CNJ-016: Package Insert and Label Information (Page 2 of 3)

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

7 DRUG INTERACTIONS

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 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.

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 104 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 (Log10 ) Obtained through Validation Studies
*
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.

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*

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 (log10 )

≥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).

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 (Cmax ) 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 Cmax 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

AUC0 — ∞ (U*h/mL)

58521 (16079)

78401 (17502)

AUC0-t (U*h/mL)

49405 (13246)

71541 (13173)

CMAX (U/mL)

161 (40.0)

232 (40.9)

TMAX (h)

1.84 (1.12)

2.61 (2.41)

T½ (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
*
Geometric mean (range)
Expressed as a percentage relative to the geometric mean of the simulated concentrations at Day 5 after 6000 U/kg intramuscular administration
Observed levels
§
Simulated levels

Dose VIGIV (U/kg)

Plasma Levels, U/mL (Range * )

Ratio of Means % (97.5% Lower Confidence Interval Bound)

VIGIV

VIGIM §

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)

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