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CLINICAL PHARMACOLOGY Mechanism Of Action Hizentra supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The mechanism of action in PI has not been fully elucidated. Pharmacokinetics Clinical Studies The pharmacokinetics (PK) of Hizentra was evaluated in a PK substudy of subjects (14 adults, 1 pediatric subject 6 to < 12 years, and 3 adolescent subjects 12 to < 16 years) with PI participating in the 15-month efficacy and safety study [see Clinical Studies]. All PK subjects were treated previously with Privigen®, Immune Globulin Intravenous (Human), 10% Liquid and were switched to weekly subcutaneous treatment with Hizentra. After a 3-month wash-in/wash-out period, doses were adjusted individually with the goal of providing a systemic serum IgG exposure (area under the IgG serum concentration vs time curve; AUC) not inferior to that of the previous weekly-equivalent IGIV dose. Table 6 summarizes PK parameters for subjects in the substudy following treatment with Hizentra and IGIV. Table 6: Pharmacokinetics Parameters of Hizentra and IGIV, US Study Hizentra IGIV* (Privigen®) Number of subjects 18 18 Dose* (mg/kg) Mean 228 152 Range 141-381 86-254 IgG peak levels (mg/dL) Mean 1616 2564 Range 1090-2825 2046-3456 IgG trough levels (mg/dL) Mean 1448 1127 Range 952-2623 702-1810 AUC† (day x mg/dL) Mean 10560 10320 Range 7210-18670 8051-15530 CL‡ (mL/day/kg) Mean 2.2 1.3§ Range 1.2-3.7 0.9-2.1 AUC, area under the curve; CL, clearance. * For IGIV: weekly-equivalent dose. † Standardized to a 7-day period. ‡ Apparent clearance (CL/F) for Hizentra (F = bioavailability) § Based on n=25 from the US Privigen PI study. For the 19 subjects completing the wash-in/wash-out period, the average dose adjustment for Hizentra was 153% (range: 126% to 187%) of the previous weekly-equivalent IGIV dose. After 12 weeks of treatment with Hizentra at this individually adjusted dose, the final steady-state AUC determinations were made in 18 of the 19 subjects. The geometric mean ratio of the steadystate AUCs, standardized to a weekly treatment period, for Hizentra vs IGIV treatment was 1.002 (range: 0.77 to 1.20) with a 90% confidence limit of 0.951 to 1.055 for the 18 subjects. With Hizentra, peak serum levels are lower (1616 vs 2564 mg/dL) than those achieved with IGIV while trough levels are generally higher (1448 vs 1127 mg/dL). In contrast to IGIV administered every 3 to 4 weeks, weekly subcutaneous administration results in relatively stable steady-state serum IgG levels.13,14 After the subjects had reached steady-state with weekly administration of Hizentra, peak serum IgG levels were observed after a mean of 2.9 days (range: 0 to 7 days) in 18 subjects. Table 7 summarizes PK parameters at steady state for pediatric subjects (age groups: 6 to < 12 and 12 to < 16 years) and adults subjects ( > 16 years) in the European Hizentra study following weekly treatment [see Clinical Studies]. Pediatric PK parameters are similar to those of adult subjects; thus no pediatric specific dose requirements are needed for Hizentra dosing. Table 7: Pediatric Pharmacokinetics Parameters of Hizentra, European Study Age Group Total (n=23) 6 to < 12 years (n=9) 12 to < 16 years (n=3) 16 to < 65 years (n=11) Dose (mg/kg) Mean 120 115 117 118 Range 71-170 72-150 87-156 71-170 IgG trough levels (mg/dL) Mean 731 764 754 746 Range 531-915 615-957 505-898 505-957 AUC0-7d (day x mg/dL) Mean 5230 5491 5452 5370 Range 3890-6950 4480-6750 3860-6810 3860-6950 CL (mL/day/kg) Mean 2.19 2.17 2.30 2.23 Range 1.57-3.05 1.38-3.34 1.82-3.01 1.38-3.34 AUC0-7d, area under the curve for the 7-day dosing interval; CL, apparent clearance (CL/F) (F = bioavailability). Pharmacokinetic Modeling And Simulation Biweekly (Every Two Weeks) or more Frequent Dosing Pharmacokinetic characterization of biweekly or more frequent dosing of Hizentra was undertaken using population PK-based modeling and simulation. Serum IgG concentration data consisted of 3837 samples from 151 unique pediatric and adult subjects with PI from four clinical studies of IGIV (Privigen®) and/or Hizentra. Of the 151 subjects, 94 were adult subjects (63 from Hizentra clinical studies) and 57 were pediatric subjects (32 from Hizentra clinical studies). Compared with weekly administration, PK modeling and simulation predicted that administration of Hizentra on a biweekly basis at double the weekly dose results in comparable IgG exposure [equivalent AUCs, with a slightly higher IgG peak (Cmax) and slightly lower trough (Cmin)]. In addition, PK modeling and simulation predicted that for the same total weekly dose, Hizentra infusions given 2, 3, 5, or 7 times per week (frequent dosing) produce IgG exposures comparable to weekly dosing [equivalent AUCs, with a slightly lower IgG peak (Cmax) and slightly higher trough (Cmin)]. Frequent dosing reduces the peak-to-trough variation in Hizentra exposure, thus resulting in more sustained IgG exposures. See Table 8 (columns for AUC, Cmax and Cmin). Dose Adjustment Factor Using data from four clinical studies, results of model-based simulations demonstrated that weekly or biweekly Hizentra dosing regimens with an IGIV:IGSC dose adjustment factor of 1:1.37 adequately maintain median AUC0-28days and Cmin ratios at ≥ 90% of values observed with 4-weekly IGIV dosing. See Table 8 (top two rows). Prediction of Trough Levels Following Regimen Changes PK modeling and simulation also predicted changes in trough levels after switching from (a) monthly IGIV to weekly or biweekly Hizentra dosing, (b) weekly to biweekly Hizentra dosing, or (c) weekly to more frequent dosing. Table 8 (last column) shows the predicted changes in steady-state IgG trough levels after switching between the various dosing regimens. Table 8: Predicted Ratios* [Median (5th, 95th percentiles)] of AUC, Cmax and Cmin and Changes in IgG Trough Levels after Switching Between IgG Dosing Regimens IgG Dosing Regimen Switch AUC Cmax Cmin Predicted Change in Trough† From: To: IGIV Weekly Hizentra† 0.97 (0.90-1.04) 0.68 (0.60-0.76) 1.16 (1.07-1.26) 16% increase IGIV Biweekly Hizentra§ 0.97 (0.91-1.04) 0.71 (0.63-0.78) 1.10 (1.02-1.18) 10% increase Weekly Hizentra Biweekly Hizentra§ 1.00 (0.98-1.03) 1.06 (1.02-1.09) 0.95 (0.92-0.98) 5% decrease Weekly Hizentra 2 times per week Hizentra 1.01 (0.98-1.03) 0.99 (0.96-1.02) 1.03 (1.00-1.06) 3% increase Weekly Hizentra 3 times per week Hizentra 1.01 (0.98-1.03) 0.99 (0.96-1.02) 1.04 (1.01-1.07) 4% increase Weekly Hizentra 5 times per week Hizentra (daily for 5 days) 1.01 (0.98-1.03) 0.99 (0.97-1.01) 1.04 (1.01-1.06) 4% increase Weekly Hizentra Daily Hizentra (7 times per week) 1.00 (0.98-1.03) 0.98 (0.95-1.01) 1.04 (1.02-1.08) 4% increase * Ratios are based on comparison of second regimen vs. first regimen. † Approximate change in trough based on predicted median Cmin ratio. ‡ Weekly dose based on dose adjustment factor of 1.37 when switching from IGIV. § Biweekly dose = 2x weekly dose, based on dose adjustment factor of 1.37 when switching from IGIV. AUC, area under the curve, calculated as AUC0-28days for the IGIV to Hizentra switches, AUC0-14days for the weekly to biweekly Hizentra switch, and AUC0-7days for weekly to more frequent Hizentra switches; Cmax, maximum IgG concentration; Cmin, minimum IgG concentration during a 28-day period (for the IGIV to Hizentra switches), a 14-day period (for the weekly to biweekly Hizentra switch), or a 7-day period (for the weekly to more frequent Hizentra switches). Pediatric Pharmacokinetics PK-based modeling and simulation results indicate that, similar to observations from the clinical study with weekly Hizentra dosing (Table 7), body weight-adjusted biweekly dosing accounted for age-related ( > 3 years) differences in clearance of Hizentra, thereby maintaining systemic IgG exposure (AUC values) in the therapeutic range. Animal Toxicology And/Or Pharmacology Long- and short-term memory loss was seen in juvenile rats in a study modeling hyperprolinemia. In this study, rats received daily subcutaneous injections with L-proline from day 6 to day 28 of life.15 The daily amounts of L-proline used in this study were more than 60 times higher than the L-proline dose that would result from the administration of 400 mg/kg body weight of Hizentra once weekly. In unpublished studies using the same animal model (i.e., rats) dosed with the same amount of L-proline with a dosing interval relevant to IGSC treatment (i.e., on 5 consecutive days on days 9 to 13, or once weekly on days 9, 16, and 23), no effects on learning and memory were observed. The clinical relevance of these studies is not known. Clinical Studies US Study A prospective, open-label, multicenter, single-arm, clinical study conducted in the US evaluated the efficacy, tolerability, and safety of Hizentra in 49 adult and pediatric subjects with PI. Subjects previously receiving monthly treatment with IGIV were switched to weekly subcutaneous administration of Hizentra for 15 months. Following a 3-month wash-in/ wash-out period, subjects received a dose adjustment to achieve an equivalent AUC to their previous IGIV dose [see Pharmacokinetics] and continued treatment for a 12-month efficacy period. The efficacy analyses included 38 subjects in the modified intention-to-treat (MITT) population. The MITT population consisted of subjects who completed the wash-in/wash-out period and received at least one infusion of Hizentra during the efficacy period. Although 5% of the administered doses could not be verified, the weekly median doses of Hizentra ranged from 72 to 379 mg/kg body weight during the efficacy period. The mean dose was 213.2 mg/kg, which was 149% of the previous IGIV dose. In the study, the number of injection sites per infusion ranged from 1 to 12. In 73% of infusions, the number of injection sites was 4 or fewer. Up to 4 simultaneous injection sites were permitted using 2 pumps; however, more than 4 sites could be used consecutively during one infusion. The infusion flow rate did not exceed 50 mL per hour for all injection sites combined. During the efficacy period, the median duration of a weekly infusion ranged from 1.6 to 2.0 hours. The study evaluated the annual rate of serious bacterial infections (SBIs), defined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. The study also evaluated the annual rate of any infections, the use of antibiotics for infection (prophylaxis or treatment), the days out of work/ school/kindergarten/day care or unable to perform normal activities due to infections, hospitalizations due to infections, and serum IgG trough levels. Table 9 summarizes the efficacy results for subjects in the efficacy period (MITT population) of the study. No subjects experienced an SBI in this study. Table 9: Summary of Efficacy Results (MITT Population) Number of subjects (efficacy period) 38 Total number of subject days 12,697 Infections Annual rate of SBIs* 0 SBIs per subject year† Annual rate of any infections 2.76 infections/subject year‡ Antibiotic use for infection (prophylaxis or treatment) Number of subjects (%) 27 (71.1) Annual rate 48.5 days/subject year Total number of subject days 12,605 Days out of work/school/kindergarten/day care or unable to perform normal activities due to infections Number of days (%) 71 (0.56) Annual rate 2.06 days/subject year Hospitalizations due to infections Number of days (%) 7 (0.06)§ Annual rate 0.2 days/subject year * Defined as bacterial pneumonia, bacteremia/septicemia, osteomyelitis/septic arthritis, bacterial meningitis, and visceral abscess. † Upper 99% confidence limit: 0.132. ‡ 95% confidence limits: 2.235; 3.370. § Based on 1 subject. The mean IgG trough levels increased by 24.2%, from 1009 mg/dL prior to the study to 1253 mg/dL during the efficacy period. European Study In a prospective, open-label, multicenter, single-arm, clinical study conducted in Europe, 51 adult and pediatric subjects with PI switched from monthly IGIV (31 subjects) or weekly IGSC (20 subjects) to weekly treatment with Hizentra. For the 46 subjects in the efficacy analysis, the weekly mean dose in the efficacy period was 120.1 mg/kg (range 59 to 243 mg/kg), which was 104% of the previous weekly equivalent IGIV or weekly IGSC dose. None of the subjects had an SBI during the efficacy period, resulting in an annualized rate of 0 (upper one-sided 99% confidence limit of 0.192) SBIs per subject. The annualized rate of any infections was 5.18 infections per subject for the efficacy period. REFERENCES 13. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:1208-1212. 14. Waniewski I, Gardulf A, Hammarström L. Bioavailability of g-globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14:90-97. 15. Bavaresco CS, Streck EL, Netto CA, et al. Chronic hyperprolinemia provokes a memory deficit in the Morris Water Maze Task. Metabolic Brain Disease 2005;20:73-80.

CLINICAL PHARMACOLOGY Vivaglobin® (immune globulin subcutaneous (human)) Immune Globulin Subcutaneous (Human), supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. Vivaglobin® (immune globulin subcutaneous (human)) is to be administered by injection into the subcutaneous tissue. Subcutaneous administration of immune globulin decreases bioavailability compared to intravenous administration.1 The bioavailability of Vivaglobin® (immune globulin subcutaneous (human)) is approximately 73% compared to immune globulin intravenous (IGIV). Various factors, such as the site of administration and IgG catabolism, can affect absorption.1,2 With Vivaglobin® (immune globulin subcutaneous (human)) administration, peak serum IgG levels are lower than those achieved with IGIV. Subcutaneous administration results in relatively stable steady-state serum IgG levels when administered on a weekly basis.2,3 This serum IgG profile is representative of that seen in a normal population. The pharmacokinetics (PK) of Vivaglobin® (immune globulin subcutaneous (human)) was evaluated in the PK phase of a pivotal 12-month clinical study conducted in the United States and Canada in subjects with primary immune deficiency (PID) (see Clinical Studies). Subjects who were previously treated with IGIV were switched over to weekly Vivaglobin® (immune globulin subcutaneous (human)) subcutaneous treatment and, after a 3-month wash-in/wash-out period, doses were individually adjusted to provide an IgG systemic exposure (area under the curve; AUC) that was not inferior to the AUC of the previous weekly-equivalent IGIV dose. For the 19 per-protocol subjects completing the wash-in/wash-out period, the average Vivaglobin® (immune globulin subcutaneous (human)) dose adjustment was 137% (range: 103 to 192%) of the previous weekly-equivalent IGIV dose. Following 10 to 12 weeks of treatment with Vivaglobin® (immune globulin subcutaneous (human)) at this adjusted dose, the final steady-state AUC determinations were made. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Vivaglobin® (immune globulin subcutaneous (human)) versus IGIV treatment was 94.5% (range: 71.4 to 110.1%) with a lower 95% confidence limit of 89.8% for the per-protocol population (n = 17). Table 2 summarizes additional pharmacokinetic parameters for this study including dosing and serum IgG peak and trough levels following treatment with IGIV and Vivaglobin® (immune globulin subcutaneous (human)) . Table 2: Summary of Additional Pharmacokinetic Parameters – US and Canada PK Sub-study – Per-protocol Subjects IGIV Vivaglobin® Number of Subjects 17 17 Dose* Mean 120 mg/kg 165 mg/kg Range 55 – 243 mg/kg 63 – 319 mg/kg IgG peak levels Mean 1735 mg/dL 1163 mg/dL Range 1110 – 3230 mg/dL 743 – 2240 mg/dL IgG trough levels Mean 883 mg/dL 1064 mg/dL Range 430 – 1600 mg/dL 547 – 2140 mg/dL *For IGIV: weekly-equivalent dose, § Standardized to a 7-day period A non-IND 6-month clinical study was conducted in Europe and Brazil in 60 subjects with PID. After the subjects had reached steady state with weekly Vivaglobin® (immune globulin subcutaneous (human)) administration, peak serum IgG levels were observed after a mean of 2.5 days (range 0 to 7 days) in 41 subjects. In contrast to serum IgG levels observed with monthly IGIV treatment (rapid peaks followed by a slow decline), the serum IgG levels in subjects receiving weekly subcutaneous Vivaglobin® (immune globulin subcutaneous (human)) therapy were relatively stable in both studies. Clinical Studies The pivotal open-label, prospective, multicenter clinical study conducted in the United States and Canada evaluated the pharmacokinetics, efficacy, safety and tolerability of Vivaglobin® Immune Globulin Subcutaneous (Human), in adult and pediatric subjects with primary immune deficiency (PID). In this study, 65 adult and pediatric PID subjects previously treated monthly with IGIV were switched to weekly subcutaneous administrations of Vivaglobin® (immune globulin subcutaneous (human)) for 12 months. The per-protocol efficacy analysis included 51 subjects. Subjects received a weekly mean Vivaglobin® (immune globulin subcutaneous (human)) dose of 158 mg/kg body weight (range: 34 to 352 mg/kg), which was 136% (range: 99 to 188%) of their previous weekly-equivalent IGIV dose. The annual rate of serious bacterial infections (defined as bacterial pneumonia, meningitis, sepsis, osteomyelitis, and visceral abscesses), the primary endpoint, was 0.04 infections per subject per year (one-sided upper 99% confidence interval: 0.14) for the per-protocol set (n = 51). Pneumonia was reported in two subjects. The annual rate of any infections, a secondary endpoint, was 4.4 infections per subject per year. The IgG subclass levels observed in this study were consistent with a physiologic distribution pattern (mean values) IgG1: 703 mg/dL, IgG2: 278 mg/dL, IgG3: 36 mg/dL, and IgG4: 30 mg/dL. Table 3 summarizes the dosing and annual rate of infections for the efficacy phase of this study. Table 3: Dose and Annual Rate of Infections with Vivaglobin® (immune globulin subcutaneous (human)) – Per-protocol Subjects Efficacy Phase of the US and Canada Study Number of Subjects (Efficacy) 51 Vivaglobin® Dose Mean % Previous IGIV Dose (range): 136% (99 – 188%) Mean: 158 mg/kg b.w. Range: 34 – 352 mg/kg b.w. Annual Rate of Serious Bacterial Infections 0.04 infections/subject year Annual Rate of Any Infections 4.4 infections/subject year b.w.: body weight Table 4 provides a summary of missed school or work and hospitalization due to infection, which were secondary endpoints. Table 4: Summary of Secondary Efficacy Endpoints – Per-protocol Subjects Efficacy Phase of the US and Canada Study Number of Subjects 51 Total Number of Subject Days 18,949 Total Number of Days Missed School/Work Due to Infection (%) 192 (1.0%) Annual Rate Missed School/Work Due to Infection (days/subject year) 3.70 Total Number of Days Hospitalized Due to Infection (%) 12 ( < 0.1%) Annual Rate of Hospitalization (days/subject year) 0.23 In a non-IND clinical study of Vivaglobin® (immune globulin subcutaneous (human)) conducted in Europe and Brazil, 60 adult and pediatric subjects with PID were switched to weekly subcutaneous administration of Vivaglobin® (immune globulin subcutaneous (human)) for six months. Forty-nine (49) subjects had been on IGIV and 11 subjects had been treated long-term with another brand of Immune Globulin Subcutaneous (Human) replacement therapy before entering the study. The forty-seven (47) per-protocol subjects received a weekly mean Vivaglobin® (immune globulin subcutaneous (human)) dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was 101% (range: 81 to 146%) of their previous immune globulin treatment. The annualized rates of serious bacterial infections (0.04 infections/subject year, one-sided upper 99% confidence interval: 0.21) and any infections (4.3 infections/subject year) were similar to those reported in the study conducted in the US and Canada. REFERENCES 1. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:1208-12. 2. Waniewski I, Gardulf A, Hammarström L. Bioavailability of ã-Globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14(2):90-7. 3. Data on file.

Find Lowest Prices on Hizentra® [Immune Globulin Subcutaneous (Human) (IGSC)] 20% Liquid for Injection WARNING THROMBOSIS Thrombosis may occur with immune globulin products1-3, including Hizentra. 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). For patients at risk of thrombosis, administer Hizentra 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 WARNINGS AND PRECAUTIONS). DESCRIPTION Hizentra, Immune Globulin Subcutaneous (Human), 20% Liquid, is a ready-to-use, sterile 20% (0.2 g/mL) protein liquid preparation of polyvalent human immunoglobulin G (IgG) for subcutaneous administration. Hizentra is manufactured from large pools of human plasma by a combination of cold alcohol 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-receptor-mediated leukocyte activation (determined with complexed IgG). Hizentra has a purity of ³98% IgG and a pH of 4.6 to 5.2. Hizentra contains approximately 250 mmol/L (range: 210 to 290 mmol/L) L-proline (a nonessential amino acid) as a stabilizer, 8 to 30 mg/L polysorbate 80, and trace amounts of sodium. Hizentra contains ≤ 50 mcg/mL IgA. Hizentra contains no carbohydrate stabilizers (e.g., sucrose, maltose) and no preservative. Plasma units used in the manufacture of Hizentra are tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to human immunodeficiency virus (HIV)-½ and hepatitis C virus (HCV) as well as FDA-licensed Nucleic Acid Testing (NAT) for HBV, HCV and HIV-1. All plasma units have been found to be nonreactive (negative) in these tests. In addition, the plasma has been tested for B19 virus (B19V) DNA by NAT. Only plasma that passes 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 Hizentra 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 non-enveloped viruses as small as approximately 20 nanometers. In addition, a depth filtration step contributes to the virus reduction capacity.12 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 Hizentra, expressed as the mean log10 reduction factor (LRF). Table 5: Virus Inactivation/Removal in Hizentra* 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; na, not applicable. * 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).12 Several of the production steps have been shown to decrease infectivity of an experimental TSE 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 12. Stucki M, Boschetti N, Schäfer W, et al. Investigations of prion and virus safety of a new liquid IVIG product. Biologicals 2008;36:239-247.

Vivaglobin® Immune Globulin Subcutaneous (Human) DESCRIPTION Vivaglobin® Immune Globulin Subcutaneous (Human), is a pasteurized, polyvalent human normal immunoglobulin for subcutaneous infusion. Vivaglobin® is manufactured from large pools of human plasma by cold alcohol fractionation and is not chemically altered or enzymatically degraded. Vivaglobin® (immune globulin subcutaneous human) is supplied as a sterile liquid to be administered by the subcutaneous route. Vivaglobin® (immune globulin subcutaneous human) is a 16% (160 mg/mL) protein solution, with a content of at least 96% immunoglobulin G (IgG). The distribution of IgG subclasses is similar to that present in normal human plasma. Vivaglobin® (immune globulin subcutaneous human) contains 2.25% glycine, 0.3% sodium chloride, and water for injection, U.S.P. The pH of Vivaglobin® (immune globulin subcutaneous human) is 6.4 to 7.2. Vivaglobin® (immune globulin subcutaneous human) contains no preservative. All plasma used in the manufacture of Vivaglobin® (immune globulin subcutaneous human) is tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 (HIV-1/2) as well as FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be nonreactive (negative). For hepatitis B virus (HBV), an investigational NAT procedure is used and the plasma found to be negative. However, the significance of a negative result has not been established. In addition, the plasma has been tested by NAT for hepatitis A virus (HAV) and parvovirus B19 (B19). Only plasma that passed virus-screening is used for production and the limit for B19 in the fractionation pool is set not to exceed 104 IU of B19 DNA per mL. The manufacturing procedure for Vivaglobin® (immune globulin subcutaneous human) includes multiple processing steps that reduce the risk of virus transmission. The virus reduction capacity of two steps was evaluated in a series of in vitro spiking experiments; the steps were ethanol - fatty alcohol / pH precipitation and pasteurization in aqueous solution at 60°C for 10 hours. Total mean cumulative virus reductions ranged from 9.0 to ≥ 14.1 log10 as shown in Table 1. Table 1: Mean Virus Reduction Factors CSL Behring Virus Studied: Ethanol - Fatty Alcohol / pH Precipitation [log10] Pasteurization [log10] Total Cumulative [log10] Enveloped Viruses HIV-1 ≥ 6.2 ≥ 6.5 ≥ 12.7 BVDV ≥ 5.3 ≥ 8.7 ≥ 14.0 WNV ≥ 4.4 ≥ 9.3 ≥ 13.7 PRV ≥ 6.2 ≥ 7.9 ≥ 14.1 Non-enveloped Viruses PEV ≥ 6.7 3.7 ≥ 10.4 CPV 6.7 2.3* 9.0 HIV-1: Human immunodeficiency virus type 1, model for HIV types 1 and 2 BVDV: Bovine viral diarrhea virus, model for HCV and WNV WNV: West Nile virus PRV: Pseudorabies virus, model for large enveloped DNA viruses (e.g., herpes virus) PEV: Porcine enterovirus, model for HAV (in an immunoglobulin product) CPV: Canine parvovirus, model for parvovirus B19 * Reduction of parvovirus B19 (evaluated using porcine IgG) by pasteurization was ≥ 3.5 log10.

INDICATIONS Hizentra is an Immune Globulin Subcutaneous (Human) (IGSC), 20% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI) in adults and pediatric patients 2 years of age and older. This includes, but is not limited to, the humoral immune defect in congenital agammaglobulinemia, common variable immunodeficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies. DOSAGE AND ADMINISTRATION For subcutaneous infusion only. Do not inject into a blood vessel. Preparation And Handling Hizentra is a clear and pale yellow to light brown solution. Do not use if the solution is cloudy or contains particulates. Prior to administration, visually inspect each vial of Hizentra for particulate matter or discoloration, whenever the solution and container permit. Do not freeze. Do not use any solution that has been frozen. Check the product expiration date on the vial label. Do not use beyond the expiration date. Do not mix Hizentra with other products. Do not shake the Hizentra vial. Use aseptic technique when preparing and administering Hizentra. The Hizentra vial is for single-use only. Discard all used administration supplies and any unused product immediately after each infusion in accordance with local requirements. Dosage Hizentra can be administered at regular intervals from daily up to every two weeks (biweekly). Individualize the dose based on the patient's clinical response to Hizentra therapy and serum immunoglobulin G (IgG) trough levels. Before receiving treatment with Hizentra: Ensure that patients have received Immune Globulin Intravenous (Human) (IGIV) treatment at regular intervals for at least 3 months. Obtain the patient's serum IgG trough level to guide subsequent dose adjustments (see below under Dose Adjustment). Dosage For Patients Switching To Hizentra From Immune Globulin Intravenous (Human) (IGIV) Establish the initial weekly dose of Hizentra by converting the monthly IGIV dose into a weekly equivalent and increasing it using a dose adjustment factor. The goal is to achieve a systemic serum IgG exposure (area under the concentration-time curve [AUC]) not inferior to that of the previous IGIV treatment. To calculate the initial weekly dose of Hizentra, divide the previous IGIV dose in grams by the number of weeks between doses during the patient's IGIV treatment (e.g., 3 or 4); then multiply this by the dose adjustment factor of 1.37. [see Pharmacokinetics, Table 8)] Initial Hizentra dose = Previous IGIV dose (in grams) x 1.37/Number of weeks between IGIV doses To convert the Hizentra dose (in grams) to milliliters (mL), multiply the calculated dose (in grams) by 5. Provided the total weekly dose is maintained, any dosing interval from daily up to biweekly can be used and will result in systemic serum IgG exposure that is comparable to the previous IGIV or weekly Hizentra treatment [see Pharmacokinetics]. For biweekly dosing, multiply the calculated Hizentra weekly dose by 2. For frequent dosing (2 to 7 times per week), divide the calculated weekly dose by the desired number of times per week (e.g., for 3 times per week dosing, divide weekly dose by 3). Dosage For Patients Switching To Hizentra From IGSC The previous weekly IGSC dose should be maintained. For biweekly dosing, multiply the previous weekly dose by 2. For frequent dosing (2 to 7 times per week), divide the previous weekly dose by the desired number of times per week (e.g., for 3 times per week dosing, divide weekly dose by 3). Start Hizentra treatment For weekly or frequent dosing, start treatment with Hizentra 1 week after the patient's last IGIV infusion or Hizentra/IGSC infusion. For biweekly dosing, start treatment 1 or 2 weeks after the last IGIV infusion or 1 week after the last weekly Hizentra/IGSC infusion. Dose Adjustment Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level, irrespective of the frequency of administration. To determine if a dose adjustment should be considered, measure the patient's serum IgG trough level 2 to 3 months after switching to Hizentra. Weekly dosing: When switching from IGIV to weekly Hizentra dosing, the target serum IgG trough level is projected to be approximately 16% higher than the last trough level during prior IGIV therapy [see Pharmacokinetics]. Biweekly dosing: When switching from IGIV to biweekly Hizentra dosing, the target serum IgG trough level is projected to be approximately 10% higher than the last IGIV trough level. When switching from weekly to biweekly Hizentra dosing, the target trough is projected to be approximately 5% lower than the last trough level on weekly therapy [see Pharmacokinetics]. Frequent dosing: When switching from weekly dosing to more frequent Hizentra dosing, the target serum IgG trough level is projected to be approximately 3 to 4% higher than the last trough level on weekly therapy [see Pharmacokinetics]. To adjust the dose based on trough levels, calculate the difference (in mg/dL) between the patient's serum IgG trough level and the target IgG trough level for weekly or biweekly dosing. Then find this difference in Table 1 (Column 1) and, based on the Hizentra dosing frequency (for weekly or biweekly) and the patient's body weight, locate the corresponding adjustment amount (in mL) by which to increase (or decrease) the dose. For frequent dosing, add the weekly increment from Table 1 to the weekly-equivalent dose and then divide by the number of days of dosing. Use the patient's clinical response as the primary consideration in dose adjustment. Additional dosage increments may be indicated based on the patient's clinical response (infection frequency and severity). Table 1: Incremental Adjustment (mL)* of the Hizentra Dose† Based on the Difference (±mg/dL) from the Target Serum IgG Trough Level Difference From Target Serum IgG Trough Level (mg/dL) Dosing Frequency Weight Adjusted Dose Increment (mL)* Weight Group > 10 to 30 kg > 30 to 50 kg > 50 to 70 kg > 70 to 90 kg > 90 kg 50 Weekly‡ n/a 2.5 5 5 10 Biweekly 5 5 10 10 20 100 Weekly 2.5 5 10 10 15 Biweekly 5 10 20 20 30 200 Weekly 5 10 15 20 30 Biweekly 10 20 30 40 60 n/a, not applicable. * Incremental adjustments based on slopes of the pharmacometric model-predicted relationship between serum IgG trough level and Hizentra dose increments of 1 mg/kg per week. † Includes biweekly, weekly or frequent dosing. ‡ To determine the dose increment for frequent dosing, add the weekly increment to the weekly-equivalent dose and then divide by the number of days of dosing. For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target trough level is 1000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of Hizentra by 10 mL. For biweekly dosing, increase the biweekly dose by 20 mL. For 2 times per week dosing, increase the dose by 5 mL. Monitor the patient's clinical response, and repeat the dose adjustment as needed. Dosage requirements for patients switching to Hizentra from another IGSC product: If a patient on Hizentra does not maintain an adequate clinical response or a serum IgG trough level equivalent to that of the previous IGSC treatment, the physician may want to adjust the dose. For such patients, Table 1 also provides guidance for dose adjustment if their desired IGSC trough level is known. Measles Exposure Administer a minimum total weekly Hizentra dose of 200 mg/kg body weight for two consecutive weeks if a patient is at risk of measles exposure (i.e., due to an outbreak in the US or travel to endemic areas outside of the US. For biweekly dosing, one infusion of a minimum of 400 mg/kg is recommended. If a patient has been exposed to measles, ensure this minimum dose is administered as soon as possible after exposure. Administration Hizentra is for subcutaneous infusion only. Do not inject into a blood vessel. Hizentra is intended for subcutaneous administration using an infusion pump. Infuse Hizentra in the abdomen, thigh, upper arm, and/or lateral hip. Injection sites – A Hizentra dose may be infused into multiple injection sites. Use up to 4 sites simultaneously or up to 12 sites consecutively per infusion. Injection sites should be at least 2 inches apart. Change the actual site of injection with each administration. Volume – For the first infusion of Hizentra, do not exceed a volume of 15 mL per injection site. The volume may be increased to 20 mL per site for the fifth infusion and then to 25 mL per site as tolerated. Rate – For the first infusion of Hizentra, the recommended flow rate is 15 mL per hour per site. For subsequent infusions, the flow rate may be increased to 25 mL per hour per site as tolerated. Follow the steps below and use aseptic technique to administer Hizentra. 1. Assemble supplies – Gather the Hizentra vial(s), disposable supplies (not provided with Hizentra), and other items (infusion pump, sharps or other container, patient's treatment diary/log book) needed for the infusion. 2. Clean surface – Thoroughly clean a flat surface using an alcohol wipe. 3. Wash hands – Thoroughly wash and dry hands. The use of gloves when preparing and administering Hizentra is optional. 4. Check vials – Carefully inspect each vial of Hizentra. Do not use the vial if the liquid looks cloudy, contains particles, or has changed color, if the protective cap is missing, or if the expiration date on the label has passed. 5. Transfer Hizentra from vial(s) to syringe Remove the protective cap from the vial to expose the central portion of the rubber stopper of the Hizentra vial. Clean the stopper with an alcohol wipe and allow it to dry. If using a transfer device, follow the instructions provided by the device manufacturer. If using a needle and a syringe to transfer Hizentra, follow the instructions below. Attach a sterile transfer needle to a sterile syringe. Pull back on the plunger of the syringe to draw air into the syringe that is equal to the amount of Hizentra to be withdrawn. Insert the transfer needle into the center of the vial stopper and, to avoid foaming, inject the air into headspace of the vial (not into the liquid). Withdraw the desired volume of Hizentra. When using multiple vials to achieve the desired dose, repeat this step. 6. Prepare infusion pump and tubing – Follow the manufacturer's instructions for preparing the pump, using subcutaneous administration sets and tubing, as needed. Be sure to prime the tubing with Hizentra to ensure that no air is left in the tubing. 7. Prepare injection site(s) The number and location of injection sites depends on the volume of the total dose. Infuse Hizentra into a maximum of 4 sites simultaneously; or up to 12 consecutively per infusion. Injection sites should be at least 2 inches apart. Using an antiseptic skin preparation, clean each site beginning at the center and working outward in a circular motion. Allow each site to dry before proceeding. 8. Insert needle(s) Grasp the skin between 2 fingers and insert the needle into the subcutaneous tissue. If necessary, use sterile gauze and tape or transparent dressing to hold the needle in place. Before starting the infusion, attach a sterile syringe to the end of the primed administration tubing and gently pull back on the plunger to make sure no blood is flowing back into the tubing. If blood is present, remove and discard the needle and tubing. Repeat the process beginning with step 6 (priming) using a new needle, new infusion tubing, and a different injection site. 9. Start infusion – Follow the manufacturer's instructions to turn on the infusion pump. 10. Record treatment – Remove the peel-off portion of the label from each vial used, and affix it to the patient's treatment diary/log book or scan the vial if recording the infusion electronically. 11. Clean up – After administration is complete, turn off the infusion pump. Take off the tape or dressing and remove the needle set from the infusion site(s). Disconnect the tubing from the pump. Immediately discard any unused product and all used disposable supplies in accordance with local requirements. Clean and store the pump according to the manufacturer's instructions. For self-administration, provide the patient with instructions and training for subcutaneous infusion in the home or other appropriate setting. HOW SUPPLIED Dosage Forms And Strengths Hizentra is a 0.2 g/mL (20%) protein solution for subcutaneous injection. Hizentra is supplied in a single-use, tamper-evident vial containing 0.2 grams of protein per mL of preservative-free liquid. Each product presentation includes a package insert and the following components: Presentation Carton NDC Number Components 5 mL 44206-451-01 Vial containing 1 gram of protein (NDC 44206-451-90) 10 mL 44206-452-02 Vial containing 2 grams of protein (NDC 44206-452-91) 20 mL 44206-454-04 Vial containing 4 grams of protein (NDC 44206-454-92) 50 mL 44206-455-10 Vial containing 10 grams of protein (NDC 44206-455-93) Storage And Handling Keep Hizentra in its original carton to protect it from light. Each vial label contains a peel-off strip with the vial size and product lot number for use in recording doses in a patient treatment record. When stored at room temperature (up to 25°C [77°F]), Hizentra is stable for up to 30 months, as indicated by the expiration date printed on the outer carton and vial label. Do not shake. Do not freeze. Do not use product that has been frozen. The components used in the packaging for Hizentra contain no latex. Manufactured by: CSL Behring AG, Bern, Switzerland. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Revised: Jan 2015

INDICATIONS Vivaglobin® Immune Globulin Subcutaneous (Human), is indicated for the treatment of patients with primary immune deficiency (PID). DOSAGE AND ADMINISTRATION Vivaglobin® Immune Globulin Subcutaneous (Human), contains no preservative. Therefore, discard unused product immediately after use. Vivaglobin® (immune globulin subcutaneous (human)) must not be mixed with other products. Vivaglobin® (immune globulin subcutaneous (human)) is to be injected subcutaneously, preferentially in the abdomen, thighs, upper arms, and/or lateral hip. DO NOT INJECT INTO A BLOOD VESSEL. Dosage All subjects who received Vivaglobin® (immune globulin subcutaneous (human)) in the clinical trials had previously been treated with immune globulin. It is recommended that the patient start treatment with Vivaglobin® (immune globulin subcutaneous (human)) one week after receiving a regularly scheduled IGIV infusion. The initial weekly Vivaglobin® (immune globulin subcutaneous (human)) dose can be calculated by multiplying the previous IGIV dose by 1.37, then dividing this dose into weekly doses based on the patient's previous IGIV treatment interval; for example, if IGIV was administered every three weeks, divide by 3. This dose of Vivaglobin® (immune globulin subcutaneous (human)) will provide a systemic IgG exposure (AUC) comparable to that of the previous IGIV treatment. Weekly administration of this dose will lead to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared to monthly IGIV treatment (see Table 2 for trough levels). The recommended weekly dose of Vivaglobin® (immune globulin subcutaneous (human)) is 100 to 200 mg/kg body weight administered subcutaneously. Doses may be adjusted over time to achieve the desired clinical response and serum IgG levels. As there can be differences in the half-life of IgG among patients with primary immune deficiencies, the dose and dosing interval of immunoglobulin therapy may vary. Doses And Associated IgG Levels The minimum serum concentration of IgG necessary for protection against infections has not been established in randomized and controlled clinical studies. However, based on clinical experience, a target serum IgG trough level (i.e., prior to the next infusion) of at least 500 mg/dL has been proposed in the literature for IGIV therapy.4 Serum IgG levels can be sampled at any time during routine weekly treatment. Subjects on Immune Globulin Subcutaneous (Human), Vivaglobin® (immune globulin subcutaneous (human)) therapy maintained relatively constant IgG levels, rather than the peak and trough pattern observed with monthly IGIV therapy. Administration DO NOT INJECT INTRAVENOUSLY. In the clinical study with Vivaglobin® (immune globulin subcutaneous (human)) , a volume of 15 mL per injection site at a rate of 20 mL per hour per site was not exceeded. Doses over 15 mL were divided and infused into several sites using an infusion pump. Multiple simultaneous injections were enabled by administration tubing and Y-site connection tubing (CADD-Legacy® pumps were used in the study conducted in the US and Canada). Injection sites were at least two inches apart. The following areas were used for subcutaneous injection of Vivaglobin® (immune globulin subcutaneous (human)) : abdomen, thighs, upper arms, and/or lateral hip. The actual point of injection was changed with each weekly administration. Instructions for Administration Prior to use, allow the solution to reach ambient room temperature. Vivaglobin® (immune globulin subcutaneous (human)) should be inspected visually for discoloration and particulate matter prior to administration. DO NOT SHAKE. The appearance of Vivaglobin® (immune globulin subcutaneous (human)) can vary from colorless to light brown. Do not use if the solution is cloudy or has particulates. Check the product expiration date on the vial. Do not use beyond the expiration date. Use aseptic technique when preparing and administering Vivaglobin® (immune globulin subcutaneous (human)) for injection. Remove the protective cap from the vial to expose the central portion of the rubber stopper. Wipe the rubber stopper with alcohol and allow to dry. Using a sterile syringe and needle, prepare to withdraw Vivaglobin® (immune globulin subcutaneous (human)) by first injecting air into the vial that is equivalent to the amount of Vivaglobin® (immune globulin subcutaneous (human)) to be withdrawn. Then withdraw the desired volume of Vivaglobin® (immune globulin subcutaneous (human)) . If multiple vials are required to achieve the desired dose, repeat this step. (Fig. 2) Follow the manufacturer's instructions for filling the pump reservoir and preparing the pump, administration tubing and Y-site connection tubing, if needed. Be sure to prime the administration tubing to ensure that no air is left in the tubing or needle by filling the tubing/needle with Vivaglobin® (immune globulin subcutaneous (human)) . Select the number and location of injection sites depending on the volume of the total dose. Note: In clinical studies with Vivaglobin® (immune globulin subcutaneous (human)) , a volume of 15 mL per injection site was not exceeded. (Fig. 3) Cleanse the injection site(s) with antiseptic solution using a circular motion working from the center of the site and moving to the outside. Sites should be clean, dry, and at least two inches apart. (Fig. 4) Grasp the skin between two fingers and insert the needle into the subcutaneous tissue. (Fig. 5) Vivaglobin® (immune globulin subcutaneous (human)) must not be injected into a blood vessel. After each needle is inserted into the tissue, test to make sure that a blood vessel has not been accidentally accessed. This must be done prior to starting the infusion. To do this, attach a sterile syringe to the end of the primed administration tubing, gently pull back on the syringe plunger and look to see if any blood is flowing back into the administration tubing. If you see any blood, remove and discard the needle and administration tubing. Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site. Secure the needle in place by applying sterile gauze or transparent dressing over the site. (Fig. 6) If using multiple, simultaneous injection sites, use Y-site connection tubing and secure to the administration tubing. Infuse Vivaglobin® (immune globulin subcutaneous (human)) following the manufacturer's instructions for the pump. (Fig. 7) Remove the peel-off label with the product lot number and expiration date from the Vivaglobin® (immune globulin subcutaneous (human)) vial and use this to complete the patient record. After administration, discard any unused solution and administration equipment in accordance with biohazard procedures. Home Treatment If the physician believes that home administration is appropriate, the physician or health professional should provide the patient with instructions on subcutaneous infusion for home treatment. This should include the type of equipment to be used along with its maintenance, proper infusion techniques, selection of appropriate infusion sites (e.g., abdomen, thighs, upper arms, and/or lateral hip), maintenance of a treatment diary, and measures to be taken in case of adverse reactions. HOW SUPPLIED Vivaglobin® Immune Globulin Subcutaneous (Human), is supplied in single-use vials containing 160 mg IgG per mL. The following dosage forms are available: NDC 0053-7596-03 Box of ten 3 mL vials NDC 0053-7596-10 10 mL vial NDC 0053-7596-15 Box of ten 10 mL vials NDC 0053-7596-20 20 mL vial NDC 0053-7596-25 Box of ten 20 mL vials Storage Store in the refrigerator at 2 - 8°C (36 - 46°F). Vivaglobin® Immune Globulin Subcutaneous (Human), is stable for the period indicated by the expiration date on its label. Do not freeze. Keep vials in storage box until use. 4. Roifmann CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobuli-naemia and chronic lung disease. Lancet1987;1(8451):1075-7. Manufactured by: CSL Behring GmbH, 35041 Marburg, Germany. Distributed by: CSL Behring LLC, Kankakee, IL 60901 USA. Issued: April, 2007.

PATIENT INFORMATION Hizentra [Immune Globulin Subcutaneous (Human)], 20% Liquid This patient package insert summarizes important information about Hizentra. Please read it carefully before using this medicine. This information does not take the place of talking with your healthcare professional, and it does not include all of the important information about Hizentra. If you have any questions after reading this, ask your healthcare professional. What is the most important information I should know about Hizentra? Hizentra is supposed to be infused under your skin only. DO NOT inject Hizentra into a blood vessel (vein or artery). What is Hizentra? Hizentra (Hi – ZEN – tra) is a prescription medicine used to treat primary immune deficiency (PI). Hizentra is made from human plasma. It contains antibodies, called immunoglobulin G (IgG), that healthy people have to fight germs (bacteria and viruses). People with PI get a lot of infections. Hizentra helps lower the number of infections you will get. Who should NOT take Hizentra? Do not take Hizentra if you have too much proline in your blood (called “hyperprolinemia”) or if you have had reactions to polysorbate 80. Tell your doctor if you have had a serious reaction to other immune globulin medicines or if you have been told that you also have a deficiency of the immunoglobulin called IgA. Tell your doctor if you have a history of heart or blood vessel disease or blood clots, have thick blood, or have been immobile for some time. These things may increase your risk of having a blood clot after using Hizentra. Also tell your doctor what drugs you are using, as some drugs, such as those that contain the hormone estrogen (for example, birth control pills), may increase your risk of developing a blood clot. How should I take Hizentra? You will take Hizentra through an infusion, only under your skin. Make sure that the infusion is not into a blood vessel. You will place up to 4 needles into different areas of your body each time you use Hizentra. The needles are attached to a pump with an infusion tube. You can have infusions as often as every day up to every two weeks. For weekly infusions, it can take about 1 to 2 hours to complete an infusion; however, this time may be shorter or longer depending on the dose and frequency your doctor has prescribed for you. Instructions for using Hizentra are at the end of this patient package insert (see “How do I use Hizentra?”). Do not use Hizentra by yourself until you have been taught how by your doctor or healthcare professional. What should I avoid while taking Hizentra? Vaccines may not work well for you while you are taking Hizentra. Tell your doctor or healthcare professional that you are taking Hizentra before you get a vaccine. Tell your doctor or healthcare professional if you are pregnant or plan to become pregnant, or if you are nursing. What are possible side effects of Hizentra? The most common side effects with Hizentra are: Redness, swelling, itching, and/or bruising at the injection site Headache/migraine Nausea and/or vomiting Pain (including pain in the chest, back, joints, arms, legs) Fatigue Diarrhea Stomach ache/bloating Cough Rash (including hives) Itching Fever and/or chills Shortness of breath Dizziness Tell your doctor right away or go to the emergency room if you have hives, trouble breathing, wheezing, dizziness, or fainting. These could be signs of a bad allergic reaction. Tell your doctor right away if you have any of the following symptoms. They could be signs of a serious problem. Reduced urination, sudden weight gain, or swelling in your legs. These could be signs of a kidney problem. 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, or numbness or weakness on one side of the body. These could be signs of a blood clot. Bad headache with nausea, vomiting, stiff neck, fever, and sensitivity to light. These could be signs of a brain swelling called meningitis. Brown or red urine, fast heart rate, yellow skin or eyes. These could be signs of a blood problem. Chest pains or trouble breathing. Fever over 100°F. This could be a sign of an infection. Tell your doctor about any side effects that concern you. You can ask your doctor to give you more information that is available to healthcare professionals. How do I use Hizentra? Infuse Hizentra only after you have been trained by your doctor or healthcare professional. Below are step-by-step instructions to help you remember how to use Hizentra. Ask your doctor or healthcare professional about any instructions you do not understand. Instructions for use Hizentra comes in single-use vials. Keep Hizentra in the storage box at room temperature. Step 1: Assemble supplies Gather the Hizentra vial(s), the following disposable supplies (not provided with Hizentra), and other items (infusion pump, sharps or other container, treatment diary or log book): Infusion administration tubing Needle or catheter sets (for subcutaneous infusion) Y-site connectors (if needed) Alcohol wipes Antiseptic skin preps Syringes Transfer device or needle(s) Gauze and tape, or transparent dressing Gloves (if recommended by your doctor) Step 2: Clean surface Thoroughly clean a table or other flat surface using one of the alcohol wipes. Step 3: Wash hands Thoroughly wash and dry your hands (Figure 1). If you have been told to wear gloves when preparing your infusion, put the gloves on. Figure 1 Step 4: Check vials Carefully look at the liquid in each vial of Hizentra (Figure 2). Hizentra is a pale yellow to light brown solution. Check for particles or color changes. Do not use the vial if: Figure 2 The liquid looks cloudy, contains particles, or has changed color. The protective cap is missing. The expiration date on the label has passed. Step 5: Transfer Hizentra from vial(s) to syringe Take the protective cap off the vial (Figure 3). Figure 3 Clean the vial stopper with an alcohol wipe (Figure 4). Let the stopper dry. Figure 4 Attach a needle or transfer device to a syringe tip, using aseptic technique. If using a transfer device, follow the instructions provided by the device manufacturer. If using a needle and a syringe to transfer Hizentra, follow the instructions below. Attach a sterile transfer needle to a sterile syringe (Figure 5). Figure 5 Pull out the plunger of the syringe to fill the syringe with air. Make sure the amount of air is the same as the amount of Hizentra you will transfer from the vial. Put the Hizentra vial on a flat surface. Keeping the vial upright, insert the transfer needle into the center of the rubber stopper. Check that the tip of the needle is not in the liquid. Then, push the plunger of the syringe down. This will inject the air from the syringe into the airspace of the vial. Leaving the needle in the stopper, carefully turn the vial upside down (Figure 6). Figure 6 Slowly pull back on the plunger of the syringe to fill the syringe with Hizentra. Take the filled syringe and needle out of the stopper. Take off the needle and throw it away in the sharps container. When using multiple vials to achieve the desired dose, repeat this step. Step 6: Prepare infusion pump and tubing Prepare the infusion pump (following the manufacturer's instructions) and prime (fill) the infusion tubing. To prime the tubing, connect the syringe filled with Hizentra to the infusion tubing and gently push on the syringe plunger to fill the tubing with Hizentra (Figure 7). Figure 7 Step 7: Prepare injection site(s) Select an area on your abdomen, thigh, upper arm, or side of upper leg/hip for the infusion (Figure 8). Figure 8 Use a different site from the last time you infused Hizentra. New sites should be at least 1 inch from a previous site. Never infuse into areas where the skin is tender, bruised, red, or hard. Avoid infusing into scars or stretch marks. If you are using more than one injection site, be sure the injection sites are at least 2 inches apart. During an infusion, do not use more than 4 injection sites at the same time. Clean the skin at each site with an antiseptic skin prep (Figure 9). Let the skin dry. Figure 9 Step 8: Insert needle(s) With two fingers, pinch together the skin around the injection site. Insert the needle under the skin (Figure 10). Figure 10 Put sterile gauze and tape or a transparent dressing over the injection site (Figure 11). This will keep the needle from coming out. Figure 11 Make sure you are not injecting Hizentra into a blood vessel. To test for this, attach a sterile syringe to the end of the infusion tubing. Pull the plunger back gently (Figure 12). If you see any blood flowing back into the tubing, take the needle out of the injection site. Throw away the tubing and needle. Start the infusion over at a different site with new infusion tubing and a new needle. Figure 12 Step 9: Start infusion Follow the manufacturer's instructions to turn on the infusion pump (Figure 13). Figure 13 Step 10: Record treatment (Figure 14) Figure 14 Peel off the removable part of the label of the Hizentra vial. Put this label in your treatment diary or log book with the date and time of the infusion. Also include the exact amount of Hizentra that you infused. Scan the vial if recording the infusion electronically. Step 11: Clean up When all the Hizentra has been infused, turn off the pump. Take off the dressing and take the needle out of the injection site. Disconnect the tubing from the pump. Throw away any Hizentra that is leftover in the single-use vial, along with the used disposable supplies, in the sharps or other container (Figure 15) as recommended by your healthcare professional. Figure 15 Clean and store the infusion pump, following the manufacturer's instructions. Be sure to tell your doctor about any problems you have doing your infusions. Your doctor may ask to see your treatment diary or log book, so be sure to take it with you each time you visit the doctor's office. Call your doctor for medical advice about side effects. You can also report side effects to FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

PATIENT INFORMATION Vivaglobin® Immune Globulin Subcutaneous (Human) [Pronounced VEE-vah-glow-bin] This summary contains important information you need to know about Vivaglobin® (immune globulin subcutaneous (human)) for treating primary immunodeficiency (also known by its abbreviation, “PID”). Please read it carefully before you start your treatment. This summary is based on information given to your doctor but does not include all available information about Vivaglobin® (immune globulin subcutaneous (human)) . The summary is not meant to take the place of your doctor's instructions and should be used only after you have received instructions from your doctor. You should discuss any questions about treatment with Vivaglobin® (immune globulin subcutaneous (human)) with your doctor. What is Vivaglobin® (immune globulin subcutaneous (human)) ? Vivaglobin® is a highly purified product, called an immune globulin, made from human plasma. Vivaglobin® (immune globulin subcutaneous (human)) contains the antibody immunoglobulin G (IgG), which is found in the blood of healthy individuals to help combat germs, such as bacteria and viruses. Because it helps the body rid itself of these bacteria and viruses, IgG is important in helping the body fight infection. Vivaglobin® (immune globulin subcutaneous (human)) also contains the following inactive ingredients: 2.25% glycine, 0.3% sodium chloride, and water for injection. What is Vivaglobin® (immune globulin subcutaneous (human)) used for? Vivaglobin® (immune globulin subcutaneous (human)) is a prescription medication used to treat patients with primary immunodeficiency. Vivaglobin® (immune globulin subcutaneous (human)) is supplied as a sterile liquid in single-use vials and is given by infusion subcutaneously (under the skin). Do not administer Vivaglobin® (immune globulin subcutaneous (human)) into a blood vessel (vein or artery) as there is no safety information in patients supporting this route of administration. For treatment to be effective, you must carefully follow your doctor's instructions regarding your dose and treatment schedule for Vivaglobin® (immune globulin subcutaneous (human)) . How does Vivaglobin® (immune globulin subcutaneous (human)) work? Vivaglobin® (immune globulin subcutaneous (human)) treats primary immunodeficiency, a condition in which a person's natural defense system – or immune system – does not function properly. Normally, our immune system helps protect us against infections by recognizing potentially harmful bacteria and viruses that enter our body every day. In response, the immune system produces special proteins called antibodies that fight these foreign invaders. However, when our immune system is not working properly, it is unable to produce these valuable antibodies, leaving us more vulnerable to infection and illness. Vivaglobin® (immune globulin subcutaneous (human)) is known as antibody replacement therapy, because it replaces the missing and much-needed IgG antibodies in people who have low levels of this infection-fighting protein. By replacing these important antibodies, Vivaglobin® (immune globulin subcutaneous (human)) helps make people with PID better able to avoid infections and fight them when they do occur. Who should NOT take Vivaglobin® (immune globulin subcutaneous (human)) ? People who have a history of allergic reactions to immunoglobulins or have a condition known as selective IgA deficiency should not use Vivaglobin® (immune globulin subcutaneous (human)) . Tell your doctor if you have ever had an allergic reaction due to either of these conditions. If a serious allergic reaction occurs at any time, stop the Vivaglobin® (immune globulin subcutaneous (human)) treatment and contact your doctor or an emergency medical professional immediately. Because clinical studies with pregnant women have not been conducted, if you are pregnant or think you may be pregnant, discuss with your doctor whether Vivaglobin® (immune globulin subcutaneous (human)) is clearly needed. Please also consult your doctor about the use of this product if you are a nursing mother. What are possible side effects of Vivaglobin® (immune globulin subcutaneous (human)) ? In clinical studies, Vivaglobin® (immune globulin subcutaneous (human)) has been shown to be safe and well tolerated in both adults and children. As with any medication, side effects may accompany treatment. The frequency of side effects was based on a review of over 5,900 injections given during the clinical trials. The most frequently reported side effect was injection site reaction, which generally consisted of mild or moderate swelling, redness, and itching at the site of injection. In clinical trials, these reactions tended to decrease substantially over time. Please contact your healthcare provider if you would like more information on managing these reactions. Other side effects may include: Headache Gastrointestinal disorder Fever Nausea Sore throat Rash Allergic reaction Increased cough Pain Diarrhea If you are concerned about these or any other side effects, please talk to your healthcare provider. What additional important information do I need to know about Vivaglobin® ? Immune Globulin Subcutaneous (Human) Vivaglobin® is made from the plasma portion of human blood. All plasma used to produce Vivaglobin® (immune globulin subcutaneous (human)) is collected in a manner that meets or exceeds U.S. Food and Drug Administration requirements. For your safety, we maintain stringent controls over plasma collection and processing every step of the way. Because Vivaglobin® (immune globulin subcutaneous (human)) is made from plasma, as are all immune globulins, the risk of transmitting infectious agents, including viruses, and theoretically, the Creutzfeldt-Jakob Disease (CJD) agent, cannot be completely eliminated. However, the risk that Vivaglobin® (immune globulin subcutaneous (human)) will transmit diseases is reduced by carefully screening plasma donors for prior exposure to certain viruses and by testing plasma for evidence of potentially harmful viruses. Only plasma that passed virus-screening is used for production of Vivaglobin® (immune globulin subcutaneous (human)) . During the manufacture of Vivaglobin® (immune globulin subcutaneous (human)) , specific viral clearance methods further decrease the chance of disease transmission. The main virus reduction step of the Vivaglobin® (immune globulin subcutaneous (human)) manufacturing process is a pasteurization technique, which involves heating the product at 140°F (60°C) for 10 hours. Additional purification procedures used in the manufacture of Vivaglobin (immune globulin subcutaneous (human)) ® further reduce the risk of disease. As with all products manufactured from human plasma, however, the risk of transmitting infectious agents cannot completely be eliminated. However, during clinical trials, no cases of infection due to hepatitis A, B, or C virus, parvovirus B19, or HIV were reported with the use of Vivaglobin® (immune globulin subcutaneous (human)) . If you believe that you have contracted an infection that was possibly transmitted by Vivaglobin® (immune globulin subcutaneous (human)) , you should report this to your doctor or healthcare provider. What medications should I avoid while taking Vivaglobin® (immune globulin subcutaneous (human)) ? Vivaglobin® (immune globulin subcutaneous (human)) can impair the efficacy of certain virus vaccines, such as measles, mumps and rubella (also known by its abbreviation “MMR”). Inform the immunizing physician of recent treatment with Vivaglobin® (immune globulin subcutaneous (human)) so appropriate precautions can be taken. Other products must not be mixed with the Vivaglobin® (immune globulin subcutaneous (human)) solution. How do I store Vivaglobin® (immune globulin subcutaneous (human)) ? Vivaglobin® (immune globulin subcutaneous (human)) is supplied in single-use vials. It contains no preservatives, so any unused portion should be discarded immediately after use. When stored in the refrigerator at 36°to 46°F (2° to 8°C) Vivaglobin® (immune globulin subcutaneous (human)) can be used until the expiration date on its label. Do not use after the expiration date. Do not freeze Vivaglobin® (immune globulin subcutaneous (human)) . Keep the vial in its box during storage. Keep Vivaglobin® (immune globulin subcutaneous (human)) and all other medications out of the reach of children. How do I use Vivaglobin® (immune globulin subcutaneous (human)) ? Vivaglobin® (immune globulin subcutaneous (human)) is infused subcutaneously (under the skin). Do not administer it into a blood vessel (vein or artery). Your doctor will determine the appropriate dose for your treatment. Your doctor or healthcare provider will teach you the proper techniques for administering Vivaglobin® (immune globulin subcutaneous (human)) . Only after such instruction should you follow the instructions below. Preparing for your treatment The following areas are recommended for subcutaneous infusion of Vivaglobin® (immune globulin subcutaneous (human)) : Abdomen Thighs Upper arms Hip For proper selection of infusion site, please consult your doctor or healthcare provider. Instructions for administration The following instructions are intended only as a guide. Before administering Vivaglobin® Immune Globulin Subcutaneous (Human) you should be under the care of a doctor and should have received proper training on proper preparation and administration from a licensed healthcare provider. 1. Prior to use, allow the vial(s) of Vivaglobin® (immune globulin subcutaneous (human)) to reach room temperature, 68° to 77°F (20° to 25°C). On a clean, flat surface, such as a table, assemble all the supplies you will need for your treatment, including Vivaglobin® (immune globulin subcutaneous (human)) vials, treatment diary/logbook, an infusion pump, administration tubing, subcutaneous needle or catheter, Y-site connection tubing (if needed), alcohol wipes, antiseptic skin preps, syringe(s), needle(s), gauze or transparent Fig. 1 dressing, tape and a sharps disposal container. Your healthcare provider can help you to identify a complete list of supplies. Discuss with your healthcare provider whether you should use gloves when preparing Vivaglobin® (immune globulin subcutaneous (human)) for infusion. (Fig.1) 2. There are several different types of ambulatory infusion pumps that may be used to administer Vivaglobin® (immune globulin subcutaneous (human)) . Your healthcare provider will help you to determine which type of pump is appropriate for you. Follow the pump manufacturer's instructions for preparing the infusion pump and priming the administration tubing. Set the rate of infusion on the pump as instructed by your healthcare provider. 3. Before preparing Vivaglobin® (immune globulin subcutaneous (human)) for infusion, thoroughly wash and dry your hands. (Fig.2) 4. Before each infusion, be sure to visually inspect each vial of Vivaglobin® (immune globulin subcutaneous (human)) for discoloration and for particles in the solution by gently swirling each vial (do not shake the vial). Vivaglobin® (immune globulin subcutaneous (human)) should be a clear solution that can vary from colorless to light brown. If the solution in a vial is cloudy or contains particles, or if the protective cap is missing, do not use it.Check the expiration date on each vial of Vivaglobin® (immune globulin subcutaneous (human)) . Do not use beyond the expiration date. (Fig.3) 5. Remove the protective cap from each vial of Vivaglobin® (immune globulin subcutaneous (human)) . Next, cleanse the top of each vial stopper with an alcohol wipe, and allow the top of the vial to dry. (Figs.4 and 5) 6. Using aseptic technique as instructed by your healthcare provider, attach a needleto the syringe tip. (Fig.6) 7. Pulling back on the syringe plunger, draw back a volume of air into the syringe that is equal to the volume of Vivaglobin® (immune globulin subcutaneous (human)) that will be withdrawn. With the Vivaglobin® (immune globulin subcutaneous (human)) vial placed on a flat surface, insert the needle into the center of the vial stopper. Then inject the air into the vial. Next, leaving the syringe and needle in the vial, carefully invert the vial as shown in the illustration. Withdraw the Vivaglobin® (immune globulin subcutaneous (human)) solution into the syringe and remove the filled syringe from the vial. Remove the needle from the syringe filled with Vivaglobin® (immune globulin subcutaneous (human)) and discard the needle into a sharps disposal container. Repeat this step if multiple vials are required to achieve the prescribed dose of Vivaglobin® (immune globulin subcutaneous (human)) . (Fig.7) 8. Follow manufacturer's instructions for filling the infusion pump reservoir and priming the administration tubing and needle/catheter.“Priming” the administration tubing refers to the removal of the air from the tubing and needle/catheter that will be used to infuse Vivaglobin® (immune globulin subcutaneous (human)) . Priming may also be done by connecting the syringe filled with Vivaglobin® (immune globulin subcutaneous (human)) to the administration tubing and gently pushing on the syringe plunger to fill the tubing with Vivaglobin® (immune globulin subcutaneous (human)) until a drop is seen exiting the needle/catheter. (Fig.8) 9. Select an appropriate infusion site(s), depending on the amount required for your total Immune Globulin Subcutaneous (Human) Vivaglobin® (immune globulin subcutaneous (human)) dose and the instructions of your healthcare provider. Cleanse the site(s) with antiseptic skin prep(s) beginning in the center of the site and working outward in a circular motion. Allow site(s) to dry before proceeding to the next step. If your healthcare provider recommends that you administer Vivaglobin® (immune globulin subcutaneous (human)) using multiple sites, ensure that each site is at least two inches apart. (The maximum recommended infusion volume per infusion site is 15 mL). (Fig.9) 10. Using two fingers, grasp the skin around the infusion site. As instructed by your healthcare provider, insert the needle directly into the subcutaneous tissue and not into a blood vessel. (Fig.10) 11. After each needle is inserted into the tissue, you must test to make sure that a blood vessel has not been accidentally entered. This must be done prior to starting your infusion. To do this attach a sterile syringe to the end of the primed administration tubing, and gently pull back on the syringe plunger. Look to see if any blood is flowing back into the administration tubing. If you see any blood, remove and discard the needle and administration tubing. Then, repeat steps 8–11 using a new needle, administration tubing and a new infusion site. (Fig. 11) 12. Secure the needle by applying sterile gauze or transparent dressing over the site and tape in place. (Fig.12) 13. Secure the administration tubing to the infusion pump following the manufacturer's instructions and turn on the pump. (Fig.13) 14. Once the infusion is complete, turn off the infusion pump. Remove the needle(s) from the infusion site(s) and discard any unused solution and administration equipment in accordance with biohazard procedures as recommended by your healthcare provider. Follow the manufacturer's instructions regarding care of the infusion pump after each use. (Fig.14) 15. On each Vivaglobin® (immune globulin subcutaneous (human)) vial, you will find a peel-off label with the product lot number and expiration date. Record the time, date, and exact dose of your infusion, then remove the labels and affix them to your treatment diary/logbook.Take this record of your treatment with you whenever you visit your physician. (Fig. 15) These instructions are intended to serve as a guide for people who have already been instructed by a healthcare professional on the proper method of preparing and administering Vivaglobin® (immune globulin subcutaneous (human)) . If you have not received such training, please consult your healthcare provider before attempting to administer Vivaglobin® (immune globulin subcutaneous (human)) . If you experience any problems or need more information regarding your subcutaneous treatment, contact your healthcare provider.

OVERDOSE No information provided. CONTRAINDICATIONS Hizentra is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of human immune globulin or to components of Hizentra, such as polysorbate 80. Hizentra is contraindicated in patients with hyperprolinemia (type I or II) because it contains the stabilizer L-proline [see DESCRIPTION]. Hizentra is contraindicated in IgA-deficient patients with antibodies against IgA and a history of hypersensitivity [see DESCRIPTION].

OVERDOSE No information provided. CONTRAINDICATIONS As with all immune globulin products, Vivaglobin® (immune globulin subcutaneous (human)) Immune Globulin Subcutaneous (Human) is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A (IgA) deficiency (serum IgA < 0.05 g/L) who have known antibody against IgA.

SIDE EFFECTS The most common adverse reactions (ARs), observed in ≥ 5% of study subjects receiving Hizentra, were local reactions (e.g., swelling, redness, heat, pain, and itching at the injection site), headache, diarrhea, fatigue, back pain, nausea, pain in extremity, cough, rash, pruritus, vomiting, abdominal pain (upper), migraine, and pain. Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, AR rates observed in clinical studies of a product cannot be directly compared to rates in the clinical studies of another product and may not reflect the rates observed in clinical practice. US Study The safety of Hizentra was evaluated in a clinical study in the US for 15 months (3-month wash-in/wash-out period followed by a 12-month efficacy period) in subjects with PI who had been treated previously with IGIV every 3 or 4 weeks. The safety analyses included 49 subjects in the intention-to-treat (ITT) population. The ITT population consisted of all subjects who received at least one dose of Hizentra [see Clinical Studies]. Subjects were treated with Hizentra at weekly median doses ranging from 66 to 331 mg/kg body weight (mean: 181.4 mg/kg) during the wash-in/wash-out period and from 72 to 379 mg/kg (mean: 213.2 mg/kg) during the efficacy period. The 49 subjects received a total of 2264 weekly infusions of Hizentra. Table 2 summarizes the most frequent adverse reactions (ARs) (experienced by at least 2 subjects) occurring during or within 72 hours after the end of an infusion. Local reactions were assessed by the investigators 15 to 45 minutes post-infusion and by the subjects 24 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments. Local reactions were the most frequent ARs observed, with injection-site reactions (e.g., swelling, redness, heat, pain, and itching at the site of injection) comprising 98% of local reactions. Table 2: Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2 or More Subjects) and Rate per Infusion (ITT Population), US Study AR ( ≥ 2 Subjects) ARs* Occurring During or Within 72 Hours of Infusion Number (%) of Subjects (n=49) Number (Rate*) of ARs (n=2264 Infusions) Local reactions‡ 49 (100) 1322 (0.584) Other ARs: Headache 12 (24.5) 32 (0.014) Diarrhea 5 (10.2) 6 (0.003) Fatigue 4 (8.2) 4 (0.002) Back pain 4 (8.2) 5 (0.002) Nausea 4 (8.2) 4 (0.002) Pain in extremity 4 (8.2) 6 (0.003) Cough 4 (8.2) 4 (0.002) Vomiting 3 (6.1) 3 (0.001) Abdominal pain, upper 3 (6.1) 3 (0.001) Migraine 3 (6.1) 4 (0.002) Pain 3 (6.1) 4 (0.002) Arthralgia 2 (4.1) 3 (0.001) Contusion 2 (4.1) 3 (0.001) Rash 2 (4.1) 3 (0.001) Urticaria 2 (4.1) 2 ( < 0.001) * Excluding infections. † Rate of ARs per infusion. ‡ Includes injection-site reactions as well as bruising, scabbing, pain, irritation, cysts, eczema, and nodules at the injection site. The ratio of infusions with ARs, including local reactions, to all infusions was 1303 to 2264 (57.6%). Excluding local reactions, the corresponding ratio was 56 to 2264 (2.5%). Table 3 summarizes injection-site reactions based on investigator assessments 15 to 45 minutes after the end of the 683 infusions administered during regularly scheduled visits (every 4 weeks). Table 3: Investigator Assessments* of Injection-Site Reactions by Infusion, US Study Injection-Site Reaction Number† (Rate‡) of Reactions (n=683 Infusions§) Edema/induration 467 (0.68) Erythema 346 (0.51) Local heat 108 (0.16) Local pain 88 (0.13) Itching 64 (0.09) * 15 to 45 minutes after the end of infusions administered at regularly scheduled visits (every 4 weeks). † For multiple injection sites, every site was judged, but only the site with the strongest reaction was recorded. ‡ Rate of injection-site reactions per infusion. § Number of infusions administered during regularly scheduled visits. Most local reactions were either mild (93.4%) or moderate (6.3%) in intensity. No deaths or serious ARs occurred during the study. Two subjects withdrew from the study due to ARs. One subject experienced a severe injection-site reaction one day after the third weekly infusion, and the other subject experienced moderate myositis. Both reactions were judged to be “at least possibly related” to the administration of Hizentra. European Study In a clinical study conducted in Europe, the safety of Hizentra was evaluated for 10 months (3-month wash-in/wash-out period followed by a 7-month efficacy period) in 51 subjects with PI who had been treated previously with IGIV every 3 or 4 weeks or with IGSC weekly. Subjects were treated with Hizentra at weekly median doses ranging from 59 to 267 mg/kg body weight (mean: 118.8 mg/kg) during the wash-in/wash-out period and from 59 to 243 mg/kg (mean: 120.1 mg/kg) during the efficacy period. The 51 subjects received a total of 1831 weekly infusions of Hizentra. Table 4 summarizes the most frequent ARs (experienced by at least 2 subjects) occurringduring or within 72 hours after the end of an infusion. Local reactions were assessed by the subjects between 24 and 72 hours post-infusion. The investigators then evaluated the ARs arising from the subject assessments. Table 4: Incidence of Subjects with Adverse Reactions (ARs)* (Experienced by 2 or More Subjects) and Rate per Infusion, European Study AR ( ≥ 2 Subjects) ARs* Occurring During or Within 72 Hours of Infusion Number (%) of Subjects (n=51) Number (Ratet) of ARs (n=1831 Infusions) Local reactions‡ 24 (47.1) 105 (0.057) Other ARs: Headache 9 (17.6) 20 (0.011) Rash 4 (7.8) 4 (0.002) Pruritus 4 (7.8) 13 (0.007) Fatigue 3 (5.9) 5 (0.003) Abdominal pain, upper 2 (3.9) 3 (0.002) Arthralgia 2 (3.9) 2 (0.001) Erythema 2 (3.9) 4 (0.002) Abdominal discomfort 2 (3.9) 3 (0.002) Back pain 2 (3.9) 2 (0.001) Hematoma 2 (3.9) 3 (0.002) Hypersensitivity 2 (3.9) 4 (0.002) * Excluding infections. † Rate of ARs per infusion. ‡ Includes infusion-related reaction; infusion-site mass; infusion/injection-site erythema, hematoma, induration, inflammation, edema, pain, pruritus, rash, reaction, swelling; injection-site extravasation, nodule; puncture-site reaction. The proportion of subjects reporting local reactions decreased over time from approximately 20% following the first infusion to < 5% by the end of the study. Three subjects withdrew from the study due to ARs of mild to moderate intensity. One subject experienced injection-site pain and injection-site pruritus; the second subject experienced injection-site reaction, fatigue, and feeling cold; and the third subject experienced injection-site reaction and hypersensitivity. All reactions were judged by the investigator to be “at least possibly related” to the administration of Hizentra. Biweekly (Every Two Weeks) Or Frequent (2 To 7 Times per Week) Dosing No data regarding ARs are available for these alternative Hizentra dosing regimens because no clinical trials using these regimens were conducted; however, it is unlikely that the safety profile is qualitatively different from that of weekly dosing. 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. Hizentra The following adverse reactions have been identified during postmarketing use of Hizentra.This list does not include reactions already reported in clinical studies with Hizentra [see Clinical Trials Experience above]. Infusion reactions: Allergic-anaphylactic reactions such as swollen face or tongue and pharyngeal edema, pyrexia, chills, dizziness, hypertension/changes in blood pressure, malaise. Cardiovascular: Chest discomfort (including chest pain) Respiratory: Dyspnea Neurological: Tremor, burning sensation The following adverse reactions have been reported during postmarketing use of immune globulin products5: Infusion reactions: Tachycardia, flushing, wheezing, rigors, myalgia Renal: Osmotic nephropathy Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, hypoxemia, pulmonary edema, bronchospasm Cardiovascular: Cardiac arrest, vascular collapse, hypotension Neurological: Coma, loss of consciousness, seizures, aseptic meningitis syndrome Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis) Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test Gastrointestinal: Hepatic dysfunction To report SUSPECTED ADVERSE REACTIONS, contact CSL Behring Pharmacovigilance at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. REFERENCES 5. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251. 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]. Serological Testing Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.

SIDE EFFECTS In clinical studies, administration of Vivaglobin® Immune Globulin Subcutaneous (Human), has been shown to be safe and well tolerated in both adult and pediatric subjects. Reactions similar to those reported with administration of other immune globulin products may also occur with Vivaglobin® (immune globulin subcutaneous (human)) . Rarely, immediate anaphylactoid and hypersensitivity reactions may occur. In exceptional cases, sensitization to IgA may result in an anaphylactic reaction (see CONTRAINDICATIONS). Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly, and appropriate treatment and supportive therapy should be administered. In the US and Canada clinical study, the safety of Vivaglobin® (immune globulin subcutaneous (human)) was evaluated for 15 months (3-month wash-in/wash-out period followed by 12-month efficacy period) in 65 subjects with PID. The most frequent adverse reaction was local reaction at the injection site. Table 5 summarizes the most frequent adverse events by subject reported in the clinical study, and Table 6 summarizes the most frequent adverse events by infusion. Table 5: Most Frequent Adverse Events by Subject Irrespective of Causality* in the US and Canada Study Adverse Events ( ≥ 10% of subjects) No. of Subjects (% of total) Adverse Events at the Injection Site 60 (92%) Non-Injection Site Reactions Headache 31 (48%) Gastrointestinal disorder 24 (37%) Fever 16 (25%) Nausea 12 (18%) Sore throat 11 (17%) Rash 11 (17%) Allergic reaction 7 (11%) Pain 6.7 (10%)† Diarrhea 6.7 (10%)† Cough increased 6.7 (10%)† *Excluding infections † Due to missing subject diary information, values listed are estimates. Table 6: Most Frequent Adverse Events by Infusion Irrespective of Causality* in the US and Canada Study Adverse Events ( ≥ 1% of infusions) (Number of Infusions: 3656) No. of Adverse Events (Rate**) Adverse Events at the Injection Site 1789 (49%) Mild 1112 (30%) Moderate 601 (16%) Severe 65 (2%) Unknown Severity 11 ( < 1%) Non-Injection Site Reactions Headache 159 (4%) Gastrointestinal disorder 40.3 (1%)† *Excluding infections **Rate = number of reactions/infusion † Due to missing subject diary information, values listed are estimates. Table 7 summarizes the most frequent related adverse events by subject reported in the clinical study, and Table 8 summarizes the most frequent related adverse events by infusion. Table 7: Most Frequent Related Adverse Events by Subject* in the US and Canada Study Related Adverse Event ( ≥ 2 subjects) No. of Subjects (% of total) Adverse Events at the Injection Site 60 (92%) Non-Injection Site Reactions Headache 21 (32%) Nausea 7 (11%) Rash 4 (6%) Asthenia 3 (5%) Gastrointestinal disorder 3 (5%) Fever 2 (3%) Skin disorder 2 (3%) Tachycardia 2 (3%) Urine abnormality 2 (3%) *Excluding infections Table 8: Most Frequent Related Adverse Events by Infusion* in the US and Canada Study Related Adverse Event ( ≥ 2 AEs) (Number of Infusions: 3656) No. of AEs (Rate**) Adverse Events at the Injection Site 1787 (49%) Non-Injection Site Reactions Headache 59 (1.6%) Rash 9 (0.2%) Nausea 9 (0.2%) Nervousness 4 (0.1%) Asthenia 3 (0.1%) Gastrointestinal disorder 3 (0.1%) Skin disorder 3 (0.1%) Urine abnormality 3 (0.1%) Fever 2 (0.1%) Dyspnea 2 (0.1%) Gastrointestinal pain 2 (0.1%) Tachycardia 2 (0.1%) *Excluding infections **Rate = number of reactions/infusion In the non-IND Europe and Brazil clinical study, the safety of Immune Globulin Subcutaneous (Human), Vivaglobin® (immune globulin subcutaneous (human)) was evaluated for 10 months in 60 subjects with PID. The adverse events and their rates reported in this study were similar to those reported in the US and Canada study, with two notable exceptions for the related adverse events. These events were 59 episodes of headache (1.6%) and 2 episodes of fever (0.1%) in the US and Canada study and no episodes of headache and 18 episodes of fever (0.8%) in the Europe and Brazil study. Local (Injection Site) Reactions Local injection site reactions consisting of mostly mild or moderate swelling, redness and itching, have been observed with the use of Vivaglobin® (immune globulin subcutaneous (human)) . No serious local site reactions were observed. The majority of injection site reactions resolved within four days. Additionally, the number of subjects reporting local injection site reactions decreased substantially after repeated use (see Figure 1). Only three subjects in the US and Canada study and one subject in the Europe and Brazil study discontinued due to local site reactions. Figure 1: Subjects Reporting Local Site Reactions By Infusion DRUG INTERACTIONS Immunoglobulin administration can transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps and rubella. The immunizing physician should be informed of recent therapy with Vivaglobin® Immune Globulin Subcutaneous (Human), so that appropriate precautions can be taken. Vivaglobin (immune globulin subcutaneous (human)) ® should not be mixed with other medicinal products.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Severe hypersensitivity reactions may occur to human immune globulin or components of Hizentra, such as polysorbate 80. If a hypersensitivity reaction occurs, discontinue the Hizentra infusion immediately and institute appropriate treatment. 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 Hizentra. Hizentra contains ≤ 50 mcg/mL IgA [see DESCRIPTION]. Thrombosis Thrombosis may occur following treatment with immune globulin products1-3, including Hizentra. 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 Hizentra 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, PATIENT INFORMATION]. Aseptic Meningitis Syndrome (AMS) AMS has been reported with use of IGIV4 or IGSC. The syndrome usually begins within several hours to 2 days following immune globulin 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 frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses ( ≥ 2 g/kg) and/or rapid infusion of immune globulin product. Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. Discontinuation of immune globulin treatment has resulted in remission of AMS within several days without sequelae. Renal Dysfunction/Failure Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death may occur with use of human immune globulin products, especially those containing sucrose.5 Hizentra does not contain sucrose. Ensure that patients are not volume depleted before administering Hizentra. For patients judged to be at risk for developing renal dysfunction, including 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, monitor renal function and consider lower, more frequent dosing [see DOSING AND ADMINISTRATION]. Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure.6 Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Hizentra and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing Hizentra. Hemolysis Hizentra can contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs') test result and hemolysis.7-9 Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.10 Monitor recipients of Hizentra for clinical signs and symptoms of hemolysis. If signs and/or symptoms of hemolysis are present after Hizentra infusion, perform appropriate confirmatory laboratory testing. Transfusion-Related Acute Lung Injury (TRALI) Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products.11 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. Monitor Hizentra recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum. Transmissible Infectious Agents Because Hizentra is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent. This also applies to unknown or emerging viruses and other pathogens. No cases of transmission of viral diseases or CJD have been associated with the use of Hizentra. All infections suspected by a physician possibly to have been transmitted by Hizentra should be reported to CSL Behring Pharmacovigilance at 1-866-915-6958. Laboratory Tests Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing. Patient Counseling Information Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION). Inform patients to immediately report the following signs and symptoms to their healthcare provider: Hypersensitivity reactions to Hizentra (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis) (see WARNINGS AND PRECAUTIONS). 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, or numbness or weakness on one side of the body (see WARNINGS AND PRECAUTIONS). Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting (see WARNINGS AND PRECAUTIONS). Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (see WARNINGS AND PRECAUTIONS). Fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine (see WARNINGS AND PRECAUTIONS). Severe breathing problems, lightheadedness, drops in blood pressure, and fever (see WARNINGS AND PRECAUTIONS). Inform patients that because Hizentra is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt-Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent (see WARNINGS AND PRECAUTIONS and DESCRIPTION). Inform patients that Hizentra may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella) and to notify their immunizing physician of recent therapy with Hizentra (see DRUG INTERACTIONS). Home Treatment for Primary Humoral Immunodeficiency with Subcutaneous Administration If self-administration is deemed to be appropriate, ensure that the patient receives clear instructions and training on subcutaneous administration in the home or other appropriate setting and has demonstrated the ability to independently administer subcutaneous infusions. Ensure the patient understands the importance of adhering to their prescribed administration schedule to maintain appropriate steady IgG levels. Instruct patients to scan the vial if recording the infusion electronically and keep a diary/log book that includes information about each infusion such as, the time, date, dose, lot number(s) and any reactions. Inform the patient that mild to moderate local injection-site reactions (e.g., swelling and redness) are a common side effect of subcutaneous therapy, but to contact their healthcare professional if a local reaction increases in severity or persists for more than a few days. Inform patients of the importance of having an infusion needle long enough to reach the subcutaneous tissue and of changing the actual site of injection with each infusion. Explain that Hizentra is for subcutaneous infusion only, and must not be injected into a blood vessel. Make sure patients know how to avoid blood vessels and check if the needle has entered a blood vessel. Inform patients to consider adjusting the injection-site location, volume per site, and rate of infusion based on how infusions are tolerated. Inform patient to interrupt or terminate the Hizentra infusion if a hypersensitivity reaction occurs. Inform patients that they should be tested regularly to make sure they have the correct levels of Hizentra (IgG) in their blood. These tests may result in adjustments to the Hizentra dose. Use In Specific Populations Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with Hizentra. It is not known whether Hizentra can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Hizentra should be given to pregnant women only if clearly needed. Nursing Mothers Hizentra has not been evaluated in nursing mothers. Pediatric Use Clinical Studies (Weekly Dosing) The safety and effectiveness of weekly Hizentra have been established in the pediatric age groups 2 to 16. Hizentra was evaluated in 10 pediatric subjects with PI (3 children and 7 adolescents) in a study conducted in the US [see Clinical Studies] and in 23 pediatric subjects with PI (18 children and 5 adolescents) in Europe. There were no differences in the pharmacokinetics, safety and efficacy profiles as compared with adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. Pharmacokinetic Modeling And Simulation (Biweekly or more Frequent Dosing) The biweekly (every two weeks) or more frequent dosing (2 to 7 times per week) regimens, developed from population PK-based modeling and simulation, included 57 pediatric subjects (32 from Hizentra clinical studies) [see Pharmacokinetics]. Hizentra dosing is adjusted to body weight. No pediatric-specific dose requirements are necessary for these regimens. Safety and effectiveness of Hizentra in pediatric patients below the age of 2 have not been established. Geriatric Use Of the 49 subjects evaluated in the US clinical study of Hizentra, 6 subjects were 65 years of age or older. No overall differences in safety or efficacy were observed between these subjects and younger subjects. The clinical study of Hizentra in Europe did not include subjects over the age of 65. 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. Gabor EP, Meningitis and skin reaction after intravenous immune globulin therapy. Ann Intern Med 1997:127:1130. 5. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev 2003;17:241-251. 6. 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. 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. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001;41:264-268.

WARNINGS Patients who receive immune globulin therapy for the first time, who are switched from another brand of immune globulin, or who have not received immune globulin therapy within the preceding eight weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting. On rare occasions, these reactions may lead to shock. Such patients should be monitored for these reactions in a clinical setting during the initial administration of Vivaglobin® Immune Globulin Subcutaneous (Human). If anaphylactic or anaphylactoid reactions are suspected, discontinue administration immediately. Treat any acute anaphylactoid reactions as medically appropriate. Vivaglobin® is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Vivaglobin® is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the CJD agent. The risk that such plasma-derived 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 during manufacture (see DESCRIPTION section for virus reduction measures). Stringent procedures utilized at plasma collection centers, plasma-testing laboratories and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction steps of the Vivaglobin® (immune globulin subcutaneous (human)) manufacturing process are pasteurization (heat treatment of the aqueous solution at 60°C for 10 hours) and ethanol - fatty alcohol / pH precipitation. Additional purification procedures used in the manufacture of Vivaglobin® (immune globulin subcutaneous (human)) also potentially provide virus reduction. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to CSL Behring at 1-800-504-5434 (in the US and Canada). The physician should discuss the risks and benefits of this product with the patient. During clinical trials, no cases of infection due to hepatitis A, B, or C virus, parvovirus B19, or HIV were reported with the use of Vivaglobin® (immune globulin subcutaneous (human)) . PRECAUTIONS General Administer Vivaglobin® Immune Globulin Subcutaneous (Human), subcutaneously. Do not administer this product intravenously. The recommended infusion rate and amount per injection site stated under DOSAGE AND ADMINISTRATION should be followed. When initiating therapy with Vivaglobin® (immune globulin subcutaneous (human)) , patients should be monitored for any adverse events during and after the infusion. Laboratory Tests After injection of immunoglobulins, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D may cause a positive direct or indirect antiglobulin (Coombs') test. Pregnancy Category C Animal reproduction studies have not been conducted with Vivaglobin® Immune Globulin Subcutaneous (Human). It is also not known whether Vivaglobin® (immune globulin subcutaneous (human)) can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. Vivaglobin® (immune globulin subcutaneous (human)) should be given to a pregnant woman only if clearly needed. Pediatric Use Vivaglobin® (immune globulin subcutaneous (human)) was evaluated in 6 children and 4 adolescents in the US and Canada study and in 16 children and 6 adolescents in the non-IND study. There were no apparent differences in the safety and efficacy profiles as compared to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and efficacy of Vivaglobin® (immune globulin subcutaneous (human)) was not studied in pediatric subjects under two years of age. Geriatric Use The clinical study of Vivaglobin® Immune Globulin Subcutaneous (Human), did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.