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 )

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 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