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CLINICAL PHARMACOLOGY Mechanism Of Action PI: Flebogamma 10% DIF supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. Flebogamma 10% DIF also contains a spectrum of antibodies capable of reacting with cells, such as erythrocytes. The role of these antibodies and the mechanism of action of IgG in Flebogamma 10% DIF have not been fully elucidated. Chronic ITP: the mechanism of action of immunoglobulins in the treatment of chronic ITP has not been fully elucidated. Pharmacokinetics In the clinical study assessing safety and efficacy in PI, the pharmacokinetics of Flebogamma 10% DIF were assessed for 21 or 28 days after administration in 19 subjects. PK analysis was performed for 10 subjects receiving Flebogamma 10% DIF on a 21-day schedule and for 9 subjects receiving treatment on a 28-day schedule. The mean dose (range) for those on the 21-day schedule was 476 mg/kg (range: 339-597) and 496 mg/kg (range: 434-588) for those on the 28-day schedule. Blood samples for PK analysis were obtained after Infusion #7 for subjects on a 28-day schedule and after Infusion #9 for subjects on a 21-day schedule. Table 5 summarizes the pharmacokinetic parameters of Flebogamma 10% DIF, measured as serum concentrations of total IgG. The half-life of IgG can vary considerably among patients. Table 5: Pharmacokinetic Variables of Total IgG in Subjects with PI Variable 3-Week Dosing Interval (n=10) 4-Week Dosing Interval (n=9) Mean ± SD Range Mean ± SD Range Cmax (mg/mL) 19.50 ± 2.83 15.10 - 24.40 20.92 ± 3.66 16.80 - 29.20 AUC0 - last (day-mg/mL) 339.51 ± 45.27 241.12 - 380.21 342.37 ± 39.72 276.83 - 408.25 Clearance (mL/day) 115 ± 31 81 - 186 144 ± 47 77 - 237 Half-life (days)a 34 ± 10 21 - 58 37 ± 13 24 - 59 Trough IgG level (mg/mL)b 9.76 ± 1.65 6.45 - 11.40 8.77 ± 1.26 7.59 - 11.70 a This half-life is an apparent value derived from a 28 day period of measurement b For subjects on the 3-week schedule, average trough levels from Infusion #9 to the end of the study was calculated; for those on a 4-week schedule, the average of the trough levels from Infusion #7 to the end of the study was calculated. Animal Toxicology And/Or Pharmacology Acute toxicity studies were performed in mice and rats at doses up to 2.5 g per kg body weight with infusion rates 6-37 times higher than the maximum rates recommended for humans. The most common clinical observations in mice studies were piloerection, ptosis, ataxia and increase in respiration all lasting 90 minutes or less. No relevant adverse effects could be confirmed affecting respiratory, circulatory, renal, autonomic and central nervous systems, somatomotor activity, and behavior of the treated mice and rats. Five of the 25 rats treated with the highest dose at approximately 8 times the maximum infusion rate recommended for humans, showed a transient “reddish urine” sign which was not confirmed as a relevant toxicity-causing phenomenon after renal macroscopic and microscopic analysis. This phenomenon was ascribed to hemolysis that occurred when the serum was analyzed, suggesting a possible relation to cross-reactivity of rodent red cells with human antibodies. No “reddish urine” was detected in any mouse, a much smaller animal where the rate of infusion was comparatively much higher than in rats. The macroscopic inspection of all treated mice did not show any renal alteration. Clinical Studies Treatment Of Primary Immunodeficiency (PI) A phase 3, multicenter, open-label, historically controlled study to assess the efficacy, safety and pharmacokinetics of Flebogamma 10% DIF in subjects with PI was conducted in the United States. Forty-six subjects were treated with Flebogamma 10% DIF for 12 months at a 3-week or 4-week dosing interval. Subjects ranged in age from 6 to 65 years; 65% were male and 35% were female; 96% were Caucasian and 4% were Hispanic. Pre-medication to alleviate potential adverse drug reactions was only allowed after the first infusions only in those subjects that exhibited adverse reactions. Of 601 infusions administered during the study, 130 (22%) infusions in 21 (47%) subjects were preceded by pre-medication (antipyretic, antihistamine, or antiemetic agent) because of experience with consecutive infusion-related adverse reactions. If the infusion was well tolerated (no adverse reaction temporally associated with the infusion), the infusion rate was increased to 0.02 mL per kg per minute for 30 minutes and then to 0.04 mL per kg per minute for another 30 minutes. If well tolerated, additional increments of 0.02 mL per kg per minute were made at 30-minute intervals up to a maximum rate of 0.08 mL per kg per minute. Since subjects in the clinical study were assigned to two different treatment intervals (3-week vs. 4-week infusion schedules), the dosage had to be adjusted to ensure that subjects received approximately the same dosage on an annualized basis. Therefore, subjects in the 3-week schedule received 75% of the monthly (4-week) dosage per infusion. This resulted in a mean annualized dosage of 468.5 mg per kg per month for subjects in the 3-week schedule (N=16, range 320-597 mg per kg per month) and 457.4 mg per kg per month for subjects in the 4-week schedule (N=30, range 307-588 mg per kg per month). Subjects received a total of 601 infusions of Flebogamma 10% DIF. The maximum infusion rate allowed during the study was 0.08 mL per kg per minute. During the study period, the annual rate of acute serious bacterial infections, defined as bacterial pneumonia, bacteremia or sepsis, osteomyelitis/septic arthritis, visceral abscess and bacterial meningitis per subject per year, was 0.025 (upper 1-sided 98% confidence interval: 0.001 to 0.133). One subject had one episode of bacterial pneumonia. There were no other serious bacterial infections (Table 6). Table 6:  Summary of Bacterial Infections (Intention-to-Treat Population, N = 46) Infections Patients (N=46) N (%) Episodes Estimatesa 98% CIb Bacterial pneumonia 1 (2.2) 1 Bacteremia or sepsis 0 (0.0) 0 Osteomyelitis/septic arthritis 0 (0.0) 0 Visceral abscess 0 (0.0) 0 Bacterial meningitis 0 (0.0) 0 Subjects with at least 1 serious bacterial infection 1 (2.2) 1 0.025 (0.001, 0.133) a Estimate = Total episodes/Total subject years. b The confidence interval is obtained by using a generalized linear model procedure for Poisson distribution. The number of days of work/school missed, hospitalizations and days of each hospitalization, the number of visits to physicians or emergency rooms, other infections documented by positive radiographic findings and fever, and days on therapeutic and prophylactic oral/parenteral antibiotic use also were evaluated. These variables were annualized by using subject-years exposure data of those subjects experiencing the events, but not the entire study cohort. The mean rate of other validated infections was < 2 days per subject per year (this calculation used all subjects, including those who had no infections). (Table 7) Table 7: Summary of Annualized Efficacy Variables Variable Subjects Mean number of events, days or visits per subject per yeara N % Work/school days missed 20 43.5 3.0 Days in hospital 5 11.0 0.6 Visits to physician/ER 24 52.2 2.1 Number of other documented infectious episodes 7 15.2 0.2 Days of therapeutic oral antibiotic use 36 78.3 56.4 Days of therapeutic parenteral antibiotic use 2 4.3 1.3 Days of other therapeutic antibiotic use 14 30.4 60.5 Days of prophylactic oral antibiotic use 19 41.3 45.8 Days of prophylactic parenteral antibiotic use 1 2.2 0.02 Days of other prophylactic antibiotic use 1 2.2 3.3 a Days of work/school missed per subject year are derived as total days of work/school missed divided by total days in study multiplied by 365. If data are missing for a period, e.g., between Infusion #2 and Infusion #3, then number of days in this period is not counted in the denominator. All other endpoints are derived similarly. Treatment Of Chronic Primary Immune Thrombocytopenia (ITP) A phase 3, prospective, open-label, single-arm, multicenter study assessed the efficacy, safety and tolerability of Flebogamma 10% DIF in 58 subjects (46 adult and 12 pediatrics) with chronic ITP and a platelet count of ≤ 20 x 109/L. Subjects ranged in age from 3 to 70 years (median age: 28 years). Females (67.2%) outnumbered males (32.8%). A majority of the subjects were Asian (67.4%); the remainder was Caucasian (26.1%), Hispanic (4.3%) and African American (2.2%). Median age of the pediatric cohort was 13 years. The ratio of males to females was 1:1. Only Caucasian subjects were enrolled. See Table 8 for the number pediatric subjects stratified by age. Table 8: Summary of Pediatric Subjects by Age Groups Age group Number of subjects (N) 3-5 years 1 6-11 years 3 12-16 years 8 Subjects received a 2 g per kg dose of Flebogamma 10% DIF administered intravenously as 1 g per kg on 2 consecutive days. Pre-medication to alleviate potential adverse drug reactions was not allowed. The starting rate of 0.01 mL per kg per minute was to be maintained for 30 minutes. If the infusion was well tolerated, the infusion rate was increased to 0.02 mL per kg per minute for 30 minutes and then to 0.04 mL per kg per minute for another 30 minutes. If well tolerated, additional increments of 0.02 mL per kg per minute were made at 30-minute intervals up to a maximum rate of 0.08 mL per kg per minute. Platelet counts were measured on infusion visits (Days 1 and 2), in clinical follow-up visits (Day 3, Day 5 ± 1, Day 8 ± 1, Day 15 ± 1, Day 22 ± 1), at final study visit (Day 30 ± 1) and daily on Day 4 through Day 8 or until counts reached or exceeded 50 × 109/L, whichever occurred first, and then every 4 ± 1 days through Day 22 ± 1. The primary efficacy endpoint was the response rate, defined as the proportion of treated subjects in whom platelet counts increased from ≤ 20 × 109/L to ≥ 50 × 109/L by Day 8 ± 1 (the day of the first infusion was Day 1) in the modified intent-to-treat population (mITT). The mITT consisted of all subjects who received at least one infusion (at any dose) of Flebogamma 10% DIF. Table 9: Response Rate (mITT Population) Adults (N = 46) Pediatrics (N = 12) All Subjects (N = 58) Number of responders (%) 35 (76.1) 12 (100.0) 47 (81.0) 95% confidence intervala (63.5, 86.0) (77.9, 100.0) (70.6, 89.0) mITT: modified intention to treat; N: number of subjects. a The lower and upper bound of the exact one-sided 95% confidence interval. Secondary efficacy endpoints included: Time to platelet count recovery, as determined by the number of days elapsed from Day 1 to the day on which the platelet count was first found to be ≥ 50 × 109/L during the clinical follow-up period ending on Day 30 ± 1. Duration of response, as determined by the number of consecutive days for which the platelet count remained ≥ 50 × 109/L during the clinical follow-up period ending on Day 30 ± 1. Regression of hemorrhage/bleeding, as determined by the proportion of treated subjects with hemorrhage/bleeding on Day 1 who improved their diathesis, assessed using a categorized rating scale, during the clinical follow-up period ending on Day 15 ± 1. A total of 47 out of 58 subjects (81%) in the mITT population were responders. The responder rate was 76.1% (35/46) in adults and 100% (12/12) in children. Analysis of the primary efficacy endpoint showed that the lower limit of the exact one-sided 95% CI was 70.6%, which was above the predefined response rate of 50%. Mean time to platelet count recovery ( ≥ 50 × 109/L) was ≤ 1.7 days among all responders ( ≤ 1.8 days in adults and ≤ 1.4 days in pediatrics). Median time to platelet count recovery was ≤ 2 days for all responders and adults, and ≤ 1 day for pediatrics. (The symbol “ ≤ ” is used because actual time to platelet count recovery could have occurred prior to the study visit since this endpoint was assessed only at study visits.) Table 10: Time to Platelet Count Recovery in Responders (mITT Population) Adults (N = 46) Pediatrics (N = 12) All Subjects (N = 58) Number of responders 35 12 47 Time to platelet count recovery (days) Mean ± SD 1.8 ± 1.0 1.4 ± 0.5 1.7 ± 0.9 Median (Min, Max) 2 (0, 4) 1 (1, 2) 2 (0, 4) mITT=modified intention to treat; N=number of subjects; SD=standard deviation of the mean; Min=minimum; Max=maximum. Mean duration of response was ≥ 10.8 days among all responders, ≥ 9.6 days in adult responders and ≥ 14.3 days in pediatric responders. (The symbol “ ≥ ” is used because actual duration of response could have persisted after the study visit since this endpoint was assessed only at study visits.) Table 11: Duration of Response in Responders (mITT Population) Adults (N = 46) Pediatrics (N = 12) All Subjects (N = 58) Number of responders 35 12 47 Duration of response (days) Mean ± SD 9.6 ± 7.8 14.3 ± 8.0 10.8 ± 8.0 Median (Min, Max) 7 (1, 29) 14 (3, 29) 10 (1, 29) mITT= modified intention to treat; N= number of subjects; SD=standard deviation of the mean; Min= minimum; Max=maximum. Approximately 67% of all subjects (39/58) presented with signs of hemorrhage/bleeding at Day 1 before the first infusion of Flebogamma 10% DIF. This cohort included 59% of adults (27/46) and all pediatric subjects (12/12, 100%). Approximately 92% of these subjects experienced improvement in bleeding diathesis during the follow-up period by Day 15 regardless of whether they were responders in terms of platelet count. Table 12: Regression of Hemorrhage (mITT population) Parameters Adults (N = 46) Pediatrics (N = 12) All Subjects (N = 58) Subjects with hemorrhage at Day 1 27 12 39 Improvement in diathesis of subjects with hemorrhage at Day 1 24/27 (88.9%) 12/12 (100.0%) 36/39 (92.3%) 95% confidence intervala (70.8, 97.6) (73.5, 100.0) (79.1, 98.4) mITT: modified intention to treat; N: number of subjects. a Lower and upper bound of the exact two-sided 95% confidence interval. Mean maximum platelet count among all responders ranged from 205.3 × 109/L (adults) to 335.2 × 109/L (pediatrics). All responders, adults and pediatrics combined, showed a mean maximum platelet count of 238.4 × 109/L. All responders, including adult and pediatric responders, had a mean time to maximum platelet count of 4.8 days. Maximum platelet count was 4.7 days for adult responders and 5.3 days for pediatric responders. The mean maximum increase in platelet count in all responders was 226.3 × 109/L, with 193.3 × 109/L in adult responders and 322.6 × 109/L in pediatric responders. Three SAEs were reported in the adult cohort, 1 case of soft-tissue inflammation and 2 cases of headache. No SAEs were reported in the pediatric cohort but the incidence of treatment-emergent adverse events was higher in pediatric subjects than in adults. (see Adverse Events) A supportive, prospective, open-label, single-arm, multicenter study assessed the efficacy, safety and tolerability of Flebogamma 10% DIF in 18 adult subjects with chronic ITP and a platelet count of ≤ 20 x 109/L. A total of 12 females and 6 males ranging in age from 18 to 82 years were enrolled. Their median age was 43 years. All subjects were Caucasian. The primary efficacy endpoint was the response rate, defined as the proportion of treated subjects in whom platelet counts increased from ≤ 20 × 109/L to ≥ 50 × 109/L at any time during the study period. The study achieved its primary endpoint: 13/18 subjects (72.2%; 95% confidence interval: 50.2, 88.4) met the criteria for treatment responders. Three SAEs were reported in two subjects and assessed as possibly related: leukopenia (mild) and decreased hemoglobin (mild) in the one subject and axillary vein thrombosis (severe) in the second subject. Both subjects recovered without sequelae. The proportion of subjects who experienced treatmentemergent adverse events (TEAE) was higher in the pediatric cohort than in the adult cohort. (see Clinical Trials Experience, and Pediatric Use)

CLINICAL PHARMACOLOGY GAMMAGARD S/D, Immune Globulin Intravenous (Human), contains a broad spectrum of IgG antibodies against bacterial and viral agents that are capable of opsonization and neutralization of microbes and toxins. Peak levels of IgG are reached immediately after infusion of GAMMAGARD S/D (immune globulin) . It has been shown that, after infusion, exogenous IgG is distributed relatively rapidly between plasma and extravascular fluid until approximately half is partitioned in the extravascular space. Therefore, a rapid initial drop in serum IgG levels is to be expected.4 As a class, IgG survives longer in vivo than other serum proteins.4,5 Studies show that the half-life of GAMMAGARD S/D (immune globulin) is approximately 37.7 ± 15 days.3 Previous studies reported IgG half-life values of 21 to 25 days.4,5 using radiolabeled IgG or 17.7 to 37.6 days measuring IgG levels during administration of IGIV to immunodeficient patients.6 The half-life of IgG can vary considerably from person to person, however. In particular, high concentrations of IgG and hypermetabolism associated with fever and infection have been seen to coincide with a shortened half-life of IgG. 4-7 REFERENCES 3. Unpublished data in the files of Baxter Healthcare Corporation. 4. Waldmann TA, Storber W. Metabolism of immunoglobulins. Prog Allergy. 1969;13:1-110. 5. Morell A, Riesen W. Structure, function and catabolism of immunoglobulins. In: Nydegger UE, ed. Immunotherapy. London: Academic Press; 1981;17-26. 6. Mankarious S, Lee M, Fischer S, Pyun KH, Ochs HD, Oxelius VA, Wedgwood RJ. The half-lifes of IgG subclasses and specific antibodies in patients with primary immunodeficiency who are receiving intravenously administered immunoglobulin. J Lab Clin Med. 1988; 112:634-40. 7. Buckley RH. Immunoglobulin replacement therapy: Indications and contraindications for use and variable IgG levels achieved In: Alving BM, Finlayson JS eds. Immunoglobulins: characteristics and use of intravenous preparations. Washington, D.C.: US Department of Health and Human Services; 1979;3-8.

CLINICAL PHARMACOLOGY Peak levels of immunoglobulin G are obtained approximately 2 days after intramuscular injection of BayGam (immune globulin) .1 The half-life of IgG in the circulation of individuals with normal IgG levels is 23 days.2 Passive immunization with BayGam (immune globulin) modifies hepatitis A, prevents or modifies measles, and provides replacement therapy in persons with hypogammaglobulinemia or agammaglobulinemia. BayGam (immune globulin) is not standardized with respect to antibody titers against hepatitis B surface antigen (HBsAg) and should not be used for prophylaxis of viral hepatitis type B. Prophylactic treatment to prevent hepatitis B can best be accomplished with use of Hepatitis B Immune Globulin (Human), often in combination with Hepatitis B Vaccine.3 BayGam (immune globulin) may be of benefit in women who have been exposed to rubella in the first trimester of pregnancy and who will not consider a therapeutic abortion.4 BayGam (immune globulin) may also be considered for use in immunocompromised patients for passive immunization against varicella if Varicella-Zoster Immune Globulin (Human) is not available.5 Immune Globulin (Human) is not indicated for routine prophylaxis or treatment of rubella, poliomyelitis, mumps, or vari-cella. It is not indicated for allergy or asthma in patients who have normal levels of immunoglobulin.6 In a clinical study in eight healthy human adults receiving another hyperimmune immune globulin product treated with solvent/detergent, Rabies Immune Globulin (Human), BayRab™, prepared by the same manufacturing process, detectable passive antibody titers were observed in the serum of all subjects by 24 hours post injection and persisted through the 21 day study period. These results suggest that passive immunization with immune globulin products is not affected by the solvent/detergent treatment. REFERENCE 1. Smith GN, Griffiths B, Mollison D, et al: Uptake of IgG after intramuscular and subcutaneous injection. Lancet1(7762): 1208-12, 1972. 2. Waldmann TA, Strober W, Blaese RM: Variations in the metabolism of immunoglobulins measured by turnover rates. In Merler E (ed.): Immunoglobulins: biologic aspects and clinical uses. Washington DC, Nat Acad Sci, 1970, pp 33-51. 3. Recommendation of the Immunization Practices Advisory Committee (ACIP): Postexposure prophylaxis of hepatitis B. MMWR 33(21): 285-90, 1984. 4. American Academy of Pediatrics, Committee on Infectious Diseases: Report. ed. 19. Evanston, 1982, p 231. 5. Gershon AA, Piomelli S, Karpatkin M, et al: Antibody to varicella-zoster virus after passive immunization against chicken-pox. J Clin Microbiol 8(6): 733-5, 1978. 6. American Academy of Pediatrics, Committee on Infectious Diseases: Report. ed. 19. Evanston, 1982, pp 134-5.

FLEBOGAMMA 10% DIF [immune globulin (Human)] Intravenous Solution WARNING THROMBOSIS, RENAL DYSFUNCTION, and ACUTE RENAL FAILURE Thrombosis may occur with immune globulin products, including FLEBOGAMMA 10% DIF. 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 WARNING AND PRECAUTIONS and Patient Counseling Information) For patients at risk of thrombosis, administer FLEBOGAMMA 10% DIF 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 patient at risk for hyperviscosity. (see DOSAGE AND ADMINISTRATION and WARNING AND PRECAUTIONS) Renal dysfunction, acute renal failure, osmotic nephrosis, and death1 have been related to intravenous immune globulin (IGIV) products. Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Administer FLEBOGAMMA 10% DIF at the minimum dose and rate of infusion practicable in patients at risk for renal dysfunction or failure. Reports of renal dysfunction and acute renal failure occur more commonly in patients receiving IGIV products containing sucrose as a stabilizer. They account for a disproportionate share of the total number of reported cases of renal dysfunction and acute renal failure. FLEBOGAMMA 10% DIF does not contain sucrose. (see DOSAGE AND ADMINISTRATION and WARNING AND PRECAUTIONS) DESCRIPTION Flebogamma 10% DIF is a ready to use, sterile, clear or slightly opalescent and colorless to pale yellow, liquid preparation of purified immunoglobulin (IgG) obtained from human plasma pools. The purification process includes cold ethanol fractionation, polyethylene glycol precipitation, ion exchange chromatography, low pH treatment, pasteurization, solvent detergent treatment and Planova nanofiltration using 20 nanometer (nm) filters. Flebogamma 10% DIF is a purified (at least 97% IgG), unmodified, human IgG. The distribution of the four IgG subclasses is approximately 66.6% IgG1, 27.9% IgG2, 3.0% IgG3 and 2.5% IgG4. Flebogamma 10% DIF contains trace amounts of IgA (typically less than 100 μg/mL) and trace amounts of sodium and IgM. Flebogamma 10% DIF contains 10 g human normal immunoglobulin and 5 g D-sorbitol (as stabilizer) in 100 mL of water for injection, and ≤ 6 mg/Ml polyethylene glycol. There is no preservative in the formulation. The pH of the solution ranges from 5 to 6 and the osmolality from 240 to 370 mOsm/kg, which is within the normal physiological range. Screening against potentially infectious agents begins with the donor selection process and continues throughout plasma collections and plasma preparation. Each individual plasma donation used in the manufacture of Flebogamma 10% DIF is collected only at FDA-approved blood establishments and is tested by FDA licensed serological test for hepatitis B surface antigen (HBsAg), and for antibodies to human immunodeficiency virus (HIV-1/HIV-2) and hepatitis C virus (HCV) in accordance with U.S. regulatory requirements. As an additional safety measure, mini-pools of plasma are tested for the presence of HBV, HIV-1 and HCV by FDA licensed nucleic acid testing (NAT) and found to be negative. In addition, plasma is tested by in-process NAT for hepatitis A virus (HAV) and parvovirus B19 (B19) on mini-pools and the viral load limit for B19 in the manufacturing pool is set not to exceed 104 IU/mL. NAT for the presence of HCV and HIV in the manufacturing plasma pool is also performed and found to be negative. To further improve the margin of safety, three dedicated, independent virus inactivation/removal steps have been integrated into the manufacturing and formulation processes, namely pasteurization at 60 °C, 10 hours, solvent-detergent treatment for 6 hours and nanofiltration down to 20 nm Planova filters. In vitro virus spiking studies have been used to validate the capability of the manufacturing process to inactivate and remove viruses. To establish the minimum applicable virus clearance capacity of the manufacturing process, these virus clearance studies were performed on seven steps of the production process (pasteurization, solvent-detergent treatment, nanofiltration, Fraction I precipitation, Fraction II+III precipitation, 4% PEG precipitation and pH treatment for 4 hours at 37 °C). The viral reduction data (in log10) from these experiments are summarized in Table 4. Table 4: Flebogamma 10% DIF: viral reduction capacity of combined steps (log10) Target virus HIV-1, HIV-2 (env. RNA) HBV Herpesvirus (env. DNA) HCV (env.RNA) WNV (env. RNA) HAV (non-env. RNA) B19 Virus (non-env. DNA) Model virus HIV-1 PRV IBR BVDV SINDBIS WNV EMC PPV Fraction I precipitation < 1.00* nd nd nd nd 2.78 nd < 1.00* Ethanol incubation (Fraction II+III) 1.48 nd nd nd nd < 1.00* nd nd PEG precipitation ≥ 6.10 ≥ 5.92 nd ≥ 5.78 nd nd ≥ 6.41 6.35 Acid pH treatment 2.47 ≥ 5.32 nd < 1.00* nd nd 1.36 na Pasteurization ≥ 5.64 ≥ 4.96 ≥ 6.33 ≥ 4.69 ≥ 6.49 ≥ 5.42 ≥ 5.56 4.08 Solvent Detergent ≥ 4.61 ≥ 6.95 nd ≥ 6.14 nd ≥ 5.59 na na Nanofiltration 20 nanometer ≥ 4.81 ≥ 4.63 nd ≥ 4.67 nd ≥ 3.63 ≥ 5.92 4.61 Overall Reduction Capacity ≥ 25.11 ≥ 27.78 ≥ 6.33 ≥ 21.28 ≥ 6.49 ≥ 17.42 ≥ 19.25 15.04 *When the RF is < 1 log10, it is not taken into account for the calculation of the overall reduction capacity. ≥ =no residual infectivity detected; nd= not done; na= non-applicable, since the virus is theoretically resistant to this treatment. Abbreviations: HIV= Human immunodeficiency virus; PRV= Pseudorabies virus; IBR= Infectious bovine rhinotracheitis virus, BVDV; Bovine viral diarrhea virus; SINDBIS= Sindbis virus; WNV= West Nile virus; EMC= Encephalomyocarditis virus; PPV= Porcine parvovirus. Additionally, the manufacturing process was investigated for its capacity to decrease infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the vCJD and CJD agents. Several individual production steps in the Flebogamma 10% DIF manufacturing process have been shown to decrease TSE infectivity of an experimental model agent. TSE reduction steps include 4% polyethylene glycol precipitation [at least 6.19 log10] and Planova nanofiltration using a 20 nanometer filter [at least 5.45 log10]. These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

GamaSTAN® S/D Immune Globulin (Human) for Injection Solvent/Detergent Treated DESCRIPTION Table 1 : Product Information Summary Route of Administration Dosage Form, Strength Clinically Relevant Nonmedicinal Ingredients intramuscular injection injectable solution, 15-18% protein For a complete listing see Dosage Forms, Composition And Packaging section. GamaSTAN® S/D treated with solvent/detergent is a sterile solution of immune globulin for intramuscular administration; it contains no preservative. GamaSTAN® S/D is prepared by cold ethanol fractionation from human plasma. The immune globulin is isolated from solubilized Cohn fraction II. The fraction II solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltration. GamaSTAN® S/D is formulated as a 15-18% protein solution at a pH of 6.4-7.2 in 0.21-0.32 M glycine. The pH is adjusted with sodium carbonate. GamaSTAN® S/D is then incubated in the final container for 21-28 days at 20-27°C.

GAMMAGARD S/D Immune Globulin Intravenous (Human) SOLVENT DETERGENT TREATED DESCRIPTION GAMMAGARD S/D, Immune Globulin Intravenous (Human) [IGIV] is a solvent/detergent treated, sterile, freeze-dried preparation of highly purified immunoglobulin G (IgG) derived from large pools of human plasma. The product is manufactured by the Cohn-Oncley cold ethanol fractionation process followed by ultrafiltration and ion exchange chromatography. Source material for fractionation may be obtained from another U.S. licensed manufacturer. The manufacturing process includes treatment with an organic solvent/detergent mixture,1,2 composed of tri-n-butyl phosphate, octoxynol 9 and polysorbate 80.3 The GAMMAGARD (immune globulin) S/D manufacturing process provides a significant viral reduction in in vitro studies.3 These studies, summarized in Table 1, demonstrate virus clearance during GAMMAGARD S/D manufacturing using infectious human immunodeficiency virus, Types 1 and 2 (HIV-1, HIV-2); bovine viral diarrhea virus (BVD), a model virus for hepatitis C virus; sindbis virus (SIN), a model virus for lipid-enveloped viruses; pseudorabies virus (PRV), a model virus for lipid-enveloped DNA viruses such as herpes; vesicular stomatitis virus (VSV), a model virus for lipid-enveloped RNA viruses; hepatitis A virus (HAV) and encephalomyocarditis virus (EMC), a model virus for non-lipid enveloped RNA viruses; and porcine parvovirus (PPV), a model virus for non-lipid enveloped DNA viruses.3 These reductions are achieved through a combination of process chemistry, partitioning and/or inactivation during cold ethanol fractionation and the solvent/detergent treatment.3 Table 1: In Vitro Virus Clearance During Gammagard S/D (immune globulin) Manufacturing Process Step Evaluated Virus Clearance (log10) Lipid Enveloped Viruses Non-Lipid Enveloped Viruses BVD HIV-1 HIV-2 PRV SIN VSV EMC HAV PPV Step 1 : Processing of Cryo-Poor Plasma to Fraction I+II+III Precipitate 0.6* 5.7 NT 1.0* NT NT NT 0.5* 0.2* Step 2 : Processing of Resuspended Suspension A Precipitate to Suspension B Filter Press Filtrate 1.3 4.9 NT 3.7 NT NT 3.7 4.1 3.5 Step 3 : Processing of Suspension B Filter Press to Suspension B Cuno 70 Filtrate 0.7* 4.0 NT 4.5 NT NT 3.0 3.9 3.9 Step 4 : Solvent/Detergent Treatment > 4.9 > 3.7 5.7 > 4.1 5.1 6.0 NA NA NA Cumulative Reduction of Virus (log10) 6.2 18.3 5.7 12.3 5.1 6.0 6.7 8.0 7.4 * These values are not included in the computation of the cumulative reduction of virus since the virus clearance is within the variability limit of the assay ( ≤ 1.0). NA Not Applicable. Solvent/detergent treatment does not affect non-lipid enveloped viruses. NT Not Tested. When reconstituted with the total volume of diluent (Sterile Water for Injection, USP) supplied, this preparation contains approximately 50 mg of protein per mL (5%), of which at least 90% is gamma globulin. The product, reconstituted to 5%, contains a physiological concentration of sodium chloride (approximately 8.5 mg/mL) and has a pH of 6.8 ± 0.4. Stabilizing agents and additional components are present in the following maximum amounts for a 5% solution: 3 mg/mL Albumin (Human), 22.5 mg/mL glycine, 20 mg/mL glucose, 2 mg/mL polyethylene glycol (PEG), 1 µg/mL tri-n-butyl phosphate, 1 µg/mL octoxynol 9, and 100 µg/mL polysorbate 80. If it is necessary to prepare a 10% (100 mg/mL) solution for infusion, half the volume of diluent should be added, as described in the DOSAGE AND ADMINISTRATION. In this case, the stabilizing agents and other components will be present at double the concentrations given for the 5% solution. The manufacturing process for GAMMAGARD S/D (immune globulin) , isolates IgG without additional chemical or enzymatic modification, and the Fc portion is maintained intact. GAMMAGARD (immune globulin) S/D contains all of the IgG antibody activities which are present in the donor population. On the average, the distribution of IgG subclasses present in this product is similar to that in normal plasma.3 GAMMAGARD S/D (immune globulin) contains only trace amounts of IgA ( ≤ 2.2 µg/mL in a 5% solution). IgM is also present in trace amounts. GAMMAGARD S/D, Immune Globulin Intravenous (Human) contains no preservative. REFERENCES 1. Prince AM, Horowitz B, Brotman B. Sterilisation of hepatitis and HTLV-III viruses by exposure to tri-n-butyl phosphate and sodium cholate. Lancet. 1986;1:706-710. 2. Horowitz B, Wiebe ME, Lippin A, et al. Inactivation of viruses in labile blood derivatives: I. Disruption of lipid enveloped viruses by tri-n-butyl phosphate detergent combinations. Transfusion. 1985;25:516-522. 3. Unpublished data in the files of Baxter Healthcare Corporation.

BayGam™ Immune Globulin (Human) Solvent/Detergent Treated DESCRIPTION Immune Globulin (Human) — BayGam™ (immune globulin) treated with solvent/detergent is a sterile solution of immune globulin for intramuscular administration; it contains no preservative. BayGam is prepared by cold ethanol fractionation from human plasma. The immune globulin is isolated from solubilized Cohn fraction II. The fraction II solution is adjusted to a final concentration of 0.3% tri-n-butyl phosphate (TNBP) and 0.2% sodium cholate. After the addition of solvent (TNBP) and detergent (sodium cholate), the solution is heated to 30°C and maintained at that temperature for not less than 6 hours. After the viral inactivation step, the reactants are removed by precipitation, filtration and finally ultrafiltration and diafiltra-tion. BayGam (immune globulin) is formulated as a 15–18% protein solution at a pH of 6.4–7.2 in 0.21–0.32 M glycine. BayGam (immune globulin) is then incubated in the final container for 21–28 days at 20–27°C. The removal and inactivation of spiked model enveloped and non-enveloped viruses during the manufacturing process for BayGam (immune globulin) has been validated in laboratory studies. Human Immunodeficiency Virus, Type 1 (HIV-1), was chosen as the relevant virus for blood products; Bovine Viral Diarrhea Virus (BVDV) was chosen to model Hepatitis C virus; Pseudorabies virus (PRV) was chosen to model Hepatitis B virus and the Herpes viruses; and Reo virus type 3 (Reo) was chosen to model non-enveloped viruses and for its resistance to physical and chemical inactivation. Significant removal of model enveloped and non-enveloped viruses is achieved at two steps in the Cohn fractionation process leading to the collection of Cohn Fraction II:the precipitation and removal of Fraction III in the processing of Fraction II + IIIW suspension to Effluent IIIand the filtration step in the processing of Effluent III to Filtrate III. Significant inactivation of enveloped viruses is achieved at the time of treatment of solubilized Cohn Fraction II with TNBP/sodium cholate.

INDICATIONS Flebogamma 10% DIF is an immune globulin intravenous (human) solution indicated for the treatment of: Primary Immunodeficiency (PI) Flebogamma 10% DIF is indicated as replacement therapy in primary immunodeficiency (PI) including the humoral immune defects in common variable immunodeficiency, x-linked agammaglobulinemia, severe combined immunodeficiency, and Wiskott-Aldrich syndrome. Chronic Primary Immune Thrombocytopenia (ITP) Flebogamma 10% DIF is indicated for the treatment of patients 2 years of age and older with chronic primary immune thrombocytopenia to raise platelet count. DOSAGE AND ADMINISTRATION For Intravenous Use Only Dosage Table 1: Recommended Infusion Rates for Flebogamma 10% DIF Indication Dose Initial Infusion Rate Maintenance Dose Rate (if tolerated) PI 300 to 600 mg per kg body weight (3.0 to 6.0 mL per kg) administered every 3 to 4 weeks 0.01 mL per kg per minute (1 mg per kg per min) 0.08 mL per kg per minute (8 mg per kg per min) ITP 1 g per kg body weight (10 mL per kg) daily for 2 consecutive days 0.01 mL per kg per minute (1 mg per kg per min) 0.08 mL per kg per minute (8 mg per kg per min) As there are significant differences in the half-life of IgG among patients with PI, the frequency and amount of immunoglobulin therapy may vary from patient to patient. Adjust the dose according to clinical response. Adjust the dosage over time to achieve the desired serum trough IgG levels and clinical responses. No randomized controlled trial data are available to determine an optimum target trough serum IgG level. Preparation And Handling Inspect Flebogamma 10% DIF visually for particulate matter and color prior to administration. Do not use the vial if particles are detected. Do not use if turbid. Several vials of Flebogamma 10% DIF may be pooled into an empty sterile solution container by using aseptic technique, if large doses are to be administered. Do not dilute with intravenous fluids. Do not inject other medications into intravenous tubing being used for Flebogamma 10% DIF. Infuse Flebogamma 10% DIF through a separate intravenous line. Do not add any medications or intravenous fluids to the Flebogamma 10% DIF infusion container. Do not mix IGIV products of different formulations or from different manufacturers. Discard unused contents and administration devices after use. Use promptly any vial that has been entered. Discard partially used vials. Do not save for future use because the solution contains no preservative. Do not use solution that has been frozen. Administration The recommended initial infusion rate of Flebogamma 10% DIF is 0.01 mL per kg body weight per minute (1 mg per kg per min) for the first thirty minutes. If tolerated, the rate may be gradually increased to 0.04 mL per kg body weight per minute (4 mg per kg per min) and if tolerated, gradually increased to a maximum of 0.08 mL per kg body weight per min (8 mg per kg per min). Monitor patient vital signs throughout the infusion. Slow or stop the infusion if adverse reactions occur. If symptoms subside promptly, the infusion may be resumed at a lower rate that is comfortable for the patient. For the first 2-3 infusions, Flebogamma 10% DIF may be administered at infusion rates slower than recommended rates. If after administration of the first few infusions no adverse drug reactions are observed, the infusion rate for subsequent infusions may be slowly increased to the maximum rate. For patients experiencing adverse drug reactions, reduce the infusion rate in subsequent infusions or administer IGIV at 5% concentration. HOW SUPPLIED Dosage Forms And Strengths Flebogamma 10% DIF is a liquid preparation containing 10% IgG (100 mg per mL). Storage And Handling Flebogamma 10% DIF is supplied in single-use, individually laser-etched vials containing the labeled amount of functionally active IgG. The following presentations of Flebogamma 10% DIF are available: NDC Number Fill Size Grams Protein 61953-0005-1 50 mL 5 g 61953-0005-2 100 mL 10 g 61953-0005-3 200 mL 20 g Each vial has an integral suspension band and a label with two peel-off strips showing the product name and lot number. Flebogamma 10% DIF may be stored at room temperature at 2 to 25 °C (36 to 77 °F) for up to 24 months, as indicated by the expiration date printed on the outer carton and container label. Discard after expiration date. Do not freeze. Keep Flebogamma 10% DIF in its original carton to protect it from light. Not made with natural rubber latex. Manufactured by: Instituto Grifols, S.A., Barcelona - SPAIN. Revised: Jan 2016.

INDICATIONS Clinical Use Passive immunization should be considered when vaccines for active immunization are not available, or in situations when vaccine has not been used prior to exposure to the infective agent or is contraindicated (1). GamaSTAN® S/D is indicated in the following situations. Hepatitis A The prophylactic value of GamaSTAN® S/D is greatest when given before or soon after exposure to hepatitis A. GamaSTAN® S/D is not indicated in persons with clinical manifestations of hepatitis A or in those exposed more than 2 weeks previously. Measles (Rubeola) GamaSTAN® S/D should be given to prevent or modify measles in susceptible person exposed fewer than 6 days previously (2). A susceptible person is one who has not been vaccinated and has not had measles previously. GamaSTAN® S/D may be especially indicated for susceptible household contacts of measles patients, particularly contacts under 1 year of age, for whom the risk of complications is highest (2). GamaSTAN® S/D and measles vaccine should not be given at the same time (2). If a child is older than 12 months and has received GamaSTAN® S/D, he should be given measles vaccine about 5 months later when the measles antibody titer will have disappeared, provided there are no contraindications to the vaccine (1). If a susceptible child exposed to measles is immunocompromised, GamaSTAN® S/D should be given immediately (3). GamaSTAN® S/D may also be considered for severely immunocompromised individuals exposed to measles regardless of immunization status. Children who are immunocompromised should not receive measles vaccine or any other live viral vaccine (4). Varicella Passive immunization against varicella in immunosuppressed patients is best accomplished by use of Varicella-Zoster Immune Globulin (Human) [VZIG]. If VZIG is unavailable, GamaSTAN® S/D, promptly given, may also modify varicella (5). Rubella The routine use of GamaSTAN® S/D for prophylaxis of rubella in early pregnancy is of dubious value and cannot be justified. Some studies suggest that the use of GamaSTAN® S/D in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, GamaSTAN® S/D may benefit those women who will not consider a therapeutic abortion (3). DOSAGE AND ADMINISTRATION Dosing Considerations For intramuscular injection only. Do not give intravenously or subcutaneously. Recommended Dose And Dosage Adjustment Hepatitis A GamaSTAN® S/D in a dose of 0.02 mL/kg is recommended for household and institutional hepatitis A case contacts. The following doses of GamaSTAN® S/D are recommended for persons who plan to travel in areas where hepatitis A is common (8). Length of Stay Dose Volume Less than 3 months 0.02 mL/kg 3 months or longer 0.06 mL/kg (repeat every 4-6 months) Measles (Rubeola) GamaSTAN® S/D should be given in a dose of 0.25 mL/kg to prevent or modify measles in a susceptible person exposed fewer than 6 days previously (1,2). A susceptible child who is exposed to measles and who is immunocompromised should receive a dose of 0.5 mL/kg (maximum dose, 15 mL) of GamaSTAN® S/D immediately (3). The dosage of Immune Globulin (Human) for exposed individuals who have underlying malignant disease should be 0.5 mL/kg or 15 mL maximum (1). Varicella If Varicella-Zoster Immune Globulin (Human) is unavailable, GamaSTAN® S/D at a dose of 0.6 to 1.2 mL/kg, promptly given, may also modify varicella (5). Rubella Some studies suggest that the use of GamaSTAN® S/D in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, GamaSTAN® S/D at a dose of 0.55 mL/kg may benefit those women who will not consider a therapeutic abortion (3). Administration GamaSTAN® S/D is administered intramuscularly (see WARNINGS AND PRECAUTIONS: General), preferably in the anterolateral aspects of the upper thigh and the deltoid muscle of the upper arm. The gluteal region should not be used routinely as an injection site because of the risk of injury to the sciatic nerve. Doses over 10 mL should be divided and injected into several muscle sites to reduce local pain and discomfort. An individual decision as to which muscle is injected must be made for each patient based on the volume of material to be administered. If the gluteal region is used when very large volumes are to be injected or multiple doses are necessary, the central region MUST be avoided; only the upper, outer quadrant should be used (9). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use Reconstitution Not required. HOW SUPPLIED Storage And Stability Store at 2-8°C. Do not freeze. Do not use after expiration date. The vials are single use. Once entered, discard any unused contents. Dosage Forms, Composition And Packaging GamaSTAN® S/D contains 15-18% immune globulin (human) as active ingredient. It also contains 0.21-0.32 M glycine, USP. GamaSTAN® S/D is supplied in 2 mL, 5 mL and 10 mL single use vials. REFERENCES 1. NACI. Canadian Immunization Guide, 6th ed. Ottawa: National Advisory Committee on Immunization. 2002. 2. CDC. Measles, mumps, and rubella - vaccine use and strategies for elimination of measles, rubella, and congenital rubella syndrome and control of mumps: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1998;47(RR-8):1-58. 3. AAP. Passive immunization. In: Pickering LK, editor. Red Book: 2003 Report of the Committee on Infectious Diseases. 26th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2003. pp. 53-66. 4. Bruton OC. Agammaglobulinemia. Pediatrics 1952;9(6):722-8. 5. Gershon AA, Piomelli S, Karpatkin M, Smithwick E, Steinberg S. Antibody to varicella-zoster virus after passive immunization against chickenpox. J Clin Microbiol 1978;8(6):733-5. 9. CDC. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP) and the American Academy of Family Physician (AAFP). MMWR 2002;51(RR-2):1-36. Grifols Therapeutics Inc. (Manufacturer) 8368 US 70 Bus. Hwy West Clayton, NC 27520. Grifols Canada Ltd. (Importer and Distributor), 5060 Spectrum Way, Suite 405, Mississauga, Ontario, L4W 5N5. Revised: Jul 2014

INDICATIONS GAMMAGARD S/D (immune globulin) is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern (see WARNINGS). Primary Immunodeficiency Diseases GAMMAGARD S/D (immune globulin) is indicated for the treatment of primary immunodeficient states, such as: congenital agammaglobulinemia, common variable immunodeficiency, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.6,7 This indication was supported by a clinical trial of 17 patients with primary immunodeficiency who received a total of 341 infusions. GAMMAGARD S/D (immune globulin) is especially useful when high levels or rapid elevation of circulating IgG are desired or when intramuscular injections are contraindicated (e.g., small muscle mass). B-cell Chronic Lymphocytic Leukemia (CLL) GAMMAGARD S/D (immune globulin) is indicated for prevention of bacterial infections in patients with hypogammaglobulinemia and/or recurrent bacterial infections associated with B-cell Chronic Lymphocytic Leukemia (CLL). In a study of 81 patients, 41 of whom were treated with GAMMAGARD, Immune Globulin Intravenous (Human), bacterial infections were significantly reduced in the treatment group.8,9 In this study, the placebo group had approximately twice as many bacterial infections as the IGIV group. The median time to first bacterial infection for the IGIV group was greater than 365 days. By contrast, the time to first bacterial infection in the placebo group was 192 days. The number of viral and fungal infections, which were for the most part minor, was not statistically different between the two groups. Idiopathic Thrombocytopenic Purpura (ITP) When a rapid rise in platelet count is needed to prevent and/or to control bleeding in a patient with Idiopathic Thrombocytopenic Purpura, the administration of GAMMAGARD S/D (immune globulin) , should be considered. The efficacy of GAMMAGARD (immune globulin) has been demonstrated in a clinical study involving 16 patients. Of these 16 patients, 13 had chronic ITP (11 adults, 2 children), and 3 patients had acute ITP (one adult, 2 children). All 16 patients (100%) demonstrated a clinically significant rise in platelet count to a level greater than 40,000/mm3 following the administration of GAMMAGARD (immune globulin) . Ten of the 16 patients (62.5%) exhibited a significant rise to greater than 80,000 platelets/ mm3. Of these 10 patients, 7 had chronic ITP (5 adults, 2 children), and 3 patients had acute ITP (one adult, 2 children). The rise in platelet count to greater than 40,000/mm3 occurred after a single 1 g/kg infusion of GAMMAGARD (immune globulin) in 8 patients with chronic ITP (6 adults, 2 children), and in 2 patients with acute ITP (one adult, one child). A similar response was observed after two 1 g/kg infusions in 3 adult patients with chronic ITP, and one child with acute ITP. The remaining 2 adult patients with chronic ITP received more than two 1 g/kg infusions before achieving a platelet count greater than 40,000/mm3. The rise in platelet count was generally rapid, occurring within 5 days. However, this rise was transient and not considered curative. Platelet count rises lasted 2 to 3 weeks, with a range of 12 days to 6 months. It should be noted that childhood ITP may resolve spontaneously without treatment. Kawasaki Syndrome GAMMAGARD S/D (immune globulin) , is indicated for the prevention of coronary artery aneurysms associated with Kawasaki syndrome. The percentage incidence of coronary artery aneurysm in patients with Kawasaki syndrome receiving GAMMAGARD (immune globulin) either at a single dose of 1 g/kg (n=22) or at a dose of 400 mg/kg for four consecutive days (n=22), beginning within seven days of onset of fever, was 3/44 (6.8%). This was significantly different (p=0.008) from a comparable group of patients that received aspirin only in previous trials and of whom 42/185 (22.7%) experienced coronary artery aneurysms.10,11,12 All patients in the GAMMAGARD (immune globulin) trial received concomitant aspirin therapy and none experienced hypersensitivity-type reactions (urticaria, bronchospasm or generalized anaphylaxis).13 Several studies have documented the efficacy of intravenous gammaglobulin in reducing the incidence of coronary artery abnormalities resulting from Kawasaki syndrome.10-12, 14-17 DOSAGE AND ADMINISTRATION Primary Immunodeficiency Diseases For patients with primary immunodeficiencies, monthly doses of approximately 300-600 mg/kg infused at 3 to 4 week intervals are commonly used.42,43 As there are significant differences in the half-life of IgG among patients with primary immunodeficiency, the frequency and amount of immunoglobulin therapy may vary from patient to patient. The proper amount can be determined by monitoring clinical response. The minimum serum concentration of IgG necessary for protection varies among patients and has not been established by controlled clinical trials

INDICATIONS Hepatitis A The prophylactic value of BayGam (immune globulin) is greatest when given before or soon after exposure to hepatitis A. BayGam (immune globulin) is not indicated in persons with clinical manifestations of hepatitis A or in those exposed more than 2 weeks previously. Measles (Rubeola) BayGam (immune globulin) should be given to prevent or modify measles in a susceptible person exposed fewer than 6 days previously.7 A susceptible person is one who has not been vaccinated and has not had measles previously. BayGam (immune globulin) may be especially indicated for susceptible household contacts of measles patients, particularly contacts under 1 year of age, for whom the risk of complications is highest.7 BayGam (immune globulin) and measles vaccine should not be given at the same time.7 If a child is older than 12 months and has received BayGam (immune globulin) , he should be given measles vaccine about 3 months later when the measles antibody titer will have disappeared. If a susceptible child exposed to measles is immunocompromised, BayGam (immune globulin) should be given immediately.8 Children who are immunocompromised should not receive measles vaccine or any other live viral vaccine. Varicella Passive immunization against varicella in immunosuppressed patients is best accomplished by use of Varicella-Zoster Immune Globulin (Human) [VZIG]. If VZIG is unavailable, BayGam (immune globulin) , promptly given, may also modify varicella.5 Rubella The routine use of BayGam (immune globulin) for prophylaxis of rubella in early pregnancy is of dubious value and cannot be justified.6 Some studies suggest that the use of BayGam (immune globulin) in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, BayGam (immune globulin) may benefit those women who will notconsider a therapeutic abortion.4 Immunoglobulin Deficiency In patients with immunoglobulin deficiencies, BayGam (immune globulin) may prevent serious infection. However, BayGam (immune globulin) may not prevent chronic infections of the external secretory tissues such as the respiratory and gastrointestinal tract. Prophylactic therapy, especially against infections due to encapsulated bacteria, is effective in Bruton-type, sex-linked, congenital agammaglobulinemia, agammaglobulinemia associated with thymoma, and acquired agammaglobulinemia. DOSAGE AND ADMINISTRATION BayGam (immune globulin) is administered intramuscularly (see PRECAUTIONS), preferably in the anterolateral aspects of the upper thigh and the deltoid muscle of the upper arm. The gluteal region should not be used routinely as an injection site because of the risk of injury to the sciatic nerve. Doses over 10 mL should be divided and injected into several muscle sites to reduce local pain and discomfort. An individual decision as to which muscle is injected must be made for each patient based on the volume of material to be administered. If the gluteal region is used when very large volumes are to be injected or multiple doses are necessary, the central region MUST be avoided; only the upper, outer quadrant should be used.10 Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Hepatitis A BayGam (immune globulin) in a dose of 0.01 mL/lb (0.02 mL/kg) is recommended for household and institutional hepatitis A case contacts. The following doses of BayGam (immune globulin) are recommended for persons who plan to travel in areas where hepatitis A is common.3 Length of Stay Dose Volume Less than 3 months 0.02 mL/kg 3 months or longer 0.06 mL/kg (repeat every 4–6 months) Measles (Rubeola) BayGam (immune globulin) should be given in a dose of 0.11 mL/lb (0.25 mL/kg) to prevent or modify measles in a susceptible person exposed fewer than 6 days previously.7 A susceptible child who is exposed to measles and who is immunocompromised should receive a dose of 0.5 mL/kg (maximum dose, 15 mL) of BayGam (immune globulin) immediately.8 Varicella If Varicella-Zoster Immune Globulin (Human) is unavailable, BayGam (immune globulin) at a dose of 0.6 to 1.2 mL/kg, promptly given, may also modify varicella.5 Rubella Some studies suggest that the use of BayGam (immune globulin) in exposed, susceptible women can lessen the likelihood of infection and fetal damage; therefore, BayGam (immune globulin) at a dose of 0.55 mL/kg may benefit those women who will not consider a therapeutic abortion.4 Immunoglobulin Deficiency BayGam (immune globulin) may prevent serious infection in patients with immunoglobulin deficiencies if circulating IgG levels of approximately 200 mg/100 mL plasma are maintained. The recommended dosage is 0.66 mL/kg (at least 100 mg/kg) given every 3 to 4 weeks.6 A double dose is given at onset of therapy; some patients may require more frequent injections. HOW SUPPLIED BayGam (immune globulin) is supplied in 2 mL and 10 mL single dose vials. NDC Number Size 0026-0635-02 2 mL vial (10 pack) 0026-0635-04 2 mL vial 0026-0635-10 10 mL vial (10 pack) 0026-0635-12 10 mL vial Storage Store at 2–8°C (36–46°F). Do not freeze. Do not use after expiration date. CAUTION U.S. federal law prohibits dispensing without prescription. LIMITED WARRANTY A number of factors beyond our control could reduce the efficacy of this product or even result in an ill effect following its use. These include improper storage and handling of the product after it leaves our hands, diagnosis, dosage, method of administration, and biological differences in individual patients. Because of these factors, it is important that this product be stored properly and that the directions be followed carefully during use. No warranty, express or implied, including any warranty of merchantability or fitness is made. Representatives of the Company are not authorized to vary the terms or the contents of the printed labeling, including the package insert for this product, except by printed notice from the Company's headquarters. The prescriber and user of this product must accept the terms hereof. REFERENCE 4. American Academy of Pediatrics, Committee on Infectious Diseases: Report. ed. 19. Evanston, 1982, p 231. 5. Gershon AA, Piomelli S, Karpatkin M, et al: Antibody to varicella-zoster virus after passive immunization against chicken-pox. J Clin Microbiol 8(6): 733-5, 1978. 6. American Academy of Pediatrics, Committee on Infectious Diseases: Report. ed. 19. Evanston, 1982, pp 134-5. 7. Recommendation of the Public Health Service Advisory Committee on Immunization Practices: Measles prevention. MMWR 27(44): 427-30; 435-7, 1978. 8. American Academy of Pediatrics, Committee on Infectious Diseases: Report. ed. 19. Evanston, 1982, pp 34-6. 10. Recommendations of the Immunization Practices Advisory Committee (ACIP): General recommendations on immunization. MMWR 38(13): 205-14: 219-27, 1989. Bayer Corporation, Pharmaceutical Division Elkhart, IN 46515 USA. Rev. April 1998. FDA revision date: n/a

PATIENT INFORMATION Instruct patients to immediately report the following signs and symptoms to their physician: Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath (see Renal Failure) Symptoms of thrombosis which may include: pain and/or swelling of an arm or leg with warmth over the affected area, discoloration of an arm or leg, unexplained shortness of breath, chest pain or discomfort that worsens on deep breathing, unexplained rapid pulse, numbness or weakness on one side of the body (see Thrombosis) Severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea and vomiting (see Aseptic Meningitis Syndrome) Increased heart rate, fatigue, yellowing of skin or eyes and dark-colored urine (see Hemolysis) Trouble breathing, chest pain, blue lips or extremities, fever (see TRALI) Inform patients that Flebogamma 10% DIF is made from human plasma and may contain infectious agents that can cause disease (e.g., viruses, the vCJD agent and, theoretically, the CJD agent). The risk of Flebogamma 10% DIF transmitting an infection has been reduced by screening plasma donors for prior exposure, testing donated plasma, and inactivating and/or removing certain viruses during manufacturing. (see WARNING AND PRECAUTIONS) Instruct patients to report any symptoms that concern them and might be caused by infections. Inform patients that Flebogamma 10% DIF may interfere with their immune response to live viral vaccines such as measles, mumps and rubella. Inform patients to notify their health care professional of this potential interaction when they are receiving vaccinations. (see DRUG INTERACTIONS)

PATIENT INFORMATION GamaSTAN® S/D Immune Globulin (Human) Solvent/Detergent Treated This leaflet is Part 3 of a three-part “Product Monograph” published when GamaSTAN® S/D was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about GamaSTAN® S/D. Contact your doctor or pharmacist if you have any questions about the drug. About This Medication What the medication is used for: GamaSTAN® S/D may be used if you have not had a vaccine for hepatitis A, measles, chickenpox, rubella, or other infections and have been around people who have been sick with these illnesses. What it does: GamaSTAN® S/D provides antibodies to help prevent or lessen the severity of hepatitis A, measles, chickenpox, rubella, or other infections. When it should not be used: You should not use this medicine if your body does not make enough immunoglobulin A (IgA), which could cause you to have an allergic reaction to blood products that contain IgA. You should not be given GamaSTAN® S/D if you have any bleeding disorder that would make it unsafe for you to be given an injection into the muscles. What the medicinal ingredient is: The medicinal ingredient of GamaSTAN® S/D is 15-18% human immune globulin protein. What the nonmedicinal ingredients are: GamaSTAN® S/D also contains the amino acid glycine (at a concentration of 0.21-0.32 M), which acts as a stabilizer. What dosage forms it comes in: GamaSTAN® S/D comes in 2 mL, 5 mL and 10 mL vials. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions GamaSTAN® S/D must be injected into muscles only. It should not be injected directly into blood vessels (intravenously) or under the skin (subcutaneously). Products made from human plasma may contain infectious agents such as viruses. However, the manufacturing process of GamaSTAN® S/D is designed to inactivate and eliminate possible infectious agents. You should discuss the risks and benefits of this product with your healthcare provider. Immune Globulin (Human) products have been reported to be associated with heart and blood circulation problems such as heart attack, stroke and blood clots (thrombosis). You should talk to your doctor if you have risk factors for these kinds of conditions. Some of these risk factors include obesity, old age, high blood pressure, diabetes, or a history of heart disease. Thrombosis may occur even in the absence of known risk factor. BEFORE you use GamaSTAN® S/D talk to your doctor or pharmacist if: you are pregnant or breastfeeding you have had an allergic reaction to immune globulin or any of the other ingredients in the medicine Interactions With This Medication GamaSTAN® S/D may interfere with some vaccines. Talk with your healthcare professional if you will receive any type of vaccine within 6 months of GamaSTAN® S/D treatment. See also ABOUT THIS MEDICATION: When it should not be used, and SIDE EFFECTS AND WHAT TO DO ABOUT THEM. Proper Use Of This Medication Usual dose Your doctor will determine the amount of GamaSTAN® S/D that is right for you and when your shots should be given. An intramuscular or IM injection is a shot given into a muscle, usually in the buttocks. A doctor, nurse or other caregiver trained to give injections will give your treatment. Overdose Although there is no information on the effects of GamaSTAN® S/D overdose, experience with similar medicines suggests that the only effect would be pain and tenderness at the needle injection site. Missed Dose It is important that you receive GamaSTAN® S/D as instructed by your healthcare professional. If your doctor tells you that more than one treatment is required, you should consult him/her if a treatment appointment is missed. Side Effects And What To Do About Them Pain may occur where the injection is given. Talk with your doctor if the pain is severe. You should talk with your healthcare professional if you experience rash or hives (swelling, redness, intense itching, and burning). or if you develop swelling of the lips, other parts of the parts of the mouth and throat, eyelids, genitals, hands or feet Allergic reactions, although rare, have been reported following the injection of human immune globulin. Talk with your doctor immediately if you experience any of these side effects: wheezing or trouble breathing chest tightness severe abdominal cramps severe vomiting severe diarrhea This is not a complete list of side effects. For any unexpected effects while taking GamaSTAN® S/D, contact your doctor or pharmacist. HOW TO STORE IT GamaSTAN® S/D should be stored at 2-8°C. It should not be frozen or used past the expiration date. Reporting Suspected Side Effects To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs. If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by: toll-free telephone: 866-234-2345 toll-free fax: 866-678-6789 By email: cadrmp@hc-sc.gc.ca By regular mail: National AR Centre Marketed Health Products Safety and Effectiveness Information Division Marketed Health Products DirectorateTunney's Pasture, AL 0701C Ottawa ON K1A 0K9 NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

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

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Although no data are available, clinical experience with other immunoglobulin preparations suggests that the only manifestations would be pain and tenderness at the injection site. CONTRAINDICATIONS GamaSTAN® S/D should not be given to patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the Dosage Forms, Composition And Packaging section. GamaSTAN® S/D should not be given to persons with isolated immunoglobulin A (IgA) deficiency. Such persons have the potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products that contain IgA (7). GamaSTAN® S/D should not be administered to patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections. REFERENCES 7. Fudenberg HH. Sensitization to immunoglobulins and hazards of gamma globulin therapy. In: Merler E, editor. Immunoglobulins: biological aspects and clinical uses. Washington, DC: Nat Acad Sci; 1970. pp. 211-20.

OVERDOSE No information provided. CONTRAINDICATIONS GAMMAGARD S/D (immune globulin) is contraindicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern (see INDICATIONS and WARNINGS). Patients may experience severe hypersensitivity reactions or anaphylaxis in the setting of detectable IgA levels following infusion of GAMMAGARD S/D (immune globulin) . The occurrence of severe hypersensitivity reactions or anaphylaxis under such conditions should prompt consideration of an alternative therapy.

OVERDOSE No information provided. CONTRAINDICATIONS BayGam (immune globulin) should not be given to persons with isolated immunoglobulin A (IgA) deficiency. Such persons have the potential for developing antibodies to IgA and could have anaphylactic reactions to subsequent administration of blood products that contain IgA.9 BayGam (immune globulin) should not be administered to patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections. REFERENCE 9. Fudenberg HH: Sensitization to immunoglobulins and hazards of gamma globulin therapy. In: Merler E (ed.): Immunoglobulins: biologic aspects and clinical uses. Washington DC, Nat Acad Sci, 1970, pp 211-20.

SIDE EFFECTS The most common adverse reactions (reported in ≥ 5% of clinical trial subjects) were: PI: headache, fever/pyrexia, shaking, tachycardia, hypotension, back pain, myalgia, hypertension, chest pain, pain, nausea, infusion site reactions and pain in extremities. ITP: headache, pyrexia, nausea, chills, vomiting, body temperature increased, dizziness, back pain, hypotension, hypertension, heart rate increased and diarrhea. To report SUSPECTED ADVERSE REACTIONS, contact Grifols Biologicals at 1-888-GRIFOLS (1-888-474-3657) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Primary Immunodeficiency (PI) In a multicenter, open-label, non-randomized, historically controlled clinical study, 46 individuals with PI received infusions of Flebogamma 10% DIF at doses of 300 to 600 mg/kg body weight every 3 weeks (mean dose 469 mg/kg) or 4 weeks (mean dose 457 mg/kg) for up to 12 months. (see Clinical Studies) One subject experienced four serious adverse events (SAE) (bacterial pneumonia, subcutaneous abscess and two episodes of cellulitis) and withdrew from the study. Two other subjects discontinued prematurely due to AEs (back pain/chest pain/headache; and chills/tachycardia). Three subjects experienced four SAEs (drug abuse/depression; hernia; and sinusitis) unrelated to the product. One or more product-related adverse reactions were reported in 38 (83%) subjects. Adverse reaction intensity was reported as mild in 117 infusions, moderate in 74 infusions, and severe in 8 infusions. The percentage of infusions associated with mild, moderate or severe adverse reactions was 19.5% (upper bound 95% CI=22.9%), 12.3% (upper bound 95% CI=15.2%) and 1.3% (upper bound 95% CI=2.6%), respectively. The total number of temporally associated adverse reactions (i.e., reported within 72 hours post-infusion) was 291. Since a total of 601 infusions were administered, the rate of temporally associated adverse reactions per infusion was 0.48 (upper bound of the 1-sided 95% confidence interval: 0.52). A total of 166 infusions (30.3%, 1-sided 95% upper bound CI = 37.6%) were associated with one or more temporally associated adverse reactions. In the 21 subjects who received pre-medication, 12 (57%) reported temporally associated adverse reactions for 48 of 130 infusions (37%). Adverse reactions that occurred with an incidence of ≥ 5% on a per-subject basis are summarized in Table 2. Table 2: Adverse Reactions Occurring in ≥ 5% of Subjects Adverse Reaction Subjects (%) N=46 Number of Events Headache 24 (52.2) 71 Pyrexiaa 19 (41.3) 11 Rigors 17 (37.0) 38 Tachycardia/heart rate increased 11 (23.9) 20 Hypotension 9 (19.6) 11 Back Pain 8 (17.4) 27 Myalgia 8 (17.4) 21 Hypertensionb 7 (15.2) 12 Chest painc 6 (13) 25 Pain 4 (8.7) 8 Nausea 4 (8.7) 6 Infusion site reaction 3 (6.5) 6 Pain in extremities 3 (6.5) 3 a includes combined reported terms of pyrexia and body temperature increase. b includes combined reported terms of hypertension, diastolic hypertension, blood pressure increased, systolic blood pressure increased and systolic hypertension. c includes combined reported terms of chest pain and chest discomfort. Other common adverse drug reactions reported in < 5% of the subjects included flatulence, fatigue, feeling cold, malaise, neck pain, dizziness, wheezing, muscle spasms/tightness and abdominal distension/pain. Forty-three of 46 subjects had a negative Coombs' test at baseline. Of these 43 subjects, 10 (23.3%) developed a positive Coombs' test at some time during the study. However, no subjects showed evidence of hemolytic anemia. Chronic Primary Immune Thrombocytopenia (ITP) In a prospective, open-label, multicenter study, 58 subjects (46 adult and 12 pediatric) with chronic ITP were treated with Flebogamma 10% DIF, administered intravenously at a dose of 1 g per kg per day for 2 consecutive days, for a total dose of 2 g per kg, at a starting rate of 0.01 mL per kg per minute for 30 minutes. Three SAEs of moderate to severe intensity were reported in 3 adult subjects during the 30 day follow-up period: soft tissue inflammation (unrelated) of unknown etiology in one subject on Day 29 and headache in two subjects (possibly related) on Day 2. All subjects recovered without sequelae. Forty-eight (82.8%) subjects had one or more product related adverse reactions at some time during the study. Adverse reactions that occurred with an incidence of at least 5% on a per subject basis are summarized in Table 3. The proportion of subjects who experienced treatment-emergent adverse events (TEAE) was higher in the pediatric cohort than in the adult cohort. (see Pediatric Use and Clinical Studies) Table 3: Adverse Reactions Occurring in ≥ 5% of Subjects Adverse Reaction Adults (N = 46) Pediatrics (N = 12) All Subjects (N = 58) n (%) Number of Events n (%) Number of Events n (%) Number of Events Headache 24 (52.2) 34 11 (91.7) 19 35 (60.3) 53 Nausea 4 (8.7) 4 8 (66.7) 9 12 (20.7) 13 Pyrexia 8 (17.4) 11 4 (33.3) 5 12 (20.7) 16 Chills 7 (15.2) 8 4 (33.3) 4 11 (19.0) 12 Vomiting 4 (8.7) 4 5 (41.7) 5 9 (15.5) 9 Body temperature increased 3 (6.5) 3 2 (16.7) 2 5 (8.6) 5 Back pain 2 (4.3) 2 2 (16.7) 2 4 (6.9) 4 Dizziness 4 (8.7) 4 0 0 4 (6.9) 4 Diarrhea 3 (6.5) 3 0 0 3 (5.2) 3 Heart rate increased 1 (2.2) 1 2 (16.7) 2 3 (5.2) 3 Hypertension 2 (4.3) 2 1 (8.3) 1 3 (5.2) 3 Hypotension 1 (2.2) 1 2 (16.7) 3 3 (5.2) 4 In a supportive study of Flebogamma 10% DIF in adults (N=18) with ITP, three SAEs in 2 subjects were reported over the 3 month follow-up period: one case of thrombosis (possibly related) in one subject, and leukopenia (from 5.3 x 109/L pre-infusion to 2.7 x 109/L at Day 3; probably related) and decreased hemoglobin (from 11.7 g/dL pre-infusion to 9.8 g/dL on Day 2; probably related) in a second subject. All subjects recovered without sequelae. Post-marketing Experience Because adverse reactions are reported voluntarily post-approval from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to product exposure. The following adverse reactions have been identified during post-approval use of IGIV products,13-14 including Flebogamma 5% and 10% DIF. Infusion reactions Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure Renal Acute renal dysfunction/failure, osmotic nephropathy Respiratory Apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion-Related Acute Lung Injury (TRALI), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular Cardiac arrest, thromboembolism, vascular collapse, hypotension Neurological Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome Integumentary Stevens-Johnson Syndrome, epidermolysis, erythema multiformae, dermatitis (e.g., bullous dermatitis) Hematologic Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs) test Musculoskeletal Back pain Gastrointestinal Hepatic dysfunction, abdominal pain General/Body as a Whole Pyrexia, rigors DRUG INTERACTIONS Passive transfer of antibodies may transiently impair the immune response to live attenuated virus vaccines such as measles, mumps and rubella. Inform the immunizing physician of recent therapy with Flebogamma 10% DIF so that appropriate measures can be taken. (see PATIENT INFORMATION) REFERENCES 13. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Transfus Med Rev 2003; 17:241-51. 14. Orbach H, Katz U, Sherer Y, Shoenfeld Y. Intravenous immunoglobulin: adverse effects and safe administration. Clin Rev Allergy Immunol, 2005; 29:173-184.

SIDE EFFECTS Adverse Drug Reaction Overview Local pain and tenderness at the injection site, urticaria, and angioedema may occur. Anaphylactic reactions, although rare, have been reported following the injection of human immune globulin preparations. Anaphylaxis is more likely to occur if GamaSTAN® S/D is given intravenously; therefore, GamaSTAN® S/D must be administered only intramuscularly. Table 2 :Adverse Drug Reactions Associated with Immune Globulin (Human) General disorders and administration site conditions Local pain and injection site tenderness Immune system disorders Angioedema Anaphylaxis Urticaria DRUG INTERACTIONS Drug-Drug Interactions Table 3 : Established or Potential Drug-drug Interactions Proper Name Ref Effect Clinical Comment Live viral vaccines T Antibodies in the globulin preparation may interfere with the response to live viral vaccines such as measles, mumps, polio and rubella (1). Use of such vaccines should be deferred until approximately 5 months after GamaSTAN® S/D administration (1). Legend: C=Case Study; CT=Clinical Trial; T=Theoretical Drug-Food Interactions No interactions are known. Drug-Herb Interactions No interactions are known. Drug-Laboratory Interactions No interactions are known. REFERENCES 1. NACI. Canadian Immunization Guide, 6th ed. Ottawa: National Advisory Committee on Immunization. 2002.

SIDE EFFECTS Increases in creatinine and blood urea nitrogen (BUN) have been observed as soon as one to two days following infusion. Progression to oliguria and anuria requiring dialysis has been observed, although some patients have improved spontaneously following cessation of treatment.35 Types of severe renal adverse reactions that have been seen following IGIV therapy include: acute renal failure acute tubular necrosis36 proximal tubular nephropathy osmotic nephrosis18 (see also 37-39) In general, reported adverse reactions to GAMMAGARD (immune globulin) , in patients with either congenital or acquired immunodeficiencies are similar in kind and frequency. Various minor reactions, such as mild to moderate hypotension, headache, fatigue, chills, backache, leg cramps, lightheadedness, fever, urticaria, flushing, slight elevation of blood pressure, nausea and vomiting may occasionally occur. Slowing or stopping the infusion usually allows the symptoms to disappear promptly. Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine and antihistamines should be available for treatment of any acute anaphylactoid reaction (See WARNINGS). Primary Immunodeficiency Diseases Twenty-one adverse reactions occurred in 341 infusions (6%), when using GAMMAGARD (immune globulin) (5% solution), in a clinical trial of 17 patients with primary immunodeficiency.40 Of the 17 patients, 12 (71%) were adults, and 5 (29%) were children (16 years or younger). In a cross-over study comparing GAMMAGARD and GAMMAGARD S/D (immune globulin) (5% solutions) conducted in a small number (n=10) of primary immunodeficient patients, no unusual or unexpected adverse reactions were observed in the GAMMAGARD S/D (immune globulin) group. The adverse reactions experienced in the GAMMAGARD S/D (immune globulin) group were similar in frequency and nature to those observed in the control group consisting of patients receiving GAMMAGARD (immune globulin) . GAMMAGARD (immune globulin) , reconstituted to a concentration of 10%, was administered intravenously at rates varying from 2 to 11 mL/kg/Hr. Systemic reactions occurred in 23 (10.5%) of 219 infusions. This compares with an adverse reaction incidence of 6% (only systemic reactions reported) for primary immunodeficient patients previously treated with a 5% solution at infusion rates varying between 2 and 8 mL/kg/Hr, as described above (see reference 40). Local pain or irritation was experienced during 35 (16%) of 219 infusions. Application of a warm compress to the infusion site alleviated local symptoms. These local reactions tended to be associated with hand vein infusions and their incidence may be reduced by infusions via the antecubital vein. B-cell Chronic Lymphocytic Leukemia (CLL) In the study of patients with B-cell Chronic Lymphocytic Leukemia, the incidence of adverse reactions associated with GAMMAGARD (immune globulin) infusions was approximately 1.3% while that associated with placebo (normal saline) infusions was 0.6%.9 Idiopathic Thrombocytopenic Purpura (ITP) During the clinical study of GAMMAGARD (immune globulin) for the treatment of Idiopathic Thrombocytopenic Purpura, the only adverse reaction reported was headache which occurred in 12 of 16 patients (75%). Of these 12 patients, 11 had chronic ITP (9 adults, 2 children), and one child had acute ITP. Oral antihistamines and analgesics alleviated the symptoms and were used as pretreatment for those patients requiring additional IGIV therapy. The remaining 4 patients did not report any side effects and did not require pretreatment. Kawasaki Syndrome In a study of patients (n=51) with Kawasaki syndrome, no hypersensitivity-type reactions (urticaria, bronchospasm or generalized anaphylaxis) were reported in patients receiving either a single 1g/kg dose of IGIV, GAMMAGARD (immune globulin) , or 400 mg/kg of IGIV, GAMMAGARD (immune globulin) , for four consecutive days.13 Mild adverse reactions, including chills, flushing, cramping, headache, hypotension, nausea, rash and wheezing, were reported with both dose regimens. These adverse reactions occurred in 7/51 (13.7%) patients and in association with 7/129 (5.4%) infusions. Of the 25 patients who received a single 1 g/kg dose, 4 patients experienced adverse reactions for an incidence of 16%. Of the 26 patients who received 400 mg/kg/day over 4 days, 3 experienced a single adverse reaction for an incidence of 11.5%.3 Postmarketing The following list of adverse reaction have been identified and reported during the post-approval use of IGIV products: Respiratory: cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm Cardiovascular: thromboembolism, hypotension Neurological: seizures, tremor Hematologic: hemolysis, positive direct antiglobulin (Coombs) test General/Body as a Whole: pyrexia, rigors Musculoskeletal: back pain Gastrointestinal:hepatic dysfunction, abdominal pain Rare and Uncommon Adverse Events: Respiratory: apnea, Acute Respiratory Distress Syndrome (ARDS), Transfusion Associated Lung Injury (TRALI) Integumentary: bullous dermatitis, epidermolysis, erythema multiforme, Stevens- Johnson syndrome Cardiovascular: cardiac arrest, vascular collapse Neurological: coma, loss of consciousness Hematologic: pancytopenia, leukopenia Because postmarketing reporting of these reactions is voluntary and the at-risk populations are of uncertain size, it is not always possible to reliably estimate the frequency of the reaction or establish a causal relationship to exposure to the product. Such is also the case with literature reports authored independently.41 (See PRECAUTIONS) DRUG INTERACTIONS See DOSAGE AND ADMINISTRATION. REFERENCES 3. Unpublished data in the files of Baxter Healthcare Corporation. 9. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia: Intravenous immunoglobulin for the prevention of infection in Chronic Lymphocytic Leukemia: A randomized, controlled clinical trial. N Eng J Med. 1988; 319:902-907. 13. Data in the files of Baxter Healthcare Corporation. 35. Winward DB, Brophy MT. Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. Pharmacotherapy. 1995;15:765-772. 18. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol. 1997;8:1788-1794. 36. Phillips AO. Renal failure and intravenous immunoglobulin. Clin Nephrol. 1992;36:83-86. 37. Anderson W, Bethea W. Renal lesions following administration of hypertonic solutions of sucrose. JAMA. 1940;114:1983-1987. 38. Lindberg H, Wald A. Renal changes following the administration of hypertonic solutions. Arch Intern Med. 1939; 63:907-918. 39. Rigdon RH, Cardwell ES. Renal lesions following the intravenous injection of hypertonic solution of sucrose: a clinical and experimental study. Arch Intern Med. 1942;69:670-690. 40. Ochs HD, Lee ML, Fischer SH, et al. Efficacy of a New Intravenous Immunoglobulin Preparation in Primary Immunodeficient Patients. Clinical Therapeutics. 1987;9:512-522. 41. Pierce LR, Jain N. Risks associated with the use of intravenous immunoglobulin. Trans Med Rev. 2003;17:241-251.

SIDE EFFECTS Local pain and tenderness at the injection site, urticaria, and angioedema may occur. Anaphylactic reactions, although rare, have been reported following the injection of human immune globulin preparations.6,9 Anaphylaxis is more likely to occur if BayGam (immune globulin) is given intravenously; therefore, BayGam (immune globulin) must be administered only intramuscularly. DRUG INTERACTIONS Clinically Significant Product Interactions Antibodies in the globulin preparation may interfere with the response to live viral vaccines such as measles, mumps, polio and rubella. Therefore, use of such vaccines should be deferred until approximately 3 months after Immune Globulin (Human) — BayGam™ (immune globulin) administration. No interactions with other products are known. REFERENCE 6. American Academy of Pediatrics, Committee on Infectious Diseases: Report. ed. 19. Evanston, 1982, pp 134-5. 9. Fudenberg HH: Sensitization to immunoglobulins and hazards of gamma globulin therapy. In: Merler E (ed.): Immunoglobulins: biologic aspects and clinical uses. Washington DC, Nat Acad Sci, 1970, pp 211-20.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Severe hypersensitivity reactions and anaphylactic reactions with a fall in blood pressure may occur, even in patients who tolerated treatment with IGIV in the past. (see CONTRAINDICATIONS) If a hypersensitivity reaction develops, discontinue Flebogamma 10% DIF infusion immediately and institute appropriate treatment. Flebogamma 10% DIF contains trace amounts of IgA (less than 100 μg/mL). (see DESCRIPTION) Patients with antibodies to IgA have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Flebogamma 10% DIF is contraindicated in patients with antibodies against IgA and a history of hypersensitivity reaction. (see CONTRAINDICATIONS) Renal Dysfunction/Failure Acute renal dysfunction/failure, acute tubular necrosis, proximal tubular nephropathy, osmotic nephrosis and death have been reported in patients receiving IGIV, particularly those products containing sucrose.2 Flebogamma 10% DIF does not contain sucrose. Ensure that patients are not volume-depleted before administering Flebogamma 10% DIF. 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 years, volume depletion, sepsis, paraproteinemia or patients receiving known nephrotoxic drugs, administer Flebogamma 10% DIF at the minimum dose and rate of infusion practicable.3 (see BOXED WARNING) (see DOSING AND ADMINISTRATION) Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure.1 Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Flebogamma 10% DIF and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuation of the product. Hyperproteinemia, Increased Serum Viscosity, And Hyponatremia Hyperproteinemia, increased serum viscosity and hyponatremia may occur in patients receiving Flebogamma 10% DIF therapy. It is critical to distinguish true hyponatremia from pseudohyponatremia that is temporally or causally related to hyperproteinemia with concomitant decreased calculated serum osmolarity or elevated osmolar gap. This is because treatment aimed at decreasing serum free water in patients with pseudohyponatremia may lead to volume depletion, a further increase in serum viscosity and increased risk of thrombosis. Thrombosis Thrombosis may occur following treatment with immune globulin products, including Flebogamma 10% DIF. 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. (see Monitoring: Laboratory Tests) For patients at risk of thrombosis, administer Flebogamma 10% DIF at the minimum dose and infusion rate practicable. Ensure adequate hydration in patients before administration. Monitor for signs and symptoms of thrombosis and assess blood viscosity in patients at risk for hyperviscosity. (see BOXED WARNING, DOSAGE AND ADMINISTRATION and PATIENT INFORMATION) Aseptic Meningitis Syndrome (AMS) AMS has been reported to occur following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.4,5 The symptoms of AMS usually begin within several hours to 2 days following IGIV treatment. AMS is characterized by the following signs and symptoms: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. (see PATIENT INFORMATION) Cerebrospinal fluid (CSF) studies frequently reveal pleocytosis up to several thousand cells per cubic millimeter predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL but negative culture results. Conduct a thorough neurological examination of patients exhibiting such signs and symptoms, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently following high doses (e.g., > 2 g per kg body weight) or rapid infusion of IGIV. Hemolysis Flebogamma 10% DIF may 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 test (DAT) (Coombs' test) and hemolysis.6,7 Delayed hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration and acute hemolysis, consistent with intravascular hemolysis.8 Cases of severe hemolysis-related renal dysfunction/failure or disseminated intravascular coagulation have occurred following infusion of IGIV. The following risk factors may be associated with the development of hemolysis following IGIV administration: high doses (e.g., > 2 g per kg), given either as a single administration or divided over several days, and non-O blood group.9 Other individual patient factors, such as an underlying inflammatory state (as may be reflected by, for example, elevated C-reactive protein or erythrocyte sedimentation rate), have been hypothesized to increase the risk of hemolysis following administration of IGIV,10 but their role is uncertain. Hemolysis has been reported following administration of IGIV for a variety of indications, including ITP and PI.11 Monitor patients for clinical signs and symptoms of hemolysis, particularly patients with risk factors noted above. Consider appropriate laboratory testing in higher risk patients, including measurement of hemoglobin or hematocrit prior to infusion and within 36 to 96 hours post infusion. If clinical signs and symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving IGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis. (see PATIENT INFORMATION) Transfusion-Related Acute Lung Injury (TRALI) Non-cardiogenic pulmonary edema has been reported in patients following IGIV treatment.12 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function and fever. Symptoms typically appear within 1 to 6 hours following treatment. Monitor patients for pulmonary adverse reactions. (see PATIENT INFORMATION) If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. TRALI may be managed using oxygen therapy with adequate ventilatory support. Infusion Reactions Individuals receiving Flebogamma 10% DIF for the first time or being restarted on the product after a treatment hiatus of more than 8 weeks may be at a higher risk for the development of fever, chills, nausea, and vomiting. Careful monitoring of recipients and adherence to recommendations regarding dosage and administration may reduce the risk of these types of events. (see DOSAGE AND ADMINISTRATION) Transmissible Infectious Agents Because Flebogamma 10% DIF 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 (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 Flebogamma 10% DIF. All infections suspected by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Biologicals at 1-888-474-3657. Before prescribing or administering Flebogamma 10% DIF, the physician should discuss the risks and benefits of its use with the patient. (see PATIENT INFORMATION) Monitoring: Laboratory Tests Periodic monitoring of renal function and urine output is particularly important in patients judged to be at increased risk of developing acute renal failure. Assess renal function, including measurement of BUN and serum creatinine, before the initial infusion of Flebogamma 10% DIF and at appropriate intervals thereafter. Consider baseline assessment of blood viscosity in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies, because of the potential for increased risk of thrombosis. If signs and/or symptoms of hemolysis are present after an infusion of Flebogamma 10% DIF, perform appropriate laboratory testing for confirmation. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies and anti-HLA antibodies in both the product and patient serum. Interference With Laboratory Tests After infusion of IgG, 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, and D) may cause a positive direct or indirect antiglobulin (Coombs') test. Hereditary Fructose Intolerance Flebogamma 10% DIF contains sorbitol. The presence of sorbitol presents a risk to those with hereditary fructose intolerance (HFI). HFI is typically suspected based on dietary history, especially in young children who becomes symptomatic after breastfeeding. Flebogamma 10% DIF must not be administered to subjects with HFI. Nonclinical Toxicology Carcinogenicity, Mutagenesis, Impairment Of Fertility No animal studies were conducted to evaluate the carcinogenic or mutagenic effect of Flebogamma 10% DIF or its effects on fertility. Use In Specific Populations Pregnancy Risk Summary There are no studies of Flebogamma 10% DIF use in pregnant women. Animal reproduction studies have not been performed with Flebogamma 10% DIF. It is also not known whether Flebogamma 10% DIF can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Immunoglobulins cross the placenta from maternal circulation increasingly after 30 weeks of gestation. Flebogamma 10% DIF should be given to a pregnant woman only if clearly needed. Lactation Risk Summary There is no information regarding the presence of Flebogamma 10% DIF in human milk, its effects on the breastfed infant, or its effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for Flebogamma 10% DIF and any potential adverse effects on the breastfed infant from Flebogamma 10% DIF or from the underlying maternal condition. Pediatric Use Primary Immunodeficiency (PI) Three (3) pediatric subjects with PI (two between the ages of 6 and 10, and one 16 years old) were included in the clinical evaluation of Flebogamma 10% DIF. This number is too small to establish safety and efficacy in the pediatric population. (see Clinical Studies) Chronic Primary Immune Thrombocytopenia (ITP) Twelve (12) pediatric subjects with chronic ITP were enrolled and treated with Flebogamma 10% DIF in a clinical trial. Of the 12 subjects enrolled and treated, 4 were children and 8 were adolescents. The proportion of subjects who experienced treatment-emergent adverse events (TEAE) was higher in the pediatric cohort than in the adult cohort. (see Clinical Trials Experience) The safety and effectiveness of Flebogamma 10% DIF has not been established in pediatric subjects under the age of 2. Geriatric Use Limited information is available for the geriatric use of Flebogamma 10% DIF. Clinical studies of Flebogamma 10% DIF did not include sufficient numbers of subjects aged ≥ 65 years to determine whether they respond differently from younger subjects. Use caution when administering Flebogamma 10% DIF to patients aged ≥ 65 years who are judged to be at increased risk for developing thrombosis or renal insufficiency. Do not exceed the recommended dose, and infuse Flebogamma 10% DIF at the minimum dose and infusion rate practicable and at less than 0.04 mL per kg per minute (4 mg per kg per min). (see BOXED WARNING, WARNING AND PRECAUTIONS and DOSAGE AND ADMINISTRATION) REFERENCES 1. 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; 8:1788-94. 2. Winward DB, Brophy MT. Acute renal failure after administration of intravenous immunoglobulin: review of the literature and case report. Pharmacotherapy 1995; 15:765-72. 3. Tan E, Hajinazarian M, Bay W, et al. Acute renal failure resulting from intravenous immunoglobulin therapy. Arch Neurol 1993; 50:137-9. 4. Sekul EA, Cupler EJ, Dalakas MC. Aseptic meningitis associated with high-dose intravenous immunoglobulin therapy: frequency and risk factors. Ann Intern Med 1994; 121:259-62. 5. Scribner CL, Kapit RM, Phillips ET, et al. Aseptic meningitis and intravenous immunoglobulin therapy. Ann Intern Med 1994; 121:305-6. 6. Thomas MJ, Misbah SA, Chapel HM, et al. Hemolysis after high-dose intravenous Ig. Blood 1993; 15:3789. 7. Reinhart WH, Berchtold PE. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 1992; 339:662-4. 8. Kessary-Shoham H, Levy Y, Shoenfeld Y, et al. In vivo administration of intravenous immunoglobulin (IVIG) can lead to enhanced erythrocyte sequestration. J Autoimmun 1999; 13:129-35. 9. Kahwaji J, Barker E, Pepkowitz S, et al. Acute hemolysis after high-dose intravenous immunoglobulin therapy in highly HLA sensitized patients. Clin J Am Soc Nephrol 2009; 4:1993-1997. 10. Wilson JR, Bhoopalam N, Fisher M. Hemolytic anemia associated with intravenous immunoglobulin. Muscle Nerve 1997; 20:1142-1145. 11. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: A case series analysis. Transfusion 2008; 48:1598-1601. 12. Rizk A, Gorson KC, Kenney L, et al. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion 2001; 41:264-8.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Serious WARNINGS AND PRECAUTIONS For intramuscular injection only. Do not give intravenously or subcutaneously (see WARNINGS AND PRECAUTIONS: General). Products made from human plasma may contain infectious agents such as viruses (see WARNINGS AND PRECAUTIONS: General). There is clinical evidence of an association between the administration of all immunoglobulins and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis. Therefore, caution should be exercised when prescribing and administering immunogloblins. Thrombosis may occur even in the absence of known risk factors. Risk factors for thromboembolic events include: obesity, advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, acquired or inherited thrombophilic disorders, prolonged periods of immobilization, severely hypovolemic patients, diseases which increase blood viscosity, hypercoagulable conditions, use of estrogens, indwelling central venous catheters, and cardiovascular risk factors (see Thromboembolic Events subsection). General GamaSTAN® S/D should not be administered intravenously or subcutaneously because of the potential for serious reactions. Injections should be made intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel. Skin tests should not be done. In most human beings the intradermal injection of concentrated gamma globulin solution with its buffers causes a localized area of inflammation which can be misinterpreted as a positive allergic reaction. In actuality, this does not represent an allergy; rather, it is localized tissue irritation of a chemical nature. Misinterpretation of the results of such tests can lead the physician to withhold badly needed human immunoglobulin from a patient who is not actually allergic to this material. True allergic responses to human gamma globulin given in the prescribed intramuscular manner are rare. Although systemic reactions to intramuscularly administered immunoglobulin preparations are rare, epinephrine should be available for treatment of acute allergic symptoms. GamaSTAN® S/D is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Canada Ltd. [1-866-482-5226]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering to the patient. Thromboembolic Events There is clinical evidence of an association between the administration of all immunoglobulins and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis. Since thrombosis may occur in the absence of known risk factors, caution should be exercised in prescribing and administering immunoglobulins. The drug product should be administered at the minimum concentration available and at the minimum rate of infusion practicable. Patients should be adequately hydrated before administration. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia / markedly high triacylglycerols (triglycerides), or monoclonal gammopathies. Patients at risk of hyperviscosity should be monitored for signs and symptoms of thrombosis and blood viscosity assessed. Risk factors for thromboembolic adverse events include: obesity, advanced age, hypertension, diabetes mellitus, history of vascular disease or thrombotic episodes, acquired or inherited thrombophilic disorders, prolonged periods of immobilisation, severely hypovolemic patients, diseases which increase blood viscosity, hypercoagulable conditions, use of estrogens, indwelling central vascular catheters, and cardiovascular risk factors. Special Populations Pregnant Women There is no experience of exposure in pregnancy during clinical trials. Animal reproduction studies have not been conducted with GamaSTAN® S/D. It is also not known whether GamaSTAN® S/D can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GamaSTAN® S/D should be given to a pregnant woman only if clearly needed. Nursing Women Because of the potential for unknown effects from GamaSTAN® S/D in infants being nursed by mothers taking GamaSTAN® S/D, a decision should be made to either discontinue nursing or discontinue the administration of GamaSTAN® S/D, taking into account the importance of GamaSTAN® S/D therapy to the mother and the possible risk to the infant. Pediatrics ( < 18 years of age) The safety and effectiveness of GamaSTAN® S/D in the pediatric population have not been established. Monitoring And Laboratory Tests None required.

WARNINGS Warning Immune Globulin Intravenous (Human) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death.18 Patients predisposed to acute renal failure include patients with any degree of pre-existing renal insufficiency, diabetes mellitus, age greater than 65, volume depletion, sepsis, paraproteinemia, or patients receiving known nephrotoxic drugs. Especially in such patients, IGIV products should be administered at the minimum concentration available and the minimum rate of infusion practicable. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number.* See PRECAUTIONS and DOSAGE AND ADMINISTRATION sections for important information intended to reduce the risk of acute renal failure. *GAMMAGARD S/D (immune globulin) does not contain sucrose. GAMMAGARD S/D, Immune Globulin Intravenous (Human) is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses (See DESCRIPTION). Despite these measures, such products can still potentially transmit disease. Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses and theoretically, the Creutzfeldt-Jakob disease (CJD) agent. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Baxter Healthcare Corporation at 1-800-423-2862 (in the U.S.). The physician should discuss the risks and benefits of this product with the patient. GAMMAGARD S/D, Immune Globulin Intravenous (Human), should only be administered intravenously. Other routes of administration have not been evaluated. Immediate anaphylactic and hypersensitivity reactions are a remote possibility. Epinephrine and antihistamines should be available for treatment of any acute anaphylactoid reactions. GAMMAGARD S/D (immune globulin) contains only trace amounts of IgA ( ≤ 2.2 µg/mL in a 5% solution). GAMMAGARD S/D (immune globulin) is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern. It should be given with caution to patients with antibodies to IgA or IgA deficiencies, that are a component of an underlying primary immunodeficiency disease for which IGIV therapy is indicated.7,19 In such instances, a risk of anaphylaxis may exist despite the fact that GAMMAGARD S/D (immune globulin) contains only trace amounts of IgA. PRECAUTIONS General Some viruses, such as B19V (formerly known as parvovirus B19) or hepatitis A, are particularly difficult to remove or inactivate at this time. B19V most seriously affects pregnant women, or immune-compromised individuals. Symptoms of B19V infection include fever, drowsiness, chills, and runny nose followed about two weeks later by a rash and joint pain. Evidence of hepatitis A may include several days to weeks of poor appetite, tiredness, and low-grade fever followed by nausea, vomiting, and abdominal pain. Dark urine and a yellowed complexion are also common symptoms. Patients should be encouraged to consult their physician if such symptoms appear. An aseptic meningitis syndrome (AMS) has been reported to occur infrequently in association with Immune Globulin Intravenous (Human) [IGIV] treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to two days following IGIV treatment. It is characterized by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dL. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IGIV treatment. Periodic monitoring of renal function tests and urine output is particularly important in patients judged to have a potential increased risk for developing acute renal failure. Assure that patients are not volume depleted prior to the initiation of the infusion of IGIV. Renal function, including measurement of blood urea nitrogen (BUN)/serum creatinine, should be assessed prior to the initial infusion of GAMMAGARD S/D (immune globulin) and again at appropriate intervals thereafter. If renal function deteriorates, discontinuation of the product should be considered. For patients judged to be at risk for developing renal dysfunction, it may be prudent to reduce the rate of infusion to less than 4 mL/kg/Hr ( < 3.3 mg IG/kg/min) for a 5% solution or at a rate less than 2 mL/kg/ Hr ( < 3.3 mg IG/kg/min) for a 10 % solution. Certain components used in the packaging of this product contain natural rubber latex. Hemolysis Immune Globulin Intravenous (Human) [IGIV] products can contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction and, rarely, hemolysis.20-23 Hemolytic anemia can develop subsequent to IGIV therapy due to enhanced RBC sequestration23 (See ADVERSE REACTIONS). IGIV recipients should be monitored for clinical signs and symptoms of hemolysis (See PRECAUTIONS: Laboratory Tests). Transfusion-Related Acute Lung Injury (TRALI) There have been reports of noncardiogenic pulmonary edema (Transfusion Related Acute Lung Injury [TRALI]) in patients administered IGIV.24 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within 1 to 6 hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support. IGIV recipients should be monitored for pulmonary adverse reactions. If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum (See PRECAUTIONS: Laboratory Tests). Thrombotic Events Thrombotic events have been reported in association with IGIV25-33 (See ADVERSE REACTIONS). Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity, hypercoaguable disorders and prolonged periods of immobilization. The potential risks and benefits of IGIV should be weighed against those of alternative therapies for all patients for whom IGIV administration is being considered. Baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylgycerols (triglycerides), or monoclonal gammopathies (See PRECAUTIONS: Laboratory Tests). Analysis of adverse event reports13,34 has indicated that a rapid rate of infusion may be a risk factor for vascular occlusive events. Laboratory Tests If signs and/or symptoms of hemolysis are present after IGIV infusion, appropriate confirmatory laboratory testing should be done (see PRECAUTIONS). If TRALI is suspected, appropriate tests should be performed for the presence of anti-neutrophil antibodies in both the product and patient serum (see PRECAUTIONS). Because of the potentially increased risk of thrombosis, baseline assessment of blood viscosity should be considered in patients at risk for hyperviscosity, including those with cryoglobulins, fasting chylomicronemia/markedly high triacylglycerols (triglycerides), or monoclonal gammopathies (see PRECAUTIONS). Pregnancy Category C Animal reproduction studies have not been conducted with GAMMAGARD S/D, Immune Globulin Intravenous (Human). It is also not known whether GAMMAGARD S/D (immune globulin) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. GAMMAGARD S/D (immune globulin) should be given to a pregnant woman only if clearly needed. REFERENCES 13. Data in the files of Baxter Healthcare Corporation. 7. Buckley RH. Immunoglobulin replacement therapy: Indications and contraindications for use and variable IgG levels achieved In: Alving BM, Finlayson JS eds. Immunoglobulins: characteristics and use of intravenous preparations. Washington, D.C.: US Department of Health and Human Services; 1979;3-8. 18. Cayco AV, Perazella MA, Hayslett JP. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J Am Soc Nephrol. 1997;8:1788-1794. 19. Burks AW, Sampson HA, Buckley RH. Anaphylactic reactions after gammaglobulin administration in patients with hypogammaglobulinemia: Detection of IgE antibodies to IgA. N Eng J Med. 1986;314:560-564. 20. Wilson JR, Bhoopalam N, Fisher M. Hemoytic anemia associated with intravenous immunoglobulin. Muscle Nerve. 1997;20: 1142-1145. 21. Copelan EA, Strohm PL, Kennedy MS, Tutschka PJ. Hemolysis following intravenous immune globulin therapy. Transfusion. 1986;26:410-412. 22. Thomas MJ, Misbah SA, Chapel HM, Jones M, Elrington G, Newsom-Davis J. Hemolysis after high-dose intravenous Ig. Blood. 1993;82:3789. 23. 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 Autoimmune. 1999;13:129-135. 24. Rizk A, Gorson KC, Kenney L, Weinstein R. Transfusion-related acute lung injury after the infusion of IVIG. Transfusion. 2001;41: 264-268. 25. Dalakas MC. High-dose intravenous immunoglobulin and serum viscosity: risk of precipitating thromboembolic events. Neurology. 1994;44:223-226. 26. Harkness K, Howell SJL, Davies-Jones GAB. Encephalopathy associated with intravenous immunoglobulin treatment for Guillain-Barre syndrome. Journal of Neurology Neurosurgery, Psychiatry. 1996;60:586-598. 27. 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. 28. 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. 29. Brannagan TH, Nagle KJ, Lange DJ, Rowland LP . Complications of intravenous immune globulin treatment in neurologic disease. Neurology. 1996;47:674-677. 30. Haplea SS, Farrar JT, Gibson GA, Laskin M, Pizzi LT, Ashbury AK. Thromboembolic Events Associated with Intravenous Immunoglobulin Therapy. Neurology. 1997;48:A54. 31. Kwan T, and Keith P. Stroke Following Intravenous Immunoglobulin Infusion in a 28-Year-Old Male with Common Variable Immune Deficiency: A Case Report and Literature Review. Canadian Journal of Allergy & Clinical Immunology. 1999;4:250-253. 32. Elkayam O, Paran D, Milo R, Davidovitz Y, Almoznino-Sarafian D, Zelster D, Yaron M, Caspi D. Acute Myocardial Infarction Associated with High Dose Intravenous Immunoglobulin Infusion for Autoimmune Disorders. A study of four cases. Ann Rheum Dis. 2000;59:77-80. 33. Gomperts ED, Darr F. Letter to the Editor. Reference article - Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology. 2002. In Press. 34. Grillo JA, Gorson KC, Ropper AH, Lewis J, Weinstein R. Rapid infusion of intravenous immune globulin in patients with neuromuscular disorders. Neurology. 2001;57:1699-1701.

WARNINGS BayGam is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Bayer Corporation [1-888-765-3203]. The physician should discuss the risks and benefits of this product with the patient, before prescribing or administering it to the patient. BayGam (immune globulin) should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immunoglobulin preparations.9 PRECAUTIONS General Immune Globulin (Human) should not be administered intravenously because of the potential for serious reactions. Injections should be made intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel. Skin tests should not be done. In most human beings the intradermal injection of concentrated gamma globulin solution with its buffers causes a localized area of inflammation which can be misinterpreted as a positive allergic reaction. In actuality, this does not represent an allergy; rather, it is localized tissue irritation of a chemical nature. Misinterpretation of the results of such tests can lead the physician to withhold badly needed human immunoglobulin from a patient who is not actually allergic to this material. True allergic responses to human gamma globulin given in the prescribed intramuscular manner are rare. Although systemic reactions to intramuscularly administered immunoglobulin preparations are rare, epinephrine should be available for treatment of acute allergic symptoms. Clinical and Laboratory Tests None required. Pregnancy Category C Animal reproduction studies have not been conducted with BayGam (immune globulin) . It is also not known whether BayGam (immune globulin) can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. BayGam (immune globulin) should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established. REFERENCE 9. Fudenberg HH: Sensitization to immunoglobulins and hazards of gamma globulin therapy. In: Merler E (ed.): Immunoglobulins: biologic aspects and clinical uses. Washington DC, Nat Acad Sci, 1970, pp 211-20.