CNJ-016

6 ADVERSE REACTIONS The adverse reactions to VIGIV treatment in clinical trials (>10%) include headache, nausea, rigors and dizziness. The adverse drug reactions to VIGIV treatment in clinical trials (>10%) include headache, nausea, rigors and dizziness.( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Emergent BioSolutions Canada Inc. at 1-800-768-2304 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In a safety/pharmacokinetics study, 60 healthy male and female volunteers received a single intravenous dose of either 6000 Units per kg or 9000 Units per kg VIGIV. The population consisted of vaccinia vaccination-naïve subjects, ages 18 to 32, with both males and females enrolled in an approximate 50:50 ratio. In a pharmacodynamic study, 32 healthy male and female volunteers were randomized to receive vaccinia vaccination (n=10), VIGIV (9000 Units per kg) 4 days prior to vaccinia vaccination (n=10), or VIGIV (9000 Units per kg) concurrent with vaccinia vaccination (n=12). The population consisted of vaccinia vaccination-naïve subjects, ages 18 to 32, with both male and female enrolled in a 75:25 ratio. The ethnic background of patients included those of Caucasian, African American, Asian and Hispanic descent, with the majority of them being Caucasian. In an additional pharmacodynamic clinical study, 50 healthy male and female volunteers were randomized to receive VIGIV at 9000 Units per kg (n=20) or at 24,000 Units per kg (n=20) or placebo (n=10) 4 days prior to vaccinia vaccination (n=30) or placebo (n=20). The population consisted of vaccinia vaccination-naïve male and female subjects, ages 18 to 33, in a 60:40 ratio. The ethnic background of patients included those of Caucasian, African American, and Hispanic descent, with the majority of them being African American. The most frequently reported adverse reactions related to VIGIV administration in all three clinical studies were headache, nausea, rigors, and dizziness. Table 1 describes the adverse reactions that were temporally related to VIGIV or placebo administration that occurred during or within three days of product infusion with a frequency of 5% or higher in any one treatment group. Table 1 Adverse Drug Reactions that Occurred Temporally Adverse events that occurred during or within 3 days of VIGIV or placebo administration. During or Following VIGIV Administration (≥5%) SYSTEM ORGAN CLASS PREFERRED TERM VIGIV (%) PLACEBO 0.9% NaCl infused at 2 mL/min. N=32 (%) 6000 U/kg Infusion rate: 4 mL/min; subjects were fasted. N=31 9000 U/kg Infusion rate: 4 mL/min or 2 mL/min; subjects were fasted. N=39 9000 U/kg Infusion rate: 2 mL/min; subjects were not fasted. N=20 24,000 U/kg N=20 All Body System All Preferred Terms 19 (61.3) 30 (76.9) 2 (10.0) 5 (25.0) 4 (12.5) Gastrointestinal Disorders Nausea 4 (12.9) 11 (28.2) 0 (0.0) 0 (0.0) 1 (3.1) Vomiting NOS 1 (3.2) 3 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) General Disorders and Administration Site Conditions Rigors 7 (22.6) 7 (17.9) 0 (0.0) 0 (0.0) 0 (0.0) Feeling cold 4 (12.9) 6 (15.4) 0 (0.0) 0 (0.0) 0 (0.0) Pain NOS 1 (3.2) 5 (12.8) 0 (0.0) 0 (0.0) 0 (0.0) Feeling hot 3 (9.7) 1 (2.6) 0 (0.0) 0 (0.0) 0 (0.0) Asthenia 2 (6.5) 2 (5.1) 0 (0.0) 0 (0.0) 1 (3.1) Pyrexia 2 (6.5) 1 (2.6) 0 (0.0) 0 (0.0) 0 (0.0) Fatigue 0 (0.0) 2 (5.1) 0 (0.0) 0 (0.0) 1 (3.1) Edema peripheral 0 (0.0) 0 (0.0) 0 (0.0) 1 (5.0) 0 (0.0) Metabolism and Nutrition Disorders Appetite decreased NOS 2 (6.5) 2 (5.1) 0 (0.0) 0 (0.0) 0 (0.0) Musculoskeletal and Connective Tissue Disorders Muscle spasm 2 (6.5) 2 (5.1) 0 (0.0) 1 (5.0) 0 (0.0) Back pain 2 (6.5) 2 (5.1) 0 (0.0) 0 (0.0) 0 (0.0) Nervous System Disorders Headache 17 (54.8) 23 (59.0) 1 (5.0) 4 (20.0) 3 (9.4) Dizziness 5 (16.1) 7 (17.9) 1 (5.0) 0 (0.0) 1 (3.1) Paraesthesia 2 (6.5) 1 (2.6) 0 (0.0) 0 (0.0) 0 (0.0) Tremor 1 (3.2) 2 (5.1) 0 (0.0) 0 (0.0) 0 (0.0) Skin and Subcutaneous Tissue Disorders Sweating increased 3 (9.7) 2 (5.1) 0 (0.0) 0 (0.0) 0 (0.0) Vascular Disorders Pallor 1 (3.2) 3 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) Most adverse reactions were of mild intensity (defined in study protocols as awareness of a sign or symptom but subject can tolerate). One subject in the 9000 Units per kg dosage group experienced syncope. There was a lower incidence of adverse reactions when VIGIV (9000 Units per kg) was infused at 2 mL/min than 4 mL/min. There was a higher incidence of adverse reactions after administration of VIGIV in fasted subjects compared to subjects that were not fasted overnight. There were no serious adverse reactions or adverse reactions of severe intensity in the clinical studies. There were no instances of VIGIV discontinuation due to an adverse event, or reduction in dose or infusion rate. 6.2 Post-marketing Experience Because post-marketing adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to exposure to the product. Severe vaccinia infection that developed possible intravascular hemolysis and transient renal injury has been reported. As VIGIV may contain blood group antigens that may have hemolysins, VIGIV doses may have contributed to the hemolysis. However, the hemolysis did not reoccur with continued VIGIV dosing. Mild and transient chest pain that occurred the same day of VIGIV infusion has been reported. The following are adverse reactions listed by body system that have been identified and reported during the post-approval use of other IGIV products: • Cardiovascular : Cardiac arrest, tachycardia • Hematologic and Lymphatic : Neutropenia, leukopenia, anemia, lymphadenopathy • Integumentary : Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis), urticaria or other skin reactions • Gastrointestinal : Hepatic dysfunction, abdominal pain, diarrhea • Muscular: Myalgia, arthralgia • Neurological : Coma, loss of consciousness, seizures • Renal : Acute kidney injury, osmotic nephropathy • Respiratory : Apnea, Acute Respiratory Distress Syndrome (ARDS), cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm, wheezing • General/Body as a Whole : Malaise, chest discomfort

4 CONTRAINDICATIONS VIGIV is contraindicated in: • Isolated vaccinia keratitis. • Individuals with a history of anaphylaxis or prior severe systemic reaction associated with the parenteral administration of this or other human immune globulin preparations. • IgA-deficient patients with antibodies against IgA and a history of IgA hypersensitivity, as it contains trace amounts of IgA (40 mcg/mL). • Isolated vaccinia keratitis ( 4 ) • History of anaphylactic or severe systemic reaction to human globulins ( 4 ) • IgA deficiency with antibodies against IgA and a history of IgA hypersensitivity ( 4 )

11 DESCRIPTION VIGIV is a solvent/detergent-treated, filtered sterile solution of purified gamma globulin (IgG) fraction of human plasma containing antibodies to vaccinia virus. It is stabilized with 10% maltose and 0.03% polysorbate 80 (pH is between 5.0 and 6.5) and contains no preservative. The product is a clear to opalescent liquid. VIGIV is manufactured from plasma collected from healthy, screened donors with high titers of anti-vaccinia antibody (meeting minimum potency specifications) that is purified by an anion-exchange column chromatography method ( 3 , 4 ). The plasma donors were boosted with vaccinia vaccine prior to donating plasma used in the production of the product. Each plasma donation used for the manufacture of VIGIV is tested for the presence of hepatitis B virus (HBV) surface antigen (HBsAg) and antibodies to human immunodeficiency viruses (HIV) 1/2 and hepatitis C virus (HCV) using FDA-licensed serological tests. Plasma used in the manufacture of this product was tested by FDA licensed Nucleic Acid Testing (NAT) for HIV-1 and HCV and found to be negative. A NAT for HBV was also performed on all Source Plasma used and found to be negative; however, the significance of a negative result has not been established. The Source Plasma has also been tested by NAT for hepatitis A virus (HAV) and parvovirus B19 and the limit for B19 in the manufacturing pool is set not to exceed 10 4 IU of B19 DNA per mL. The manufacturing process contains two steps implemented specifically for virus clearance. The solvent and detergent step (using tri-n-butyl phosphate and Triton X-100) is effective in the inactivation of enveloped viruses, such as HBV, HCV and HIV ( 5 ). Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses ( 6 ). In addition to the two specific steps, the anion-exchange chromatography step contributes to the removal of small non–lipid enveloped viruses. The inactivation and reduction of known enveloped and non–enveloped model viruses were validated in laboratory studies as summarized in Table 2 . Table 2 Virus Reduction Values (Log 10 ) Obtained through Validation Studies Enveloped Enveloped Non-Enveloped Genome RNA DNA RNA DNA Virus HIV-1 BVDV PRV Vaccinia HAV EMC MMV PPV Family retro flavi herpes pox picorna parvo Size (nm) 80–100 50–70 120–200 220–450 long x 140–260 wide 25–30 30 20–25 18–24 Anion Exchange Chromatography (partitioning) Not evaluated 2.3 n.e. 3.4 n.e. 20N Filtration (size exclusion) ≥4.7 ≥3.5 ≥5.6 The PRV was retained by the 0.1 μm pre-filter during the virus validation. Since manufacturing employs a 0.1 μm pre-filter before the 20N filter, the claim of ≥5.6 reduction is considered applicable. n.e. n.e. 4.8 n.e. 4.1 Solvent/Detergent (inactivation) ≥4.7 ≥7.3 ≥5.5 ≥3.7 Not evaluated Total Reduction (log 10 ) ≥9.4 ≥10.8 ≥11.1 ≥3.7 7.1 7.5 Abbreviations: HIV-1: human immunodeficiency virus-1; relevant virus for human immunodeficiency virus-1 and model for HIV-2 BVDV: bovine viral diarrhea virus; model virus for hepatitis C virus (HCV) and West Nile virus (WNV) PRV: pseudorabies virus; model for large enveloped DNA viruses, including herpes HAV: human hepatitis A virus; relevant virus for HAV and model for small non-enveloped viruses in general EMC: encephalomyocarditis virus; model for HAV and for small non-enveloped viruses in general MMV: murine minute virus; model for human parvovirus B19 and for small non-enveloped viruses in general PPV: porcine parvovirus; model for human parvovirus B19 and for small non-enveloped viruses in general n.e.: not evaluated The product potency (as determined by a plaque reduction neutralization test) is expressed in arbitrary units (U) by comparison to the FDA reference standard. Each vial contains approximately 40 to 80 mg/mL total protein and ≥50,000 units of vaccinia antibody neutralizing activity. The product contains ≤40 mcg/mL of Immune globulin A (IgA).

2 DOSAGE AND ADMINISTRATION For intravenous use only. • For intravenous use only. • VIGIV is administered at a dose of 6000 Units per kg, as soon as symptoms for complication(s) due to vaccinia vaccination appear ( 2.1 ). • Higher doses (e.g. 9000 Units per kg or 24,000 Units per kg) may be considered in the event that the patient does not respond to the initial dose of 6000 Units per kg ( 2.1 ). • For patients with risk factors for thrombosis, the maximum daily dose of VIGIV should not exceed 12,000 Units per kg ( 2.3 ). 2.1 Dosage for Treatment of Severe Complications of Vaccinia Vaccination Administer VIGIV at a dose of 6000 Units per kg, as soon as symptoms appear and are judged to be due to severe vaccinia-related complication. Consider repeat dosing, depending on the severity of the symptoms and response to treatment; however, clinical data on repeat doses are lacking. Consider higher doses (e.g. 9000 Units per kg) if the patient does not respond to the initial 6000 Units per kg dose. Doses up to 24,000 Units per kg administered to healthy volunteers were well tolerated in clinical trials [see 14 CLINICAL STUDIES ]. 2.2 Preparation • Bring VIGIV vials to room temperature prior to dosing. • If frozen, thaw vial by placing in a refrigerator at 36 to 46°F (2 to 8°C) until the contents are thawed for approximately 14 hours. Product can be thawed rapidly by placing at room temperature for one hour followed by a water bath at 98.6°F (37°C) until thawed. • Do not thaw this product in a microwave oven. • Do not refreeze the vial. • DO NOT SHAKE VIAL. SHAKING VIAL MAY CAUSE FOAMING. • Remove the entire contents of the vial to obtain the labeled dosage of VIGIV. If partial vials are required for the dosage calculation, withdraw the entire contents of the vial to ensure accurate calculation of the dosage requirement. • VIGIV is compatible with 0.9% Sodium Chloride USP. No other drug interactions or compatibilities have been evaluated. If a pre-existing catheter must be used, flush the line with 0.9% Sodium Chloride USP before use. VIGIV may be administered either undiluted or diluted no more than 1:2 (v/v). • VIGIV vial is for single use only. Do not reuse or save VIGIV for future use. • VIGIV contains no preservatives. Discard partially used vials. 2.3 Administration • Inspect the product prior to use and do not use if solution is cloudy, discolored or contains particulates. • Administer VIGIV intravenously through a dedicated intravenous line with the rate of infusion of no greater than 2 mL/min. • For patients weighing less than 50 kg, infuse the product at a rate no greater than 0.04 mL/kg/minute (133.3 Units per kg/minute). • Adverse drug reactions may be related to the rate of infusion. Slower infusion rate may be needed for patients who develop a minor adverse reaction (e.g. flushing) or for patients with risk factors for thrombosis/thromboembolism. • Closely monitor and carefully observe patients and their vital signs for any symptoms throughout the infusion period and immediately following an infusion. • For patients with pre-existing renal insufficiency, or at increased risk of acute kidney injury, thrombosis, or volume overload, do not exceed the recommended infusion rate and follow the infusion schedule closely. • For patients with risk factors for thrombosis, the maximum daily dose of VIGIV should not exceed 12,000 Units per kg [see 5.4 Thrombosis ]

7 DRUG INTERACTIONS • Efficacy of live attenuated virus vaccines may be impaired by immune globulin administration; revaccination may be necessary ( 7.1 ) • Antibodies in VIGIV may interfere with some serological tests ( 7.2 ) 7.1 Live, Attenuated Vaccines Immune globulin administration may impair the efficacy of live attenuated vaccines such as measles, rubella, mumps and varicella. Defer vaccination with live virus vaccines until approximately three months after administration of VIGIV. Revaccinate people who received VIGIV shortly after live virus vaccination three months after the administration of the VIGIV. 7.2 Drug/Laboratory Interactions • VIGIV contains maltose, which can be misinterpreted as glucose by certain types of blood glucose testing systems (for example, those based on the GDH-PQQ or glucose-dye-oxidoreductase methods). Due to the potential for falsely elevated glucose readings, only use testing systems that are glucose-specific to test or monitor blood glucose levels in patients receiving VIGIV [see BOXED WARNING and 5.3 Blood Glucose Monitoring • Antibodies present in VIGIV may interfere with some serological tests. After administration of immune globulins like VIGIV, a transitory increase of passively transferred antibodies in the patient’s blood may result in positive results in serological testing (e.g. Coombs’ test) [see 5.5 Hemolysis ].

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action VIGIV provides passive immunity for individuals with complications to vaccinia virus vaccination. The exact mechanism of action is not known. 12.2 Pharmacodynamics Two double-blind pharmacodynamic studies were conducted in which 82 healthy volunteers were randomized to receive vaccinia vaccination with or without VIGIV. In the first study, the efficacy of 9000 Units per kg of VIGIV on the immunologic and local response to Dryvax was evaluated. A total of 32 healthy subjects were randomized to receive single IV infusions of either VIGIV (9000 Units per kg) or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either Placebo or VIGIV (9000 Units per kg) concurrently with vaccinia (Dryvax) vaccination on Day 4. In a second study, 50 healthy subjects were randomized to receive a single IV infusion of either VIGIV (9000 Units per kg), VIGIV (24,000 Units per kg), or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either placebo or vaccinia (Dryvax) vaccination on Day 4. The effect of VIGIV on the immunologic response to Dryvax was determined by measuring vaccinia antibody titer (vaccinia IgG) in plasma and comparing titer levels across all three treatment arms. In addition, the effect of VIGIV on the local response (tissue) to Dryvax was assessed by evaluating the size of the pox reaction, as well as the area of erythema and induration following vaccination. VIGIV (9000 Units per kg and 24,000 Units per kg) reduced the local and immunological response to vaccinia vaccination when it was administered 4 days prior to vaccination compared to vaccination alone. This is consistent with the hypothesis that VIGIV can neutralize vaccinia virus in vivo [see 14 CLINICAL STUDIES ] . In addition, infusions of VIGIV of up to 24,000 Units per kg were well tolerated [see 6.1 Clinical Trials Experience ]. 12.3 Pharmacokinetics A double-blind study was conducted in which 60 healthy subjects were randomized to receive either 6000 Units per kg or 9000 Units per kg VIGIV. After intravenous administration of 6000 Units per kg to 31 healthy subjects, a mean peak plasma concentration of 161 Units per mL was achieved within two hours. The half-life of VIGIV was 30 days (range of 13 to 67 days) and the volume of distribution was 6630 mL. Pharmacokinetic parameters were calculated based on antibody levels determined by an ELISA. The levels of vaccinia immune globulin remained in circulation for a prolonged period of time, with a mean half-life ranging from approximately 26 to 30 days. Maximum plasma concentrations (C max ) of VIGIV reached levels ranging from approximately 160 to 232 Units per mL in 1.8 to 2.6 hours. In addition, the drug had a large volume of distribution, as demonstrated by both non-compartmental and compartmental analyses. Non-compartmental analyses demonstrated that at the two dose levels studied, the drug exhibited dose-proportionality (AUC and C max values) ( Table 3 ). The pharmacokinetic parameters estimated by compartmental analysis were similar to those calculated by non-compartmental methods. Table 3 Non-compartmental Pharmacokinetic Parameters (mean (±SD)) of VIGIV VIGIV (6000 U/kg or 9000 U/kg) from Measured Data Arithmetic Mean (±SD) Parameter 6000 U/kg 9000 U/kg AUC 0 - ∞ (U*h/mL) 58521 (16079) 78401 (17502) AUC 0-t (U*h/mL) 49405 (13246) 71541 (13173) C MAX (U/mL) 161 (40.0) 232 (40.9) T MAX (h) 1.84 (1.12) 2.61 (2.41) T ½ (days) 30.0 (10.0) 26.2 (5.08) The plasma concentration of circulating VIGIV was also compared to a theoretical value obtained from a model of previously licensed Baxter Vaccinia Immune Globulin (VIG) product at Day 5 after IV administration of VIGIV. Since Baxter VIG was administered intramuscularly (IM) and VIGIV is administered IV, the comparison was made at approximately five days to account for equilibration between the extravascular and intravascular compartments following IM injection. The binding capacity and neutralizing antibody activity of anti-vaccinia antibody in these subjects five days after intravenous administration of VIGIV (both 6000 Units per kg and 9000 Units per kg dosages) were at least as high as the theoretical values that would be achieved following the intramuscular administration of the comparator VIG (see Table 4 ). Five days represents the approximate time of peak serum anti-vaccinia antibody concentration following intramuscular administration of other Immune Globulin (Human) products. No historical pharmacokinetic data are available for the theoretical intramuscular comparator VIG. Table 4 Test of Non-inferiority Dose VIGIV (U/kg) Plasma Levels, U/mL (Range Geometric mean (range) ) Ratio of Means % (97.5% Lower Confidence Interval Bound) Expressed as a percentage relative to the geometric mean of the simulated concentrations at Day 5 after 6000 U/kg intramuscular administration VIGIV Observed levels VIGIM Simulated levels 6000 60.1 (36.1–84.6) 66.2 (42.3–94.9) 90.82 (86.94) 9000 90.3 (63.4–133.8) 64.8 (47.6–87.2) 139.40 (135.27)

12.1 Mechanism of Action VIGIV provides passive immunity for individuals with complications to vaccinia virus vaccination. The exact mechanism of action is not known.

12.2 Pharmacodynamics Two double-blind pharmacodynamic studies were conducted in which 82 healthy volunteers were randomized to receive vaccinia vaccination with or without VIGIV. In the first study, the efficacy of 9000 Units per kg of VIGIV on the immunologic and local response to Dryvax was evaluated. A total of 32 healthy subjects were randomized to receive single IV infusions of either VIGIV (9000 Units per kg) or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either Placebo or VIGIV (9000 Units per kg) concurrently with vaccinia (Dryvax) vaccination on Day 4. In a second study, 50 healthy subjects were randomized to receive a single IV infusion of either VIGIV (9000 Units per kg), VIGIV (24,000 Units per kg), or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either placebo or vaccinia (Dryvax) vaccination on Day 4. The effect of VIGIV on the immunologic response to Dryvax was determined by measuring vaccinia antibody titer (vaccinia IgG) in plasma and comparing titer levels across all three treatment arms. In addition, the effect of VIGIV on the local response (tissue) to Dryvax was assessed by evaluating the size of the pox reaction, as well as the area of erythema and induration following vaccination. VIGIV (9000 Units per kg and 24,000 Units per kg) reduced the local and immunological response to vaccinia vaccination when it was administered 4 days prior to vaccination compared to vaccination alone. This is consistent with the hypothesis that VIGIV can neutralize vaccinia virus in vivo [see 14 CLINICAL STUDIES ] . In addition, infusions of VIGIV of up to 24,000 Units per kg were well tolerated [see 6.1 Clinical Trials Experience ].

12.3 Pharmacokinetics A double-blind study was conducted in which 60 healthy subjects were randomized to receive either 6000 Units per kg or 9000 Units per kg VIGIV. After intravenous administration of 6000 Units per kg to 31 healthy subjects, a mean peak plasma concentration of 161 Units per mL was achieved within two hours. The half-life of VIGIV was 30 days (range of 13 to 67 days) and the volume of distribution was 6630 mL. Pharmacokinetic parameters were calculated based on antibody levels determined by an ELISA. The levels of vaccinia immune globulin remained in circulation for a prolonged period of time, with a mean half-life ranging from approximately 26 to 30 days. Maximum plasma concentrations (C max ) of VIGIV reached levels ranging from approximately 160 to 232 Units per mL in 1.8 to 2.6 hours. In addition, the drug had a large volume of distribution, as demonstrated by both non-compartmental and compartmental analyses. Non-compartmental analyses demonstrated that at the two dose levels studied, the drug exhibited dose-proportionality (AUC and C max values) ( Table 3 ). The pharmacokinetic parameters estimated by compartmental analysis were similar to those calculated by non-compartmental methods. Table 3 Non-compartmental Pharmacokinetic Parameters (mean (±SD)) of VIGIV VIGIV (6000 U/kg or 9000 U/kg) from Measured Data Arithmetic Mean (±SD) Parameter 6000 U/kg 9000 U/kg AUC 0 - ∞ (U*h/mL) 58521 (16079) 78401 (17502) AUC 0-t (U*h/mL) 49405 (13246) 71541 (13173) C MAX (U/mL) 161 (40.0) 232 (40.9) T MAX (h) 1.84 (1.12) 2.61 (2.41) T ½ (days) 30.0 (10.0) 26.2 (5.08) The plasma concentration of circulating VIGIV was also compared to a theoretical value obtained from a model of previously licensed Baxter Vaccinia Immune Globulin (VIG) product at Day 5 after IV administration of VIGIV. Since Baxter VIG was administered intramuscularly (IM) and VIGIV is administered IV, the comparison was made at approximately five days to account for equilibration between the extravascular and intravascular compartments following IM injection. The binding capacity and neutralizing antibody activity of anti-vaccinia antibody in these subjects five days after intravenous administration of VIGIV (both 6000 Units per kg and 9000 Units per kg dosages) were at least as high as the theoretical values that would be achieved following the intramuscular administration of the comparator VIG (see Table 4 ). Five days represents the approximate time of peak serum anti-vaccinia antibody concentration following intramuscular administration of other Immune Globulin (Human) products. No historical pharmacokinetic data are available for the theoretical intramuscular comparator VIG. Table 4 Test of Non-inferiority Dose VIGIV (U/kg) Plasma Levels, U/mL (Range Geometric mean (range) ) Ratio of Means % (97.5% Lower Confidence Interval Bound) Expressed as a percentage relative to the geometric mean of the simulated concentrations at Day 5 after 6000 U/kg intramuscular administration VIGIV Observed levels VIGIM Simulated levels 6000 60.1 (36.1–84.6) 66.2 (42.3–94.9) 90.82 (86.94) 9000 90.3 (63.4–133.8) 64.8 (47.6–87.2) 139.40 (135.27)

20190517

6

3 DOSAGE FORMS AND STRENGTHS • Solution of gamma globulin (5% or 50 mg/mL) • 20 mL single-dose vial containing antibodies to vaccinia virus at ≥50,000 Units per vial Sterile solution available as 20 mL single-use vial containing a dose of ≥50,000 Units per vial ( 3 ).

CNJ-016 Vaccinia Immune Globulin (Human) MALTOSE, UNSPECIFIED FORM POLYSORBATE 80 HUMAN VACCINIA VIRUS IMMUNE GLOBULIN HUMAN VACCINIA VIRUS IMMUNE GLOBULIN

13.2 Animal Toxicology and/or Pharmacology The efficacy of VIGIV against vaccinia virus in a mouse-tail lesion model was assessed. A range of doses of VIGIV and a previously licensed VIG were compared for their ability to reduce pox formation in this model. Using this model, it was demonstrated that VIGIV exerted an in vivo protective effect against vaccinia infection when compared to a negative control. In addition, when using the mouse-tail lesion model with two different strains of vaccinia virus, it was observed that the protective effect of VIGIV appeared similar to that of the previously licensed VIG and a CBER reference standard. A single study in rabbits has demonstrated increased corneal scarring upon intramuscular vaccinia immune globulin administration in vaccinia keratitis ( 7 ). Since VIGIV is a product of human origin, secondary pharmacodynamics, safety pharmacology and pharmacodynamic drug interactions were not investigated in animals.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genotoxicity and fertility studies have not been conducted with VIGIV.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity, genotoxicity and fertility studies have not been conducted with VIGIV. 13.2 Animal Toxicology and/or Pharmacology The efficacy of VIGIV against vaccinia virus in a mouse-tail lesion model was assessed. A range of doses of VIGIV and a previously licensed VIG were compared for their ability to reduce pox formation in this model. Using this model, it was demonstrated that VIGIV exerted an in vivo protective effect against vaccinia infection when compared to a negative control. In addition, when using the mouse-tail lesion model with two different strains of vaccinia virus, it was observed that the protective effect of VIGIV appeared similar to that of the previously licensed VIG and a CBER reference standard. A single study in rabbits has demonstrated increased corneal scarring upon intramuscular vaccinia immune globulin administration in vaccinia keratitis ( 7 ). Since VIGIV is a product of human origin, secondary pharmacodynamics, safety pharmacology and pharmacodynamic drug interactions were not investigated in animals.

BLA125109

CNJ-016

Vaccinia Immune Globulin (Human)

60492-0173

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

Principal Display Panel - Carton Label C:\Users\garcian.EMERGENT\Desktop\Vig Carton label.png

DOSAGE AND ADMINISTRATION, Preparation ( 2.2 ) 11/2018 DOSAGE AND ADMINISTRATION, Administration ( 2.3 ) 11/2018 WARNINGS AND PRECAUTIONS, Thrombosis ( 5.4 ) 11/2018 WARNINGS AND PRECAUTIONS, Aseptic Meningitis Syndrome ( 5.6 ) 11/2018

Manufactured by: Emergent BioSolutions Canada Inc. 155 Innovation Drive Winnipeg, MB Canada R3T 5Y3

17 PATIENT COUNSELING INFORMATION Discuss the risks and benefits of VIGIV with the patient before prescribing or administration. • Inform patients of the potential for hypersensitivity reactions, especially in individuals with previous reactions to human immune globulin and in individuals deficient in IgA [see 4 CONTRAINDICATIONS and 5.1 Hypersensitivity ]. Advise patients to be aware of the following symptoms associated with allergic reactions: hives, rash, chest tightness, wheezing, shortness of breath, or feeling light headed or dizzy when they stand. Caution patients to seek medical attention immediately should they experience any one or more of the above mentioned symptoms, as well as other side effects including injection site pain, chills, fever, headache, nausea, vomiting, and joint pain. • Advise patients that the maltose contained in VIGIV can interfere with some types of blood glucose monitoring systems. Patients must use testing systems that are glucose-specific for monitoring blood glucose levels as the interference of maltose could result in falsely elevated glucose readings, which could lead to untreated hypoglycemia or to inappropriate insulin administration, resulting in life-threatening hypoglycemia [see 5.2 Interference with Blood Glucose Testing ]. • Advise patients that VIGIV may impair the effectiveness of certain live virus vaccines such as measles, rubella (i.e. German measles), mumps, and varicella (i.e. chickenpox). Patients recently vaccinated must notify their treating physician [see 7.1 Live, Attenuated Vaccines ]. • Inform patients that VIGIV is prepared 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 during manufacturing. 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 [see 5.9 Transmission of Infectious Agents from Human Plasma ]

14 CLINICAL STUDIES The pharmacokinetic, pharmacodynamic and safety profiles of VIGIV were evaluated in three clinical trials. In these clinical studies, VIGIV was shown to have an acceptable safety profile when administered as single infusions of 6000 Units per kg, 9000 Units per kg or 24,000 Units per kg to healthy subjects. For the safety/pharmacokinetics study, see 12.3 Pharmacokinetics . 14.1 Pharmacodynamic Effect of VIGIV on Immune and Local Responses to Dryvax In a randomized, single center, double-blind study with three parallel treatment arms, the efficacy of 9000 Units per kg of VIGIV on the immunologic and local response to the smallpox vaccine Dryvax was evaluated. Thirty-two healthy female and male subjects were randomized to receive single IV infusions of either VIGIV (9000 Units per kg) or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either Placebo or VIGIV (9000 Units per kg) concurrently with vaccinia (Dryvax) vaccination on Day 4. In this study, the curves for antibody titre vs. time were similar between administration of VIGIV four days prior to vaccination with Dryvax and concurrent administration of VIGIV with Dryvax. Based on area under the effective time curve from Day 4 to 32 (AUEC4-32) results, the administration of VIGIV four days prior to vaccination with Dryvax slightly reduced the pox reaction and erythema area by 4 to 9% and 8 to 12%, respectively, as compared to the concurrent administration of VIGIV with the Dryvax vaccine, or with Dryvax alone. In an additional randomized, single center, double-blind, study with five parallel treatment arms, the efficacy of two different doses of VIGIV (9000 Units per kg and 24,000 Units per kg) on the immunologic and local response to Dryvax was evaluated. Fifty healthy subjects were randomized to receive a single IV infusion of either VIGIV (9000 Units per kg), VIGIV (24,000 Units per kg), or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either placebo or vaccinia (Dryvax) vaccination on Day 4. The administration of VIGIV four days prior to vaccinia vaccination decreased the endogenous immune response to Dryvax in a dose-dependent manner. In addition, the mean pox reaction and erythema area diameters were smaller in size when 24,000 Units per kg of VIGIV was administered prior to vaccination with Dryvax compared to those when 9000 Units per kg of VIGIV was administered prior to vaccination with Dryvax or to those from administration of Dryvax alone. These data are consistent with the hypothesis of vaccinia virus neutralization in vivo by VIGIV.

15 REFERENCES 1. Kahwaji J et al., Acute Hemolysis after High-Dose Intravenous Immunoglobulin Therapy in Highly HLA Sensitized Patients. Clin J Am Soc Nephrol. 2009 December 4;1993–97. 2. Daw Z, Padmore R, Neurath D, et al. Hemolytic transfusion reactions after administration of intravenous immune (gamma) globulin: A case series analysis. Transfusion 2008;48:1598-601. 3. Bowman JM, Friesen AD, Pollock JM, Taylor WE. WinRho: Rh immune globulin prepared by ion exchange for intravenous use. Canadian Med Assoc J. 1980;123:1121-5. 4. Friesen AD, Bowman JM, Price HW. Column ion-exchange preparation and characterization of an Rh immune globulin (WinRho) for intravenous use. Journal Appl Biochem. 1981;3:164-75. 5. Horowitz B. Investigations into the application of tri(n-butyl)phosphate/detergent mixtures to blood derivatives. Curr Stud Hematol Blood Transfus. 1989;56:83-96. 6. Burnouf T. Value of virus filtration as method for improving the safety of plasma products. Vox Sang. 1996;70:235-6. 7. Fulginiti VA, Winograd LA, Jackson M, Ellis P. Therapy of experimental vaccinal keratitis: Effect of idoxuridine and VIG. Arch Ophthal. 1965;74:539-44.

8.5 Geriatric Use Safety and effectiveness in the geriatric population (>65 yrs of age) has not been established for VIGIV.

8.4 Pediatric Use Safety and effectiveness in the pediatric population (<16 yrs of age) has not been established for VIGIV.

8.1 Pregnancy Risk Summary There are no data on the use of VIGIV in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted with VIGIV.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no data on the use of VIGIV in pregnant women to inform on drug-associated risk. Animal reproduction studies have not been conducted with VIGIV. 8.2 Lactation Risk Summary There are no data to assess the presence or absence of VIGIV in human milk, the effects on the breastfed child or the effects on milk production/excretion. 8.4 Pediatric Use Safety and effectiveness in the pediatric population (<16 yrs of age) has not been established for VIGIV. 8.5 Geriatric Use Safety and effectiveness in the geriatric population (>65 yrs of age) has not been established for VIGIV.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NDC 60492-0173-1 The product is supplied as a 20 mL single dose vial containing ≥50,000 Units per vial. It is packaged in a shelf carton with 24 vials and four package inserts. VIGIV does not contain natural rubber latex. 16.2 Storage and Handling Product may be stored frozen at or below 5°F (≤-15°C) or refrigerated at 36 to 46°F (2 to 8°C); refer to label for appropriate storage conditions. Do not use after expiration date. If product is received frozen, use within 60 days of thawing at 2 to 8°C. Begin intravenous infusion within 4 hours after entering the vial. Do not reuse or save VIGIV for future use. This product contains no preservative; therefore, discard partially used vials.

WARNING: INTERACTIONS WITH GLUCOSE MONITORING SYSTEMS Blood glucose measurement in patients receiving VIGIV must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose contained in VIGIV. Glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase method (monitor and test strips) must not be used for blood glucose testing in patients receiving VIGIV, since maltose in IGIV products has been shown to give falsely high blood glucose levels in these testing systems. This could result in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Carefully review the product information of the blood glucose testing system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products [see 5.3 Blood Glucose Monitoring ]. WARNING: INTERACTIONS WITH GLUCOSE MONITORING SYSTEMS See full prescribing information for complete boxed warning Blood glucose measurement in patients receiving VIGIV (vaccinia immune globulin intravenous, human) must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose contained in VIGIV. Maltose in IGIV products may give falsely high blood glucose levels in certain types of blood glucose testing systems (for example those based on the GDH-PQQ or glucose-dye-oxidoreductase methods) resulting in inappropriate administration of insulin and life-threatening hypoglycemia. Cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings.