Vaccinia Immune Globulin Intravenous (Human)

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 )

• 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 ).

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 )

• 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 system, including that of the test strips, to determine if the system is appropriate for use with maltose-containing parenteral products. If any uncertainty exists, contact the manufacturer of the testing system to determine if the system is appropriate for use with maltose-containing parenteral products.

5.4 Thrombosis Thrombotic events may occur in association with IGIV treatment. Patients at risk include those with a history of cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, history of arterial or venous thrombosis, estrogen use, indwelling central vascular catheters, and/or known or suspected hyperviscosity. Weigh the potential risks and benefits of VIGIV against those of alternative therapies for all patients for whom VIGIV administration is being considered. Because of the potentially increased risk of thrombosis, 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. In patients where the benefits of VIGIV administration out-weigh the potential risks of thrombotic and thromboembolic events, administer VIGIV at the minimum concentration available and at the minimum rate of infusion 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. While there are currently no prospective data in patients with thrombosis/thromboembolism to identify a maximum safe dose, concentration, and/or rate of infusion for VIGIV, the maximum daily dose of VIGIV should not exceed 12,000 Units per kg in patients with thrombotic risk factors.

5.5 Hemolysis VIGIV may contain blood group antibodies which may act as hemolysins and induce in vivo coating of red blood cells with immune globulin, causing a positive direct antiglobulin reaction and hemolysis. Acute hemolysis, consistent with intravascular hemolysis, has been reported and hemolytic anemia can develop subsequent to IGIV therapy due to enhanced red blood cell sequestration. The following risk factors may be associated with the development of hemolysis following Immune Globulin Intravenous (Human) (IGIV) products: high doses, given either as a single administration or divided over several days, and non-O blood group ( 1 ). 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 ( 2 ), but their role is uncertain. Closely monitor VIGIV recipients 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 approximately 36 to 96 hours post infusion. If signs and/or symptoms of hemolysis or a significant drop in hemoglobin or hematocrit have been observed after VIGIV infusion, perform additional confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving VIGIV, perform adequate cross-matching to avoid exacerbating on-going hemolysis.

5.6 Aseptic Meningitis Syndrome (AMS) AMS may occur in association with IGIV administration. AMS usually begins within several hours to two days following IGIV treatment. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae. AMS is characterized by the following symptoms and signs: severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. […]

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

• 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.

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.

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