranted intervention), and 9 were severe (incapacitating with inability to do usual activities or significantly affected clinical status, and warranted intervention). One subject experienced a serious AR (aseptic meningitis). Eight subjects, all of whom had a positive DAT, experienced transient drug-related hemolytic reactions, which were associated with elevated bilirubin, elevated lactate dehydrogenase, and a decrease in hemoglobin level within two days after the infusion of Privigen. Two of the eight subjects were clinically anemic but did not require clinical intervention; these cases resolved uneventfully. Four other subjects with active bleeding were reported to have developed anemia without evidence of hemolysis. In this study, there was a decrease in hemoglobin after the first Privigen infusion (median decrease of 1.2 g/dL by Day 8) followed by a return to near baseline by Day 29. Fifty-six of the 57 subjects in this study had a negative DAT at baseline. Of these 56 subjects, 12 (21.4%) developed a positive DAT during the 29-day study period. Postmarketing Experience Because adverse reactions are reported voluntarily post-approval 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. Privigen The following adverse reactions have been identified during postmarketing use of Privigen. This list does not include reactions already reported in clinical studies with Privigen [see Clinical Trials Experience]. Infusion reactions: Changes in blood pressure, dyspnea, tachycardia, flushing Hematologic: hemoglobinuria/hematuria/chromaturia, renal failure Neurological: photophobia Integumentary: pruritus, rash General In addition, the following adverse reactions have been identified and reported during the post-approval use of immune globulin products.14 Infusion Reactions: Tachycardia, malaise, flushing, rigors Renal: Acute renal dysfunction/failure, osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, bronchospasm Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, tremor Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia Gastrointestinal: Hepatic dysfunction DRUG INTERACTIONS Live Virus Vaccines The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles, mumps, rubella, and varicella [see PATIENT INFORMATION].15 Inform the immunizing physician of recent therapy with Privigen so that appropriate measures can be taken. REFERENCES 14. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251.

SIDE EFFECTS The most serious adverse reactions in patients receiving Rh0(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].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. Hemolysis (manifested by an increase in bilirubin, a decrease in hemoglobin, or a decrease in haptoglobin) was also observed. 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 Rh0(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 Rh0(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]. 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 Rh0(D)-positive adult subjects with chronic ITP received anintravenous dose of Rhophylac 250 IU (50 mcg) per kg body weight [see Clinical Studies]. 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. 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* 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%) * Defined as TEAEs with a possible, probable, definite, or unknown relationship to the study drug. 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. 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. There have been reports of lack of effect in patients with a body mass index ≥ 30 when administration via the intramuscular route was attempted [see DOSING AND ADMINISTRATION]. ITP Transient hemoglobinuria has been reported in a patient being treated with Rhophylac for ITP. DRUG INTERACTIONS Live Virus Vaccines Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps, rubella, and varicella [see PATIENT INFORMATION]. REFERENCES 1. Pollack W, Ascari WQ, Kochesky RJ, O'Connor RR, Ho TY, Tripodi D. Studies on Rh prophylaxis. 1. relationship between doses of anti-Rh and size of antigenic stimulus. Transfusion. 1971;11:333-339.

SIDE EFFECTS Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria or anuria, requiring dialysis has been observed. Types of severe renal adverse events that have been seen following IGIV therapy include: acute renal failure, acute tubular necrosis, proximal tubular nephropathy and osmotic nephrosis.9-14,64,71–73 Inflammatory adverse reactions have been described in agammaglobulinemic and hypogammaglobulinemic patients who have never received immunoglobulin substitution therapy before or in patients whose time from last treatment is greater than 8 weeks and whose initial infusion rate exceeds 2 mg/kg/min. This occurs in approximately 10% of such cases. Such reactions may also be observed in some patients during chronic substitution therapy. Reactions, which may become apparent only 30 minutes to 1 hour after the beginning of the infusion, are as follows: flushing of the face, feelings of tightness in the chest, chills, fever, dizziness, nausea, diaphoresis, and hypotension or hypertension. In such cases, the infusion should be slowed or temporarily stopped until the symptoms subside. The infusion may then be resumed at a lower rate that is comfortable for the patient. If anaphylaxis or other severe reactions occur, the infusion should be stopped immediately. Arthralgia, myalgia, and transient skin reactions (such as rash, erythema, pruritus, urticaria, eczema or dermatitis) have also been reported. Immediate anaphylactoid and hypersensitivity reactions due to previous sensitization of the recipient to certain antigens, most commonly IgA, may be observed in exceptional cases, described under CONTRAINDICATIONS.30,31,65 In patients with ITP, who receive higher doses (0.4 g/kg/day or greater), 2.9% of infusions may result in adverse reactions.21 Headache, generally mild, is the most common symptom noted, occurring during or following 2% of infusions. A few cases of usually mild hemolysis have been reported after infusion of intravenous immunoglobulin products.59–61 These were attributed to transferal of blood group (e.g., anti-D) antibodies. Postmarketing The following adverse reactions have been identified and reported during the post-approval use of IGIV products: Respiratory Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological Coma, loss of consciousness, seizures, tremor Integumentary Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test General/Body as a Whole Pyrexia, rigors Musculoskeletal Back pain Gastrointestinal Hepatic dysfunction, abdominal pain Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently.66 DRUG INTERACTIONS No information provided. REFERENCES 1. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223–226. 2. Caress JB, Cartwright MS, Donofrio PD, Peacock JE: The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 2003; 60:1822–1824. 3. Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; 2:217–218. 4. Jordan S, Cunningham-Rundles C, McEwan R: Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transplant 2003; 3:653–664. 5. Wolberg AS, Kon RH, Monroe DM, Hoffman M: Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30–34. 6. Zaidan R, Al Moallem M, Wani BA, Shameena AR, Al Tahan AR, Daif AK, Al Rajeh S: Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurology 2003; 10:367–372. 7. Okuda D, Flaster M, Frey J, Sivakumar, K: Arterial thrombosis induced by IVIg and its treatment with tPA. Neurology 2003; 60:1825–1826. 8. Dalakas MC, Clark WM: Strokes, thromboembolic events, and IVIg. Rare incidents blemish an excellent safety record. Neurology 2003; 60:1736–1737. 9. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: Review of the literature and case report. Pharmacotherapy 1995; 15:765–772. 10. Cantú TG, Hoehn-Saric EW, Burgess KM, Racusen L, Scheel P: Acute renal failure associated with immunoglobulin therapy. Am J Kidney Dis 1995; 25:228–234.11. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Amer Soc Nephrology 1997; 8:1788–1793. 12. Rault R, Piraino B, Johnston JR, Oral A: Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol 1991, 36:83–86. 13. Michail S, Nakopoulou L, Stravrianopoulos I, Stamatiadis D, Avdikou K, Vaiopoulos G, Stathakis C: Acute renal failure associated with immunoglobulin administration. Nephrol Dial Transplant 1997; 12:1497–99. 14. Ashan N, Wiegand LA, Abendroth CS, Manning EC: Acute renal failure following immunoglobulin therapy. Am J Nephrol 1996; 16:532–6. 15. Gardi A: Quality control in the production of an immunoglobulin for intravenous use. Blut 1984; 48:337–344. 16. Römer J, Morgenthaler JJ, Scherz R, et al: Characterization of various immunoglobulinpreparations for intravenous application. I. Protein composition and antibody content. Vox Sang 1982; 42:62–73. 17. Römer J, Späth PJ, Skvaril F, et al: Characterization of various immunoglobulin preparations for intravenous application. II. Complement activation and binding to Staphylococcus protein A. Vox Sang 1982; 42:74–80. 18. Gregori L, Maring JA, MacAuley C et al: Partitioning of TSE infectivity during ethanol fractionation of human plasma. Biologicals 2004; 32:1–10. 19. Omar A, and Kempf C: Removal of neutralized model Parvoviruses and Enteroviruses in human IgG solutions by nanofiltration. Transfusion 2002; 42:1005–1010. 20. Späth P, Kempf C, and Gold R: Herstellung, Verträglichkeit und Virussicherheit von intravenösem Immunglobulin. In “Immunglobuline in der Neurobiologie” (P. Berlit, ed.), Steinkopff Verlag, Darmstadt, BRD 2001, pp 1–42. 21. Kempf C, Morgenthaler JJ, Rentsch M, and Omar A: Viral safety and manufacturing of an intravenous immunoglobulin. In “Intravenous Immunoglobulin Research and Therapy” Kazatchkine and Morell, eds. Parthenon Publishing Group. 1996, pp 11–18. 22. Römer J, Späth PJ: Molecular composition of immunoglobulin preparations and its relation to complement activation, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press 1981, pp 123–130. 23. Skvaril F, Roth-Wicky B, and Barandun S: IgG subclasses in human-g-globulin preparations for intravenous use and their reactivity with Staphylococcus protein A. Vox Sang 1980; 38:147. 24. Skvaril F: Qualitative and quantitative aspects of IgG subclasses in i.v. immunoglobulin preparations, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 113–122. 25. Skvaril F, and Barandun S: In vitro characterization of immunoglobulins for intravenous use, in Alving BM, Finlayson JS (eds): Immunoglobulins: Characteristics and Uses of Intravenous Preparations, DHHS Publication No. (FDA)-80-9005. US Government Printing Office, 1980, pp 201–206. 26. Burckhardt JJ, Gardi A, Oxelius V, et al: Immunoglobulin G subclass distribution in three human intravenous immunoglobulin preparations. Vox Sang 1989; 57:10–14. 27. Morell A, and Skvaril F: Struktur und biologische Eigenschaften von Immunglobulinen und g-Globulin-Präparaten. II. Eigenschaften von g-Globulin-Präparaten. Schweiz Med Wochenschr 1980; 110:80. 28. Morell A, Schürch B, Ryser D, et al: In vivo behaviour of gamma globulin preparations. Vox Sang 1980; 38:272. 29. Imbach P, Barandun S, d'Apuzzo V, et al: High-dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; 1:1228. 30. Barandun S, Morell A, Skvaril F: Clinical experiences with immunoglobulin for intravenous use, in Alving BM, Finlayson JS (eds): Immunoglobulins: Characteristics and Uses of Intravenous Preparations. DHHS Publication No. (FDA)-80-9005. US Government Printing Office, 1980, pp 31–35. 31. Schiff R, Sedlak D, Buckley R: Rapid infusion of Sandoglobulin™ in patients with primary humoral immunodeficiency. J Allergy Clin Immunol 88:61, 1991. 32. Joller PW, Barandun S, Hitzig WH: Neue Möglichkeiten der Immunglobulin- Ersatztherapie bei Antikörpermangel-Syndrom. Schweiz Med Wochenschr 1980; 110:1451. 33. Barandun S, Imbach P, Morell A, et al: Clinical indications for immunoglobulin infusion, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 275–282. 34. Cunningham-Rundles C, Smithwick EM, Siegal FP, et al: Treatment of primary humoral immunodeficiency disease with intravenous (pH 4.0 treated) gamma globulin, in Nydegger UE (ed): Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 283–290. 35. Imbach P, Wagner HP, Berchtold W, et al: Intravenous immunoglobulin versus oral corticosteroids in acute immune thrombocytopenic purpura in childhood. Lancet 1985; 2:464. 36. Fehr J, Hofmann V, Kappeler U: Transient reversal of thrombocytopenia in idiopathic thrombocytopenic purpura by high-dose intravenous gamma globulin. N Engl J Med 1982; 306:1254. 37. Müller-Eckhardt C, Küenzlen E, Thilo-Körner D, et al: High-dose intravenous immunoglobulin for posttransfusion purpura. N Engl J Med 1983; 308:287. 38. Wenske G, Gaedicke G, Küenzlen E, et al: Treatment of idiopathic thrombocytopenic purpura in pregnancy by high-dose intravenous immunoglobulin. Blut 1983; 46:347–353. 39. Newland AC, Treleaven JG, Minchinton B, et al: High-dose intravenous IgG in adults with autoimmune thrombocytopenia. Lancet 1983; 1:84–87. 40. Bussel JB, Kimberly RP, Inman RD, et al: Intravenous gammaglobulin for chronic idiopathic thrombocytopenic purpura. Blood 1983; 62:480–486. 41. Abe T, Matsuda J, Kawasugi K, et al: Clinical effect of intravenous immunoglobulin in chronic idiopathic thrombocytopenic purpura. Blut 1983; 47:69–75. 42. Bussel JB, Schulman I, Hilgartner MW, et al: Intravenous use of gamma globulin in the treatment of chronic immune thrombocytopenic purpura as a means to defer splenectomy. J Pediatr 1983; 103:651–654. 43. Imholz B, et al: Intravenous immunoglobulin (i.v. IgG) for previously treated acute or for chronic idiopathic thrombocytopenic purpura (ITP) in childhood: A prospective multicenter study. Blut 1988; 56:63–68. 44. Lusher JM, and Warrier I: Use of intravenous gamma globulin in children with idiopathic thrombocytopenic purpura and other immune thrombocytopenias. Am J Med 1987; 83 (suppl 4A):10–16. 45. Hammarstrom L, and Smith CI: Placental transfer of intravenous immunoglobulin. Lancet 1986; 1:681. 46. Sidiropoulos D, et al: Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 1986; 109:505–508. 47. Wenske G, et al: Idiopathic thrombocytopenic purpura in pregnancy and neonatal period. Blut 1984; 48:377–382. 48. Fabris P, et al: Successful treatment of a steroid-resistant form of idiopathic thrombocytopenic purpura in pregnancy with high doses of intravenous immunoglobulins. Acta Haemat 1987; 77:107–110. 49. Coller BS, et al: Management of severe ITP during pregnancy with intravenous immunoglobulin (IVIgG). Clin Res 1985; 33:545A. 50. Tchernia G, et al: Management of immune thrombocytopenia in pregnancy: Response to infusions of immunoglobulins. Am J Obstet Gynecol 1984; 148:225–226. 51. Newland AC, et al: Intravenous IgG for autoimmune thrombocytopenia in pregnancy. N Engl J Med 1984; 310:261–262. 52. Morgenstern GR, et al: Autoimmune thrombocytopenia in pregnancy: New approach to management. Br Med J 1983; 287:584. 53. Ciccimarra F, et al: Treatment of neonatal passive immune thrombocytopenia. J Pediat 1984; 105:677–678. 54. Rose VL, and Gordon LI: Idiopathic thrombocytopenic purpura in pregnancy. Successful management with immunoglobulin infusion. JAMA 1985; 254:2626–2628. 55. Gounder MP, et al: Intravenous gammaglobulin therapy in the management of a patient with idiopathic thrombocytopenic purpura and a warm autoimmune erythrocyte panagglutinin during pregnancy. Obstet Gynecol 1986; 67:741–746. 56. Siber GR, Werner BG, Halsey NA, et al: Interference of immune globulin with measles and rubella immunisation. J Pediatr 1993; 122:204–211. 57. American Academy of Pediatrics, Committee on Infectious Diseases: Recommended timing of routine measles immunization for children who have recently received immune globulin preparations. Pediatrics 1994; 93:682–685. 58. Centers of Disease Control and Prevention. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the advisory committee on immunization practices (ACIP). MMWR, Morbidity and Mortality Weekly Report. May 22, 1998; vol 47/No. RR-8, 1–57. 59. Copelan EA, Strohn PL, Kennedy MS, Tutschka PJ: Hemolysis following intravenous immune globulin therapy. Transfusion 1986; 26:410–412. 60. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J: Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789. 61. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997; 20:1142–1145. 62. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H: In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999; 13:129–135. 63. Rizk A, Gorson KC, Kenney L, Weinstein R: Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41:264–268. 64. Phillips AO: Renal failure and intravenous immunoglobulin [letter; comment]. Clin Nephrol 1992; 37:217. 65. Cunningham-Rundles C, Day NK, Wahn V, et al: Reactions to intravenous gamma globulin infusions and immune complex formation, in Nydegger UE (ed): Immunohemotherapy: A Guide to Immunoglobulin Prophylaxis and Therapy. London, Academic Press, 1981, pp 447–449. 66. Pierce LR, Jain N: Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003; 17:241–251. 67. Aukrust P, Froland SS, Liabakk N-B, Müller F., et al: Release of cytokines, soluble cytokine receptors, and interleukin-1 receptor antagonist after intravenous immunoglobulin administration in vivo. Blood 1994; 84:2136–2143. 68. Bagdasarian A, Tonetta S, Harel W, Mamidi R., Uemura Y: IVIG adverse reactions: potential role of cytokines and vasoactive substances. Vox Sang 1998; 74:74–82. 69. Bussel JB, Pham LC, Hilgartner MW, et al: Long-term maintenance of adults with ITP using intravenous gamma globulin. Abstract, American Society of Hematology. New Orleans, December, 1985. 70. Imbach PA, Kühne T, Holländer G: Immunologic aspects in the pathogenesis and treatment of immune thrombocytopenic purpura in children. Current opinion in Pediatrics 1997; 9:35–40. 71. Anderson W, Bethea W: Renal lesions following administration of hypertonic solutions of sucrose. JAMA 1940; 114:1983–1987. 72. Lindberg H, Wald A: Renal lesions following the administration of hypertonic solutions: Arch Intern Med 1939; 63:907–918. 73. Rigdon RH, Cardwell ES: Renal lesions following the intravenous injection of hypertonic solution of sucrose: A clinical and experimental study. Arch Intern Med 1942; 69:670–690.

SIDE EFFECTS Adverse Drug Reaction Overview The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for PI was an exacerbation of autoimmune pure red cell aplasia in one subject. The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for ITP was myocarditis in one subject that occurred 50 days post study drug infusion and was not considered drug related. The most serious adverse reaction observed in clinical study subjects receiving GAMUNEX (immune globulin intravenous (human) 10%) for CIDP was pulmonary embolism (PE) in one subject with a history of PE. The most common drug related adverse reactions observed at a rate >5% in subjects with PI were headache, cough, injection site reaction, nausea, pharyngitis and urticaria. The most common drug related adverse reactions observed at a rate >5% in subjects with ITP were headache, vomiting, fever, nausea, back pain and rash. The most common drug related adverse reactions observed at a rate >5% in subjects with CIDP were headache, fever, chills and hypertension Clinical Trials Adverse Drug Reactions Because clinical studies are conducted under 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. Adverse events similar to those previously reported with the administration of intravenous and intramuscular immunoglobulin products may occur. Cases of reversible aseptic meningitis, migraine, isolated cases of reversible hemolytic anemia and reversible increases in liver function tests have been observed with GAMUNEX (immune globulin intravenous (human) 10%) . Immediate anaphylactic reactions can possibly occur (<0.01%). Epinephrine should be available for treatment of any acute anaphylactoid reaction. (see WARNINGS and PRECAUTIONS) Treatment of Primary Humoral Immunodeficiency The following table shows the number of subjects treated with GAMUNEX (immune globulin intravenous (human) 10%) in clinical trials to study PI, and the reason for discontinuation due to adverse events: Table 1: Reasons for Discontinuation Due to Adverse Events: All PI Studies Study Number Number of Subjects Treated with GAMUNEX Number of Subjects Discontinued Due to Adverse Events Adverse Event 100152 18 0 ----- 100174 20 1 Coombs negative hypochromic anemia* 100175 87 1 Autoimmune pure red cell aplasia* * Both events were considered unrelated to study drug as per the investigator. In study 100175, 9 subjects in each treatment group were pretreated with non-steroidal medication prior to infusion. Generally, diphenhydramine and acetaminophen were used. Any adverse events in trial 100175, irrespective of the causality assessment, are given in the following table. Table 2: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100175) Adverse Event GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 87 No of subjects with AE (percentage of all subjects) GAMIMUNE N No. of subjects: 85 No of subjects with AE (percentage of all subjects) Cough increased 47 (54%) 46 (54%) Rhinitis 44 (51%) 45 (53%) Pharyngitis 36 (41%) 39 (46%) Headache 22 (25%) 28 (33%) Fever 24 (28%) 27 (32%) Diarrhea 24 (28%) 27 (32%) Asthma 25 (29%) 17 (20%) Nausea 17 (20%) 22 (26%) Ear Pain 16 (18%) 12 (14%) Asthenia 9 (10%) 13 (15%) The subset of drug related adverse events in trial 100175 reported by at least 5% of subjects during the 9-month treatment are given in the following table. Table 3: Subjects with At Least One Drug Related Adverse Event (Study 100175) Drug Related Adverse Event GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 87 No. of subjects with drug related AE (percentage of all subjects) GAMIMUNE N No. of subjects: 85 No. of subjects with drug related AE (percentage of all subjects) Headache 7 (8%) 8 (9%) Cough increased 6 (7%) 4 (5%) Injection site reaction 4 (5%) 7 (8%) Nausea 4 (5%) 4 (5%) Pharyngitis 4 (5%) 3 (4%) Urticaria 4 (5%) 1 (1%) Adverse events, which were reported by at least 5% of subjects, were also analyzed by frequency and in relation to infusions administered. The analysis is displayed in the following table. Table 4: Adverse Event Frequency (Study 100175) Adverse Event GAMUNEX (immune globulin intravenous (human) 10%) No. of infusions: 825 Number of AE (percentageof all infusions) GAMIMUNE N No. of infusions: 865 Number of AE (percentageof all infusions) Cough increased All 154 (18.7%) 148 (17.1%) Drug related 14 (1.7%) 11 (1.3%) Pharyngitis All 96 (11.6%) 99 (11.4) Drug related 7 (0.8%) 9 (1.0%) Headache All 57 (6.9%) 69 (8.0%) Drug related 7 (0.8%) 11 (1.3%) Fever All 41 (5.0%) 65 (7.5%) Drug related 1 (0.1%) 9 (1.0%) Nausea All 31 (3.8%) 43 (5.0%) Drug related 4 (0.5%) 4 (0.5%) Urticaria All 5 (0.6%) 8 (0.9%) Drug related 4 (0.5%) 5 (0.6%) The mean number of adverse events per infusion that occurred during or on the same day as an infusion was 0.21 in both the GAMUNEX (immune globulin intravenous (human) 10%) and GAMIMUNE N treatment groups. In all three trials in primary humoral immundeficiencies, the maximum infusion rate was 0.08 mL/kg/min (8 mg/kg/min). The infusion rate was reduced for 11 of 222 exposed subjects (7 GAMUNEX (immune globulin intravenous (human) 10%) , 4 GAMIMUNE N) at 17 occasions. In most instances, mild to moderate hives/urticaria, itching, pain or reaction at infusion site, anxiety or headache was the main reason. There was one case of severe chills. There were no anaphylactic or anaphylactoid reactions to GAMUNEX (immune globulin intravenous (human) 10%) or GAMIMUNE N. In trial 100175, serum samples were drawn to monitor the viral safety at baseline and one week after the first infusion (for parvovirus B19), eight weeks after first and fifth infusion, and 16 weeks after the first and fifth infusion of IGIV (for hepatitis C) and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, Polymerase Chain Reaction (PCR), and serological testing. There were no treatment emergent findings of viral transmission for either GAMUNEX (immune globulin intravenous (human) 10%) , or GAMIMUNE N. [1, 3, 4] Treatment of Idiopathic Thrombocytopenic Purpura The following table shows the number of subjects treated with GAMUNEX (immune globulin intravenous (human) 10%) in clinical trials to study ITP, and the reason for discontinuation due to adverse events: Table 5: Reasons for Discontinuation Due to Adverse Events: All ITP Studies Study Number Number of Subjects Treated with GAMUNEX Number of Subjects Discontinued Due to Adverse Events Adverse Event 100213 28 1 Hives 100176 48 1 Headache, Fever, Vomiting One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX (immune globulin intravenous (human) 10%) . The death was judged to be unrelated to GAMUNEX (immune globulin intravenous (human) 10%) . No pre-medication with corticosteroids was permitted by the protocol. Twelve (12) ITP subjects treated in each treatment group were pretreated with medication prior to infusion. Generally, diphenhydramine and/or acetaminophen were used. More than 90% of the observed drug related adverse events were of mild to moderate severity and of transient nature. The infusion rate was reduced for 4 of the 97 exposed subjects (1 GAMUNEX (immune globulin intravenous (human) 10%) , 3 GAMIMUNE N) on 4 occasions. Mild to moderate headache, nausea, and fever were the reported reasons. There were no anaphylactic or anaphylactoid reactions to GAMUNEX (immune globulin intravenous (human) 10%) or GAMIMUNE N. Any adverse events in trial 100176, irrespective of the causality assessment, reported by at least 5% of subjects during the 3-month trial are given in the following table. Table 6: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100176) Adverse Event GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 48 No of subjects with AE (percentage of all subjects) GAMIMUNE N No. of subjects: 49 No of subjects with AE (percentage of all subjects) Headache 28 (58%) 30 (61%) Ecchymosis, Purpura 19 (40%) 25 (51%) Hemorrhage (All systems) 14 (29%) 16 (33%) Epistaxis 11 (23%) 12 (24%) Petechiae 10 (21%) 15 (31%) Fever 10 (21%) 7 (14%) Vomiting 10 (21%) 10 (20%) Nausea 10 (21%) 7 (14%) Thrombocytopenia 7 (15%) 8 (16%) Accidental injury 6 (13%) 8 (16%) Rhinitis 6 (13%) 6 (12%) Pharyngitis 5 (10%) 5 (10%) Rash 5 (10%) 6 (12%) Pruritis 4 (8%) 1 (2%) Asthenia 3 (6%) 5 (10%) Abdominal Pain 3 (6%) 4 (8%) Arthralgia 3 (6%) 6 (12%) Back Pain 3 (6%) 3 (6%) Dizziness 3 (6%) 3 (6%) Flu Syndrome 3 (6%) 3 (6%) Neck Pain 3 (6%) 1 (2%) Anemia 3 (6%) 0 (0%) Dyspepsia 3 (6%) 0 (0%) The subset of drug related adverse events in trial 100176 reported by at least 5% of subjects during the 3-month trial are given in the following table. Table 7: Subjects with At Least One Drug Related Adverse Event (Study 100176) Drug Related Adverse Event GAMUNEX (immune globulin intravenous (human) 10%) No. of subjects: 48 No. of subjects with drug related AE (percentage of all subjects) GAMIMUNE N No. of subjects: 49 No. of subjects with drug related AE (percentage of all subjects) Headache 24 (50%) 24 (49%) Vomiting 6 (13%) 8 (16%) Fever 5 (10%) 5 (10%) Nausea 5 (10%) 4 (8%) Back Pain 3 (6%) 2 (4%) Rash 3 (6%) 0 (0%) Serum samples were drawn to monitor the viral safety of the ITP subjects at baseline, nine days after the first infusion (for parvovirus B19), and 3 months after the first infusion of IGIV and at any time of premature discontinuation of the study. Viral markers of hepatitis C, hepatitis B, HIV-1, and parvovirus B19 were monitored by nucleic acid testing (NAT, PCR), and serological testing. There were no treatment related emergent findings of viral transmission for either GAMUNEX (immune globulin intravenous (human) 10%) , or GAMIMUNE N [11]. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy In study 100538, 113 subjects were exposed to GAMUNEX and 95 were exposed to Placebo (See Clinical Studies). As a result of the study design, the drug exposure with GAMUNEX (immune globulin intravenous (human) 10%) was almost twice that of Placebo, with 1096 GAMUNEX (immune globulin intravenous (human) 10%) infusions versus 575 Placebo infusions. Therefore, adverse reactions are reported per infusion (represented as frequency) to correct for differences in drug exposure between the 2 groups. The majority of loading-doses were administered over 2 days. The majority of maintenance-doses were administered over 1 day. Infusions were administered in the mean over 2.7 hours. The following table shows the numbers of subjects per treatment group in the CIDP clinical trial, and the reason for discontinuation due to adverse events: Table 8: Reasons for Discontinuation Due to Adverse Events: CIDP Number of Subjects Number of Subjects Discontinued due to Adverse Events Adverse Event GAMUNEX 113 3 (2.7%) Urticaria, Dyspnea, Bronchopneumonia Placebo 95 2 (2.1%) Cerebrovascular Accident, Deep Vein Thrombosis Adverse events reported by at least 5% of subjects in any treatment group irrespective of causality are shown in the following table. Table 9: Subjects with At Least One Adverse Event Irrespective of Causality (Study 100538) MedDRA Preferred Term a GAMUNEX No. of subjects: 113 Placebo No. of subjects: 95 No. of Subjects (%) No. of Adverse Events Incidence density b No. of Subjects (%) No. of Adverse Events Incidence density b Any Adverse Event 85 (75) 377 0.344 45 (47) 120 0.209 Headache 36 (32) 57 0.052 8 (8) 15 0.026 Pyrexia (fever) 15 (13) 27 0.025 0 0 0 Hypertension 10 (9) 20 0.018 4 (4) 6 0.010 Rash 8 (7) 13 0.012 1 (1) 1 0.002 Arthralgia 8 (7) 11 0.010 1 (1) 1 0.002 Asthenia 9 (8) 10 0.009 3 (3) 4 0.007 Chills 9 (8) 10 0.009 0 0 0 Back pain 9 (8) 10 0.009 3 (3) 3 0.005 Nausea 7 (6) 9 0.008 3 (3) 3 0.005 Dizziness 7 (6) 3 0.006 1 (1) 1 0.002 Influenza 6 (5) 6 0.005 2 (2) 2 0.003 a Reported in ≥ 5% of subjects in any treatment group irrespective of causality. b Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMUNEX (immune globulin intravenous (human) 10%) and 575 for Placebo) Drug-related adverse events reported by at least 5% of subjects in any treatment group are reported in the following table. The most common drug-related events with GAMUNEX (immune globulin intravenous (human) 10%) were headache and pyrexia: Table 10: Subjects with At Least 1 Drug Related Adverse Event (Study 100538) MedDRA Preferred term a GAMUNEX No. of subjects:113 Placebo No. of subjects: 95 No. of Subjects (%) No. of Adverse Events Incidence density b No. of Subjects (%) No. of Adverse Events Incidence density b Any drug-related adverse event 62 (55) 194 0.177 16 (17) 25 0.043 Headache 31 (27) 44 0.040 6 (6) 7 0.012 Pyrexia (fever) 15 (13) 26 0.024 0 0 0 Chills 8 (7) 9 0.008 0 0 0 Hypertension 7 (6) 16 0.015 3 (3) 3 0.005 Rash 6 (5) 8 0.007 1 (1) 1 0.002 Nausea 6 (5) 7 0.006 3 (3) 3 0.005 Asthenia 6 (5) 6 0.005 0 0 0 a Reported in ≥ 5% of subjects in any treatment group. b Calculated by the total number of adverse events divided by the number of infusions received (1096 for GAMUNEX (immune globulin intravenous (human) 10%) and 575 for Placebo). Laboratory Abnormalities During the course of the clinical program, ALT and AST elevations were identified in some subjects. For ALT, in the primary humoral immunodeficiency (PI) study (100175) treatment emergent elevations above the upper limit of normal were transient and observed among 14/80 (18%) of subjects in the GAMUNEX (immune globulin intravenous (human) 10%) group versus 5/88 (6%) of subjects in the GAMIMUNE N group (p = 0.026). In the ITP study which employed a higher dose per infusion, but a maximum of only two infusions, the reverse finding was observed among 3/44 (7%) of subjects in the GAMUNEX (immune globulin intravenous (human) 10%) group versus 8/43 (19%) of subjects in the GAMIMUNE N group (p = 0.118). In the CIDP study (100538), 15/113 (13%) of subjects in the GAMUNEX (immune globulin intravenous (human) 10%) group and 7/95 (7%) in the Placebo group (p=0.168) had a treatment emergent transient elevation of ALT. Elevations of ALT and AST were generally mild (<3 times upper limit of normal), transient, and were not associated with obvious symptoms of liver dysfunction. GAMUNEX (immune globulin intravenous (human) 10%) class. may contain low levels of anti-Blood Group A and B antibodies primarily of the IgG4 Direct antiglobulin tests (DAT or direct Coombs tests), which are carried out in some centers as a safety check prior to red blood cell transfusions, may become positive temporarily. Hemolytic events not associated with positive DAT findings were observed in clinical trials.[1, 3, 4, 11, 36] 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. GAMUNEX (immune globulin intravenous (human) 10%) Postmarketing Experience The following adverse reactions have been identified and reported during the post marketing use of GAMUNEX (immune globulin intravenous (human) 10%) : Hematologic:Hemolytic anemia Infections and Infestations: Aseptic meningitis General The following adverse reactions have been identified and reported during the post marketing use of IGIV products [37]: Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular:Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures/convulsions, tremor Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, bullous dermatitis Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs test) General/Body as a Whole: Pyrexia, rigors Musculoskeletal: Back pain Gastrointestinal:Hepatic dysfunction, abdominal pain DRUG INTERACTIONS GAMUNEX (immune globulin intravenous (human) 10%) may be diluted with 5% dextrose in water (D5/W). Admixtures of GAMUNEX (immune globulin intravenous (human) 10%) with other drugs and intravenous solutions have not been evaluated. It is recommended that GAMUNEX (immune globulin intravenous (human) 10%) be administered separately from other drugs or medications which the patient may be receiving. The product should not be mixed with IGIVs from other manufacturers. The infusion line may be flushed before and after administration of GAMUNEX (immune globulin intravenous (human) 10%) with 5% dextrose in water. Various passively transferred antibodies in immunoglobulin preparations can confound the results of serological testing. Antibodies in GAMUNEX (immune globulin intravenous (human) 10%) may interfere with the response to live viral vaccines such as measles, mumps and rubella. Physicians should be informed of recent therapy with IGIVs, so that administration of live viral vaccines, if indicated, can be appropriately delayed 3 or more months from the time of IGIV administration. (See Patient Counseling Information) REFERENCES 1. Kelleher J, F.G., Cyrus P, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Immune Deficiency (PID), 2000. Report on file. 3. Bayever E, M.F., Sundaresan P, Collins S, Randomized, Double-Blind, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100152). MMRR-1512/1, 1999. 4. Lathia C, E.B., Sundaresan PR, Schwartz L, A Randomized, Open-Label, Multicenter, Repeat Dosing, Cross-Over Trial Comparing the Safety, Pharmacokinetics, and Clinical Outcomes of IGIV-Chromatography, 5% with IGIV-Chromatography 10% in Patients with Primary Humoral Immune Deficiency (BAY-41-1000-100174). 2000. 11. Cyrus P, F.G., Kelleher J, Schwartz L,, A Randomized, Double-Blind, Multicenter, Parallel Group Trial Comparing the Safety, and Efficacy of IGIV-Chromatography, 10% (Experimental) with IGIV-Solvent Detergent Treated, 10% (Control) in Patients with Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2000. Report on file. 36. Kelleher J, S.L., IGIV-C 10% Rapid Infusion Trial in Idiopathic (Immune) Thrombocytopenic Purpura (ITP), 2001. Report on file. 37. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003; 17,241-251.

SIDE EFFECTS General Various mild and moderate reactions, such as headache, fever, fatigue, chills, flushing, dizziness, urticaria, wheezing or chest tightness, nausea, vomiting, rigors, back pain, chest pain, muscle cramps, and changes in blood pressure may occur with infusions of Immune Globulin Intravenous (Human). In general, reported adverse reactions to GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) in patients with Primary Immunodeficiency are similar in kind and frequency to those observed with other IGIV products. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. Although hypersensitivity reactions have not been reported in the clinical studies with GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine and antihistamines should be available for treatment of any acute anaphylactic reactions (see WARNINGS). Clinical Study Adverse experiences were examined among a total of 61 enrolled subjects with Primary Immunodeficiency who received at least one infusion of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) during the Phase 3 multicenter clinical study. For this study, temporally associated adverse events are defined by the FDA as those occurring during or within 72 hours of completion of an infusion. Adverse drug reactions (ADR's) are those adverse events that were deemed by the investigators as causally related to the infusion of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) . Of all adverse experiences, 15 events in 8 subjects were serious. Two serious events, two episodes of aseptic meningitis in one patient, were deemed to be possibly related to the infusion of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) . 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 (immune globulin intravenous (human) 10%) . Of these, 136 were mild, 106 were moderate, and 16 were severe. 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). Of the 345 temporally related adverse experiences, those occurring in > 5% of subjects are shown in Table 5. Of these events, only headache occurred in association with more than 5% of infusions. All events were expected based on past experiences with intravenous gammaglobulin products. Table 5: Adverse Events*, Regardless of Causality, that Occurred within 72 Hours of Infusion Event By Infusion By Subject Number Percentage Number Percentage Headache 57 6.90 22 36.1 Fever 19 2.30 13 21.3 Fatigue 18 2.18 10 16.4 Vomiting 10 1.21 9 14.8 Chills 14 1.69 8 13.1 Infusion site events 8 0.97 8 13.1 Nausea 9 1.09 6 9.8 Dizziness 7 0.85 6 9.8 Pain in Extremity 7 0.85 5 8.2 Diarrhea 7 0.85 5 8.2 Cough 5 0.61 5 8.2 Pruritus 5 0.61 4 6.5 Pharyngeal Pain 5 0.61 4 6.5 * Excluding Infections The majority (227/258) of the non-serious adverse experiences deemed related to study product were considered expected based on previous experience with IGIV products and 31 were considered unexpected. In virtually every case, these unexpected events were either consistent with the subject's specific type of immunodeficiency or with the subject's medical history prior to entering the study. A total of 14 hospitalizations occurred during the study but none were related to infection. Hematology and clinical chemistry parameters were monitored in all subjects prior to each infusion throughout the 12-month period of study. Mean values for all laboratory parameters remained consistent throughout the study period. Three of the hematology values in one subject were outside of the normal range and reported as non-serious adverse experiences that resolved completely. These were a red cell count of 3.9 x106/jL, hematocrit of 31%, and white cell count of 3.88 x 103/jL. All spontaneously returned to baseline. One subject had an elevated BUN (45 mg/dL) and creatinine (1.4 mg/dL) on one occasion that were reported as non-serious adverse experiences and resolved completely. These values improved to 30 mg/dL and 0.8 mg/dL, respectively, by the next infusion. Six of the patients had a single, transient elevation in serum transaminases. Two additional patients had persistent elevations in transaminases, ALT and AST, which were present at the initiation of the study, prior to the infusion of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) . There was no other evidence of liver abnormalities. None of the hematology or chemistry laboratory abnormalities that occurred during the course of the study required clinical intervention and none had clinical consequences. During the Phase 3 clinical study, viral safety was assessed by serological screening for HBsAg and antibodies to HCV and HIV-1 and HIV-2 prior to, during, and at the end of the study and by Polymerase Chain Reaction (PCR) tests for HBV, HCV, and HIV-1 genomic sequences prior to and at the end of the study. None of the 61 treated subjects were positive prior to study entry and none converted from negative to positive during the 12-month period of study. Postmarketing: The following is a list of adverse reactions that have been identified and reported during the post-approval use of IGIV products: Respiratory cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular thromboembolism, hypotension Neurological seizures, tremor Hematologic hemolysis, positive direct antiglobulin (Coombs) test General/Body as a Whole pyrexia, rigors Musculoskeletal back pain Gastrointestinal hepatic dysfunction, abdominal pain Rare and Uncommon Adverse Events: Respiratory apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Related Acute Lung Injury (TRALI) Integumentary bullous dermatitis, epidermolysis, erythema multiforme, Stevens-Johnson syndrome Cardiovascular cardiac arrest, vascular collapse Neurological coma, loss of consciousness Hematologic pancytopenia, leukopenia Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction to establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently45 (see PRECAUTIONS). DRUG INTERACTIONS See DOSAGE AND ADMINISTRATION section. REFERENCES 45. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfusion Med Rev. 2003;17:241-251.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Severe hypersensitivity reactions may occur [see CONTRAINDICATIONS]. In case of hypersensitivity, discontinue the Privigen infusion immediately and institute appropriate treatment. Medications such as epinephrine should be available for immediate treatment of acute hypersensitivity reactions. Privigen contains trace amounts of IgA ( ≤ 25 mcg/mL) [see DESCRIPTION]. Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions with administration of Privigen. Privigen is contraindicated in patients with antibodies against IgA and a history of hypersensitivity. Renal Dysfunction And Acute Renal Failure Renal dysfunction, acute renal failure, osmotic nephrosis, and death may occur with immune globulin intravenous (IGIV) products in predisposed patients. Renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose.4 Privigen does not contain sucrose. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Privigen and at appropriate intervals thereafter. Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure.4 If renal function deteriorates, consider discontinuing Privigen. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency, or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are obese, those who use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Privigen at the minimum rate of infusion practicable [see BOXED WARNING, Administration]. Thrombosis Thrombosis may occur following treatment with immune globulin products1-3, including Privigen. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. 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 at risk of thrombosis, administer Privigen at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity [see BOXED WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION]. Hyperproteinemia, Increased Serum Viscosity, And Hyponatremia Hyperproteinemia, increased serum viscosity, and hyponatremia may occur following treatment with IGIV products, including Privigen. The hyponatremia is likely to be a pseudohyponatremia, as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. It is critical to distinguish true hyponatremia from pseudohyponatremia, as treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity, and a possible predisposition to thromboembolic events.5 Aseptic Meningitis Syndrome (AMS) AMS may occur infrequently following treatment with Privigen [see ADVERSE REACTIONS] and other human immune globulin products. Discontinuation of treatment has resulted in remission of AMS within several days without sequelae.6 AMS usually begins within several hours to 2 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. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination on patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV. Hemolysis Privigen may contain blood group antibodies that can act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin test (DAT) (Coombs' test) result and hemolysis.7-9 Delayed hemolytic anemia can develop subsequent to Privigen therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.10 Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of Privigen. The following risk factors may be associated with the development of hemolysis: high doses (e.g., ≥ 2 g/kg), given either as a single administration or divided over several days, and non-O blood group.11 Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration of IGIV,12 but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP and PI.9 Closely monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within approximately 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform additional confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur following treatment with IGIV products, including Privigen.13 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 treatment. Monitor patients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-human leukocyte antigen (HLA) antibodies in both the product and the patient's serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. Volume Overload Carefully consider the relative risks and benefits before prescribing the high dose regimen (for chronic ITP) in patients at increased risk of thrombosis, hemolysis, acute kidney injury, or volume overload. Transmissible Infectious Agents Because Privigen 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 Privigen. Report any infection thought to be possibly transmitted by Privigen to CSL Behring Pharmacovigilance at 1-866-915-6958. Interference With Laboratory Tests Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing. Use In Specific Populations Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Privigen. It is not known whether Privigen can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Privigen should be given to pregnant women only if clearly needed. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation.16,17 Nursing Mothers Use of Privigen in nursing mothers has not been evaluated. Pediatric Use Treatment Of Primary Humoral Immunodeficiency Privigen was evaluated in 31 pediatric subjects (19 children and 12 adolescents) with PI (pivotal study). There were no apparent differences in the safety and efficacy profiles as compared to those in adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and effectiveness of Privigen have not been established in pediatric patients with PI who are under the age of 3. Treatment Of Chronic Immune Thrombocytopenic Purpura The safety and effectiveness of Privigen have not been established in pediatric patients with chronic ITP who are under the age of 15. Geriatric Use Clinical studies of Privigen did not include sufficient numbers of subjects age 65 and over to determine whether they respond differently from younger subjects. Use caution when administering Privigen to patients age 65 and over who are judged to be at increased risk of developing acute renal insufficiency and thrombosis [see BOXED WARNING, WARNINGS AND PRECAUTIONS]. Do not exceed recommended doses, and administer Privigen at the minimum dose and infusion rate practicable. REFERENCES 1. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994;44:223-226. 2. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986;2:217-218. 3. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000;65:30-34. 4. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol 1997;8:1788-1793. 5. Steinberger BA, Ford SM, Coleman TA. Intravenous immuneglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol 2003;73:97-100. 6. Gabor EP. Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997;127:1130. 7. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion 1986;26:410-412. 8. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood 1993;15:3789. 9. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997;20:1142-1145. 10. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999;13:129-135. 11. Kahwaji J, Barker E, Pepkowitz S, et al. Acute Hemolysis After High-Dose Intravenous Immunoglobulin Therapy in Highly HLA Sensitized Patients. Clin J Am Soc Nephrol 2009;4:1993-1997. 12. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: A case series analysis. Transfusion 2008;48:1598-1601. 13. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268. 15. Siber GA, Werner BG, Halsey NA, et al. Interference of immune globulin with measles and rubella immunization. J Pediatr 1993;122:204-211. 16. Hammarström L, Smith CIE. Placental transfer of intravenous immunoglobulin. Lancet 1986;1:681. 17. Sidiropoulos D, Herrmann U, Morell A, von Muralt G, Barandun S. Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 1986;109:505-508.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Both Indications 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 to Rhophylac or any of its components. Rhophylac contains trace amounts of IgA (less than 5 mcg/mL) [see DESCRIPTION]. 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]. Interference With Laboratory Tests The administration of Rh0(D) immune globulin may affect the results of blood typing, the antibody screening test, and the direct antiglobulin (Coombs') test. Antepartum administration of Rh0(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. 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. ITP Intravascular Hemolysis Intravascular hemolysis has occurred in a clinical study with Rhophylac. All cases resolved completely. However, as reported in the literature, some Rh0(D)-positive patients treated with Rh0(D) Immune Globulin Intravenous (Human) for ITP developed clinically compromising anemia, acute renal insufficiency, and, very rarely, disseminated intravascular coagulation (DIC) and death.2 Note: This warning does not apply to Rh0(D)-negative patients treated for the suppression of Rh isoimmunization. Monitor patients in a healthcare setting for at least 8 hours after administrationof 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, Rh0(D)-negative packed RBCs should be used to avoid exacerbating ongoing hemolysis. Pre-existing Anemia The safety of Rhophylac in the treatment of ITP has not been established in patients with pre-existing anemia. Rhophylac may increase the severity of anemia. Use In Specific Populations Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Rhophylac. Suppression Of Rh Isoimmunization The available evidence suggests that Rhophylac does not harm the fetus or affect future pregnancies or reproduction capacity when given to pregnant Rh0(D)-negative women for suppression of Rh isoimmunization.3 ITP Rhophylac has not been evaluated in pregnant women with ITP. Nursing Mothers Suppression Of Rh Isoimmunization Rhophylac is used in nursing mothers for the suppression of Rh isoimmunization. No undesirable effects on a nursing infant are expected during breastfeeding. ITP Rhophylac has not been evaluated in nursing mothers with ITP. Pediatric Use Suppression Of Rh Isoimmunization In Incompatible Transfusions The safety and effectiveness of Rhophylac have not been established in pediatric subjects being treated for an incompatible transfusion. The physician should weigh the potential risks against the benefits of Rhophylac, particularly in girls whose later pregnancies may be affected if Rh isoimmunization occurs. Chronic ITP The safety and effectiveness of Rhophylac have not been established in pediatric subjects with chronic ITP. Dosing in the treatment of children with chronic ITP is expected to be similar to adults. Geriatric Use Suppression Of Rh Isoimmunization In Incompatible Transfusions Rhophylac has not been evaluated for treating incompatible transfusions in subjects 65 years of age and older. ITP Of the 98 subjects evaluated in the clinical study of Rhophylac for treatment of ITP [see Clinical Studies], 19% were 65 years of age and older. No overall differences in effectiveness or safety were observed between these subjects and younger subjects. REFERENCES 2. Gaines AR. Disseminated intravascular coagulation associated with acute hemoglobinemia or hemoglobinuria following Rh0(D) immune globulin intravenous administration for immune thrombocytopenic purpura. Blood. 2005;106:1532- 1537. 3. Thornton JG, Page C, Foote G, Arthur GR, Tovey LAD, Scott JS. Efficacy and long term effects of antenatal prophylaxis with anti-D immunoglobulin. Br Med J. 1989;298:1671-1673.

WARNINGS Immune Globulin Intravenous (Human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.9-14 Patients predisposed to acute renal failure include patients with: any degree of pre-existing renal insufficiency diabetes mellitus age greater than 65 volume depletion sepsis paraproteinemia patients receiving known nephrotoxic drugs In such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Carimune® NF contains sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. IgA deficient patients, especially those with known antibodies against IgA, are at greater risk of developing severe hypersensitivity and anaphylactic reactions. Carimune® NF is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. 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 through the application of viral elimination/reduction steps such as alcohol fractionation in the presence of filter aids, nanofiltration and pH 4/pepsin treatment19-21 (see Table 1). Despite these measures, such products may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. 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 this product should be reported by the physician or other healthcare provider to CSL Behring Pharmacovigilance at 1-866- 915-6958. The physician should discuss the risks and benefits of this product with the patient. Patients with agamma- or extreme hypogammaglobulinemia who have never before received immunoglobulin substitution treatment or whose time from last treatment is greater than 8 weeks, may be at risk of developing inflammatory reactions on rapid infusion (greater than 2 mg/kg/min) of Carimune® NF. These reactions are manifested by a rise in temperature, chills, nausea, and vomiting. The patient's vital signs should be monitored continuously. The patient should be carefully observed throughout the infusion, since these reactions on rare occasions may lead to shock. Epinephrine and other appropriate resuscitative drugs and equipment should be available for treatment of an acute anaphylactic reaction. PRECAUTIONS Please see DOSAGE AND ADMINISTRATION below, for important information on Carimune® NF compatibility with other medications or fluids. Patients should not be volume depleted prior to the initiation of the infusion of IGIV. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, should be assessed prior to the initial infusion of Carimune® NF and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, Carimune® NF should be infused at a rate less than 2 mg/kg/min. Laboratory Tests IGIV recipients should be monitored for clinical signs and symptoms of hemolysis. IGIV recipients should be monitored for pulmonary adverse reactions. If Transfusion-Related Acute Lung Injury (TRALI) is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. Pregnancy Category C Animal reproduction studies have not been conducted with Carimune® NF. It is also not known whether Carimune® NF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Carimune® NF should be given to a pregnant woman only if clearly needed.38 Intact immune globulins such as those contained in Carimune® NF cross the placenta from maternal circulation increasingly after 30 weeks gestation.45,46 In cases of maternal ITP where Carimune® was administered to the mother prior to delivery, the platelet response and clinical effect were similar in the mother and neonate.38,46–55 Pediatric Use High dose administration of Carimune® in pediatric patients with acute or chronic Immune Thrombocytopenic Purpura did not reveal any pediatric-specific hazard.29 Antibodies in Immune Globulin Intravenous (Human) may impair the efficacy of live attenuated viral vaccines such as measles, rubella, and mumps.56-58 Immunizing physicians should be informed of recent therapy with Immune Globulin Intravenous (Human) so that appropriate precautions may be taken. Geriatric Use Carimune® NF should be used with caution in patients over 65 years of age and judged to be at increased risk of developing renal insufficiency (see DOSAGE AND ADMINISTRATION). In the absence of prospective data, recommended doses should not be exceeded and the concentration and infusion rate selected should be the minimum practicable. The product should be infused at a rate less than 2 mg/kg/min. Aseptic Meningitis Syndrome An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) (IGIV) treatment. The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. Hemolysis Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.59-61 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration62 (see ADVERSE REACTIONS). IGIV recipients should be monitored for clinical signs and symptoms of hemolysis (see PRECAUTIONS: Laboratory Tests). Transfusion-Related Acute Lung Injury (TRALI) There have been reports of noncardiogenic pulmonary edema Transfusion-Related Acute Lung Injury (TRALI) in patients administered IGIV.63 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1–6 hours after transfusion. Patients with TRALI may be managed by using oxygen therapy with adequate ventilatory support. IVIG recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum (see PRECAUTIONS: Laboratory Tests). Thrombosis Thrombosis may occur following treatment with immune globulin products1-8, including Carimune NF. Risk factors may include: advanced age, prolonged immobilization, hypercoagulable conditions, history of venous or arterial thrombosis, use of estrogens, indwelling central vascular catheters, hyperviscosity, and cardiovascular risk factors. Thrombosis may occur in the absence of known risk factors. 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 at risk of thrombosis, administer Carimune NF at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity (see BOXED WARNING, DOSAGE AND ADMINISTRATION, PATIENT INFORMATION). REFERENCES 1. Dalakas MC: High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology 1994; 44:223–226. 2. Caress JB, Cartwright MS, Donofrio PD, Peacock JE: The clinical features of 16 cases of stroke associated with administration of IVIg. Neurology 2003; 60:1822–1824. 3. Woodruff RK, Grigg AP, Firkin FC, Smith IL: Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet 1986; 2:217–218. 4. Jordan S, Cunningham-Rundles C, McEwan R: Utility of intravenous immune globulin in kidney transplantation: efficacy, safety, and cost implications. Am J Transplant 2003; 3:653–664. 5. Wolberg AS, Kon RH, Monroe DM, Hoffman M: Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol 2000; 65:30–34. 6. Zaidan R, Al Moallem M, Wani BA, Shameena AR, Al Tahan AR, Daif AK, Al Rajeh S: Thrombosis complicating high dose intravenous immunoglobulin: report of three cases and review of the literature. Eur J Neurology 2003; 10:367–372. 7. Okuda D, Flaster M, Frey J, Sivakumar, K: Arterial thrombosis induced by IVIg and its treatment with tPA. Neurology 2003; 60:1825–1826. 8. Dalakas MC, Clark WM: Strokes, thromboembolic events, and IVIg. Rare incidents blemish an excellent safety record. Neurology 2003; 60:1736–1737. 9. Winward DB, Brophy MT: Acute renal failure after administration of intravenous immunoglobulin: Review of the literature and case report. Pharmacotherapy 1995; 15:765–772. 10. Cantú TG, Hoehn-Saric EW, Burgess KM, Racusen L, Scheel P: Acute renal failure associated with immunoglobulin therapy. Am J Kidney Dis 1995; 25:228–234.11. Cayco AV, Perazella MA, Hayslett JP: Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Amer Soc Nephrology 1997; 8:1788–1793. 12. Rault R, Piraino B, Johnston JR, Oral A: Pulmonary and renal toxicity of intravenous immunoglobulin. Clin Nephrol 1991, 36:83–86. 13. Michail S, Nakopoulou L, Stravrianopoulos I, Stamatiadis D, Avdikou K, Vaiopoulos G, Stathakis C: Acute renal failure associated with immunoglobulin administration. Nephrol Dial Transplant 1997; 12:1497–99. 14. Ashan N, Wiegand LA, Abendroth CS, Manning EC: Acute renal failure following immunoglobulin therapy. Am J Nephrol 1996; 16:532–6. 19. Omar A, and Kempf C: Removal of neutralized model Parvoviruses and Enteroviruses in human IgG solutions by nanofiltration. Transfusion 2002; 42:1005–1010. 20. Späth P, Kempf C, and Gold R: Herstellung, Verträglichkeit und Virussicherheit von intravenösem Immunglobulin. In “Immunglobuline in der Neurobiologie” (P. Berlit, ed.), Steinkopff Verlag, Darmstadt, BRD 2001, pp 1–42. 21. Kempf C, Morgenthaler JJ, Rentsch M, and Omar A: Viral safety and manufacturing of an intravenous immunoglobulin. In “Intravenous Immunoglobulin Research and Therapy” Kazatchkine and Morell, eds. Parthenon Publishing Group. 1996, pp 11–18. 29. Imbach P, Barandun S, d'Apuzzo V, et al: High-dose intravenous gamma globulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1981; 1:1228. 38. Wenske G, Gaedicke G, Küenzlen E, et al: Treatment of idiopathic thrombocytopenic purpura in pregnancy by high-dose intravenous immunoglobulin. Blut 1983; 46:347–353. 45. Hammarstrom L, and Smith CI: Placental transfer of intravenous immunoglobulin. Lancet 1986; 1:681. 46. Sidiropoulos D, et al: Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr 1986; 109:505–508. 47. Wenske G, et al: Idiopathic thrombocytopenic purpura in pregnancy and neonatal period. Blut 1984; 48:377–382. 48. Fabris P, et al: Successful treatment of a steroid-resistant form of idiopathic thrombocytopenic purpura in pregnancy with high doses of intravenous immunoglobulins. Acta Haemat 1987; 77:107–110. 49. Coller BS, et al: Management of severe ITP during pregnancy with intravenous immunoglobulin (IVIgG). Clin Res 1985; 33:545A. 50. Tchernia G, et al: Management of immune thrombocytopenia in pregnancy: Response to infusions of immunoglobulins. Am J Obstet Gynecol 1984; 148:225–226. 51. Newland AC, et al: Intravenous IgG for autoimmune thrombocytopenia in pregnancy. N Engl J Med 1984; 310:261–262. 52. Morgenstern GR, et al: Autoimmune thrombocytopenia in pregnancy: New approach to management. Br Med J 1983; 287:584. 53. Ciccimarra F, et al: Treatment of neonatal passive immune thrombocytopenia. J Pediat 1984; 105:677–678. 54. Rose VL, and Gordon LI: Idiopathic thrombocytopenic purpura in pregnancy. Successful management with immunoglobulin infusion. JAMA 1985; 254:2626–2628. 55. Gounder MP, et al: Intravenous gammaglobulin therapy in the management of a patient with idiopathic thrombocytopenic purpura and a warm autoimmune erythrocyte panagglutinin during pregnancy. Obstet Gynecol 1986; 67:741–746. 56. Siber GR, Werner BG, Halsey NA, et al: Interference of immune globulin with measles and rubella immunisation. J Pediatr 1993; 122:204–211. 57. American Academy of Pediatrics, Committee on Infectious Diseases: Recommended timing of routine measles immunization for children who have recently received immune globulin preparations. Pediatrics 1994; 93:682–685. 58. Centers of Disease Control and Prevention. Measles, mumps, and rubella-vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the advisory committee on immunization practices (ACIP). MMWR, Morbidity and Mortality Weekly Report. May 22, 1998; vol 47/No. RR-8, 1–57. 59. Copelan EA, Strohn PL, Kennedy MS, Tutschka PJ: Hemolysis following intravenous immune globulin therapy. Transfusion 1986; 26:410–412. 60. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J: Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789. 61. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle & Nerve 1997; 20:1142–1145. 62. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H: In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999; 13:129–135. 63. Rizk A, Gorson KC, Kenney L, Weinstein R: Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41:264–268.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Sensitivity Severe hypersensitivity reactions may occur. In case of hypersensitivity, IGIV infusion should be immediately discontinued and appropriate treatment instituted. Epinephrine should be immediately available for treatment of acute severe hypersensitivity reaction. (See Patient Counseling Information) GAMUNEX (immune globulin intravenous (human) 10%) contains trace amounts of IgA (average 46 micrograms/mL). It is contraindicated in IgA deficient patients with antibodies against IgA and history of hypersensitivity. (See Patient Counseling Information) Renal Failure Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of GAMUNEX (immune globulin intravenous (human) 10%) and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. (See Patient Counseling Information) For patients judged to be at risk for developing renal dysfunction and/or at risk of developing thrombotic events, it may be prudent to reduce the amount of product infused per unit time by infusing GAMUNEX at a rate less than 8 mg IG/kg/min (0.08 mL/kg/min). (See Boxed Warning) (See DOSAGE AND ADMINISTRATION) Hyperproteinemia Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving IGIV therapy. The hyponatremia is likely to be a pseudohyponatremia as demonstrated by a decreased calculated serum osmolality or elevated osmolar gap. Distinguishing true hyponatremia from pseudohyponatremia is clinically critical, as treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and a disposition to thromboembolic events. [45] Thrombotic Events Thrombotic events have been reported in association with IGIV [33,34,35]. Patients at risk may 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 or suspected hyperviscosity. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. Aseptic Meningitis Syndrome (AMS) An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. [25-27]The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cu mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. It appears that patients with a history of migraine may be more susceptible. (See Patient Counseling Information) Hemolysis Immune Globulin Intravenous (Human) (IGIV) products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.[28,29,30] Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration. IGIV recipients should be monitored for clinical signs and symptoms of hemolysis. [31] If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done. (See Patient Counseling Information) Transfusion-related Acute Lung Injury (TRALI) There have been reports of noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] in patients administered IGIV.[32] TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1-6 hrs after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions (See Patient Counseling Information) If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum. Volume Overload The high dose regimen (1g/kg x 1-2 days) is not recommended for individuals with expanded fluid volumes or where fluid volume may be a concern. General Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g. viruses, and, theoretically, the Creutzfeldt-Jakob (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Talecris Biotherapeutics, Inc. [1-800-520-2807]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient (See Patient Counseling Information) Laboratory Tests If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum. Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. Use In Specific Populations Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with GAMUNEX (immune globulin intravenous (human) 10%) . It is not known whether GAMUNEX (immune globulin intravenous (human) 10%) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMUNEX (immune globulin intravenous (human) 10%) should be given to a pregnant woman only if clearly needed. Nursing Mothers GAMUNEX (immune globulin intravenous (human) 10%) has not been evaluated in nursing mothers. Pediatric Use Treatment of Primary Immunodeficiency GAMUNEX (immune globulin intravenous (human) 10%) was evaluated in 18 pediatric subjects (age range 0-16 years). Twenty-one percent of PI subjects (Study 100175) exposed to GAMUNEX (immune globulin intravenous (human) 10%) were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that vomiting was more frequently reported in pediatrics (3 of 18 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels. One subject, a 10-year-old boy, died suddenly from myocarditis 50 days after his second infusion of GAMUNEX (immune globulin intravenous (human) 10%) . The death was judged to be unrelated to GAMUNEX (immune globulin intravenous (human) 10%) . Treatment of Idiopathic Thrombocytopenic Purpura GAMUNEX (immune globulin intravenous (human) 10%) was evaluated in 12 pediatric subjects with acute ITP. Twenty-five percent of the acute ITP subjects (Study 100176) exposed to GAMUNEX (immune globulin intravenous (human) 10%) were children. Pharmacokinetics, safety and efficacy were similar to those in adults with the exception that fever was more frequently reported in pediatrics (6 of 12 subjects). No pediatric-specific dose requirements were necessary to achieve serum IgG levels. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy The safety and effectiveness of GAMUNEX (immune globulin intravenous (human) 10%) has not been established in pediatric subjects with CIDP. Geriatric Use Patients > 65 years of age may be at increased risk for developing certain adverse reactions such as thromboembolic events and acute renal failure. (See Boxed Warning, WARNINGS and PRECAUTIONS) Clinical studies of GAMUNEX (immune globulin intravenous (human) 10%) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Table 11: Clinical Studies of GAMUNEX (immune globulin intravenous (human) 10%) by Age Group Clinical Study Indication Number of Subjects

WARNINGS Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.27 Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Glycine, an amino acid, is used as a stabilizer. GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) does not contain sucrose. See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. Immune Globulin Intravenous (Human), 10% is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. 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 inactivating and/or removing certain viruses (see DESCRIPTION). Despite these measures, such products can still potentially transmit disease. Because this product 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. ALL infections thought by a physician possibly to 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.). The physician should discuss the risks and benefits of this product with the patient. GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) should only be administered intravenously. Other routes of administration have not been evaluated. Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine and antihistamines should be available for treatment of any acute anaphylactoid reactions. PRECAUTIONS General Some viruses, such as B19V (formerly known as Parvovirus B19) or Hepatitis A, are particularly difficult to remove or inactivate. B19V most seriously affects pregnant women, or immune-compromised individuals. Symptoms of B19V infection include fever, drowsiness, chills and runny nose followed about two weeks later by a rash and joint pain. Evidence of Hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting and abdominal pain. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear. Components used in the packaging of this product are latex-free. Renal Function Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Assure that patients are not volume depleted prior to the initiation of infusion of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) . Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of IGIV products and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk of developing renal dysfunction, it may be prudent to reduce the rate of infusion to less than 3.3 mg IgG/kg/min ( < 2 mL/kg/hr). Hemolysis IGIV products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.28,29,30 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced red blood cells (RBC) sequestration (see ADVERSE REACTIONS).31 IGIV recipients should be monitored for clinical signs and symptoms of hemolysis (see PRECAUTIONS: Laboratory Tests). Transfusion-Related Acute Lung Injury (TRALI) There have been reports of noncardiogenic pulmonary edema (Transfusion Related Acute Lung Injury [TRALI]) in patients administered IGIV.32 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever, and typically occurs within 1-6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum< (see PRECAUTIONS: Laboratory Tests). Thrombotic Events Thrombotic events have been reported in association with IGIV (see ADVERSE REACTIONS).33,34,35,36,37,38,39,40,41 Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity, hypercoagulable disorders and prolonged periods of immobilization. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies (see PRECAUTIONS: Laboratory Tests). Aseptic Meningitis Syndrome An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with IGIV treatment. 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. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic mm, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IGIV treatment. Laboratory Tests If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done [see PRECAUTIONS]. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum [see PRECAUTIONS]. Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies [see PRECAUTIONS]. Pregnancy Category C Animal reproduction studies have not been conducted with GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) . It is also not known whether GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) should be given to a pregnant woman only if clearly indicated. Maternally administered IGIV products have been shown to cross the placenta, increasingly after 30 weeks gestation.42,43,44 Use in Pediatrics The safety and efficacy of GAMMAGARD LIQUID (immune globulin intravenous (human) 10%) has not been evaluated in neonates or infants. REFERENCES 27. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol. 1997;8:1788-1794. 28. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion. 1986;26:410-412. 29. Wilson JR, Bhoopalam H, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve. 1997;20:1142-1145. 30. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood. 1993;82:3789. 31. Kessary-Shoham H, Levy Y, Shoenfeld Y, Lorber M, Gershon H. In vivo administration of intravenous immunoglobulin (IVIg) can lead to enhanced erythrocyte sequestration. J Autoimmun. 1999;13:129-135. 32. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion. 2001;41:264-268. 33. Brannagan TH, III, Nagle KJ, Lange DJ, Rowland LP. Complications of intravenous immune globulin treatment in neurologic disease. Neurology. 1996;47:674-677. 34. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44:223-226. 35. ElKayam O, Paran D, Milo R, et al. Acute myocardial infarction associated with high dose intravenous immunoglobulin infusion for autoimmune disorders. A study of four cases. Ann Rheum Dis. 2000;59:77-80. 36. Gomperts ED, Darr F. Rapid infusion of intravenous immunoglobulin in patients with neuromuscular diseases. Neurology. 2002;58:1444. 37. Haplea SS, Farrar JT, Gibson GA, Laskin M, Pizzi LT, Ashbury AK. Thromboembolic events associated with intravenous immunoglobulin therapy [abstract]. Neurology. 1997;48:A54. 38. Harkness K, Howell SJ, Davies-Jones GA. Encephalopathy associated with intravenous immunoglobulin treatment for Guillain-Barre syndrome. J Neurol Neurosurg Psychiatry. 1996;60:586. 39. Kwan T, Keith P. Stroke following intravenous immunoglobulin infusion in a 28-year-old male with common variable immune deficiency: a case report and literature review. Can J Allergy Clin Immunol. 1999;4:250-253. 40. Wolberg AS, Kon RH, Monroe DM, Hoffman M. Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations. Am J Hematol. 2000;65:30-34. 41. Woodruff RK, Grigg AP, Firkin FC, Smith IL. Fatal thrombotic events during treatment of autoimmune thrombocytopenia with intravenous immunoglobulin in elderly patients. Lancet. 1986;2:217-218. 42. Hammarstrom L, Smith CI. Placental transfer of intravenous immunoglobulin. Lancet. 1986;1:681. 43. Morell A, Sidiropoulos D, Herrmann U, et al. IgG subclasses and antibodies to group B streptococci, pneumococci, and tetanus toxoid in preterm neonates after intravenous infusion of immunoglobulin to the mothers. Pediatr Res. 1986;20:933-936. 44. Sidiropoulos D, Herrmann U, Jr., Morell A, von Muralt G, Barandun S. Transplacental passage of intravenous immunoglobulin in the last trimester of pregnancy. J Pediatr. 1986;109:505-508.