CNJ-016

1 INDICATIONS AND USAGE VIGIV (vaccinia immune globulin intravenous, human) is indicated for the treatment and/or modification of the following conditions: • Eczema vaccinatum • Progressive vaccinia • Severe generalized vaccinia • Vaccinia infections in individuals who have skin conditions such as burns, impetigo, varicella-zoster, or poison ivy; or in individuals who have eczematous skin lesions because of either the activity or extensiveness of such lesions • Aberrant infections induced by vaccinia virus that include its accidental implantation in eyes (except in cases of isolated keratitis), mouth, or other areas where vaccinia infection would constitute a special hazard. VIGIV is not considered to be effective in the treatment of postvaccinial encephalitis. VIGIV is an Immune Globulin (Human), 5% Liquid, indicated for the treatment of complications due to vaccinia vaccination ( 1 ), including: • Eczema vaccinatum • Progressive vaccinia • Severe generalized vaccinia • Vaccinia infections in individuals who have skin conditions • Aberrant infections induced by vaccinia virus (except in cases of isolated keratitis) VIGIV is not indicated for postvaccinial encephalitis ( 1 )

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 2°C to 8°C (36°F to 46°F) 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 37°C (98.6°F ) 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 ].

5 WARNINGS AND PRECAUTIONS • Hypersensitivity to human immune globulin (acute anaphylaxis) ( 5.1 ) • Acute renal dysfunction/failure ( 5.2 ) • Thrombosis may occur with immune globulin products, including VIGIV. For patients at risk of thrombosis, administer VIGIV 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 ( 5.4 ) • Hemolysis or hemolytic anemia ( 5.5 ) • Aseptic meningitis syndrome (AMS) ( 5.6 ) • Noncardiogenic pulmonary edema [Transfusion-Related Acute Lung Injury (TRALI)] ( 5.7 ) • Transmission of infectious agents from human plasma ( 5.8 ) • Monitor renal function and urine output in patients at risk of renal failure; check baseline blood viscosity in patients at risk of hyperviscosity; and conduct confirmatory tests if hemolysis or TRALI is suspected ( 5.9 ) 5.1 Hypersensitivity Severe immediate hypersensitivity reactions to plasma-derived products may occur, for example, in patients with IgA deficiency or hypersensitivity to human globulin. Although acute systemic allergic reactions were not seen in clinical trials with VIGIV [see 6.1 Clinical Trials Experience ], administer the product only in a setting where appropriate equipment and personnel trained in the management of acute anaphylaxis are available. In case of hypotension, allergic or anaphylactic reaction, discontinue the administration of VIGIV immediately and give supportive care as needed. In case of shock, observe the current medical standards for shock treatment. 5.2 Acute Renal Dysfunction/Failure Renal dysfunction, acute renal failure, osmotic nephropathy, proximal tubular nephropathy, and death may occur upon use of immune globulin intravenous (Human) (IGIV) products. Use VIGIV with caution in patients with pre-existing renal insufficiency and in patients at risk of developing renal insufficiency (including, but not limited to those with diabetes mellitus, age greater than 65 years, volume depletion, paraproteinemia, sepsis, and patients receiving known nephrotoxic drugs), and administer VIGIV at the minimum rate of infusion practicable. In these cases, it is important to ensure that patients are not volume depleted before VIGIV infusion. Do not exceed the recommended infusion rate and follow the infusion schedule closely [see 2.3 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. Assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of VIGIV and at appropriate intervals thereafter. If renal function deteriorates, consider discontinuing VIGIV. Most cases of renal insufficiency following administration of IGIV have occurred in patients receiving total doses containing 400 mg/kg of sucrose or greater. VIGIV does not contain sucrose. No prospective data are currently available in patients with risk factors for renal insufficiency to identify a maximum safe dose, concentration, and/or rate of infusion for VIGIV. 5.3 Blood Glucose Monitoring Some types of blood glucose testing systems (for example those based on the glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase methods) could falsely interpret the maltose contained in VIGIV as glucose [see BOXED WARNING ]. This could result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Also, cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings. Accordingly, when administering VIGIV or other parenteral maltose-containing products, measure blood glucose with a glucose-specific method. Carefully review the product information of the blood glucose testing sys…

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 )

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 ].

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.

6 ADVERSE REACTIONS The adverse drug 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* During or Following VIGIV Administration (≥5%) *Adverse events that occurred during or within 3 days of VIGIV or placebo administration. a 0.9% NaCl infused at 2 mL/min. b Infusion rate: 4 mL/min; subjects were fasted. c Infusion rate: 4 mL/min or 2 mL/min; subjects were fasted. d Infusion rate: 2 mL/min; subjects were not fasted. SYSTEM ORGAN CLASS PREFERRED TERM VIGIV (%) 6000 U/kg b N=31 VIGIV (%) 9000 U/kg c N=39 VIGIV (%) 9000 U/kg d N=20 VIGIV (%) 24,000 U/kg d N=20 PLACEBO a N=32 (%) 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 Syste…