keen about [16:65 yrs of age) has not been established for VIGIV. Renal Insufficiency Use VIGIV with caution in patients with pre-existing renal insufficiency and in patients at increased risk of developing renal insufficiency [see 5.8 Acute Renal Dysfunction/Failure ]. CNJ-016 Injection 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 (, ). 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 ( 7 ). Virus filtration, using a Planova 20N virus filter, is effective for the removal of viruses based on their size, including some non-enveloped viruses ( 8 ). 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 * 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 (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 70 mg/mL total protein and 50,000 units of vaccinia antibody neutralizing activity. The product contains 40 mcg/mL of Immune globulin A (IgA). CNJ-016 Injection - Clinical Pharmacology Mechanism of Action VIGIV provides passive immunity for individuals with complications to vaccinia virus vaccination. The exact mechanism of action is not known. Pharmacodynamics Two phase 2, 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 9,000 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 (9,000 Units per kg) or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either Placebo or VIGIV (9,000 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 (9,000 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 (9,000 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 ]. Pharmacokinetics A phase 1, double-blind study was conducted in which 60 healthy subjects were randomized to receive either 6,000 Units per kg or 9,000 Units per kg VIGIV. After intravenous administration of 6,000 Units per kg to 31 healthy subjects, a mean peak plasma concentration of 161 Units per mL was achieved within 2 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 Vaccinia Immune Globulin Intravenous (Human) VIGIV (6,000 U/kg or 9,000 U/kg) from Measured Data Arithmetic Mean ( SD) Parameter 6,000 U/kg 9,000 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 (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 IM and VIGIV is to be 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 6,000 Units per kg and 9,000 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 6,000 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 6,000 60.1 (36.1 84.6) 66.2 (42.3 94.9) 90.82 (86.94) 9,000 90.3 (63.4 133.8) 64.8 (47.6 87.2) 139.40 (135.27) Nonclinical Toxicology Immune globulins are normal constituents of the human body. Toxicology studies have not been performed with VIGIV as the product has been formulated with ingredients that are known to be non-toxic at the levels present in the final product. 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. Since VIGIV is a product of human origin, secondary pharmacodynamics, safety pharmacology and pharmacodynamic drug interactions were not investigated in animals. 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 6,000 Units per kg, 9,000 Units per kg or 24,000 Units per kg to healthy subjects. For the phase 1 safety/pharmacokinetics study, see 12.3 Pharmacokinetics . Pharmacodynamic Effect of VIGIV on Immune and Local Responses to Dryvax In a phase 2, randomized, single center, double-blind study with three parallel treatment arms, the efficacy of 9,000 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 (9,000 Units per kg) or Placebo (0.9% Sodium Chloride Injection USP) on Day 0, and either Placebo or VIGIV (9,000 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 (AUEC 4-32 ) 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 phase 2, randomized, single center, double-blind, study with five parallel treatment arms, the efficacy of two different doses of VIGIV (9,000 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 (9,000 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 9,000 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. REFERENCES Fulginiti VA, Winograd LA, Jackson M, Ellis P. Therapy of experimental vaccinal keratitis: Effect of idoxuridine and VIG. Arch Ophthal. 1965;74:539-44. 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. 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. Bowman JM. Antenatal suppression of Rh alloimmunization. Clin Obst & Gynec. 1991;34:296-303. 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. 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. 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. Burnouf T. Value of virus filtration as method for improving the safety of plasma products. Vox Sang. 1996;70:235-6. How Supplied/Storage and Handling 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 a package insert. VIGIV does not contain latex. 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. Intravenous infusion should begin within 4 hours after entering the vial. Do not reuse or save VIGIV for future use. This product contains no preservative; therefore, partially used vials should be discarded. 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. Patients should be cautioned 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. They must use only testing systems that are glucose-specific for monitoring blood glucose levels as the interference of maltose could result in falsely elevated glucose readings. This 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). Should the patient have been recently vaccinated, they should 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 ]. Manufactured by: Cangene Corporation, a subsidiary of Emergent BioSolutions Inc. 155 Innovation Drive Winnipeg, MB Canada R3T 5Y3 Principal Display Panel - Carton Label Principal Display Panel - Vial Label CNJ-016 vaccinia immune globulin (human) injection Product Information Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC:60492-0173 Route of Administration INTRAVENOUS DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength HUMAN VACCINIA VIRUS IMMUNE GLOBULIN (HUMAN VACCINIA VIRUS IMMUNE GLOBULIN) HUMAN VACCINIA VIRUS IMMUNE GLOBULIN 1 [iU] in 1 mL Inactive Ingredients Ingredient Name Strength MALTOSE POLYSORBATE 80 Packaging # Item Code Package Description 1 NDC:60492-0173-2 24 VIAL, SINGLE-USE in 1 CARTON 1 NDC:60492-0173-1 12 mL in 1 VIAL, SINGLE-USE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date BLA BLA125109 05/02/2005 Labeler - Cangene Corporation (244844056) Revised: 03/2016 Cangene Corporation Next Interactions Print this page Add to My Med List More about CNJ-016 Injection (vaccinia immune globulin) Side Effects During Pregnancy Dosage Information Drug Interactions 0 Reviews Add your own review/rating]} FEATURED: CAR-T Cell Therapy Overview Mechanism of Action KTE-C19 Studies KTE-C19 Cancer Targets Adverse Events Manufacturing Drug Status Availability Discontinued C Pregnancy Category Risk cannot be ruled out Recently Approved Lonhala Magnair Lonhala Magnair (glycopyrrolate) is a long-acting muscarinic antagonist (LAMA) bronchodilator for... 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