Cnj-016

Name: CNJ-016

Indications

CNJ-016® [Vaccinia Immune Globulin Intravenous (Human)] (VIGIV) 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, varicellazoster, 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.

Exercise caution when using VIGIV in the treatment of patients having complication due to vaccinia vaccination that include concomitant vaccinia keratitis, since a single study in rabbits has demonstrated increased corneal scarring upon intramuscular vaccinia immune globulin administration in vaccinia keratitis (1).

VIGIV is not considered to be effective in the treatment of postvaccinial encephalitis.

Side effects

Drug exposure to date has primarily been evaluated in healthy volunteers. The most common adverse reactions to VIGIV treatment (>10%) include headache, nausea, rigors and dizziness in clinical trials involving VIGIV. Although there were no serious adverse events reported in VIGIV clinical trials, there has been a post-marketing case of severe vaccinia infection that developed intravascular hemolysis, leukopenia and thrombocytopenia during VIGIV treatment.

Clinical Trials Experience

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

In a safety/pharmacokinetics study, 60 healthy male and female volunteers received a single intravenous dose of either 6,000 Units per kg or 9,000 Units per kg VIGIV. The population consisted of vaccinia vaccination-naive 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 (9,000 Units per kg) 4 days prior to vaccinia vaccination (n=10), or VIGIV (9,000 Units per kg) concurrent with vaccinia vaccination (n=12). The population consisted of vaccinia vaccination-naive 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 9,000 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-naive 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%)

SYSTEM ORGAN CLASS PREFERRED TERM CNJ-016 (%) PLACEBO†
N=32 (%)
6,000 U/kg‡
N=31
9,000 U/kg§
N=39
9,000 U/kg¶
N=20
24,000 U/kg¶
N=20
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) 0 (0.0)
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)
* Adverse events that occurred during or within 3 days of VIGIV or placebo administration.
† 0.9% NaCl infused at 2 mL/min.
‡ Infusion rate: 4 mL/min; subjects were fasted.
§ Infusion rate: 4 mL/min or 2 mL/min; subjects were fasted.
¶ Infusion rate: 2 mL/min; subjects were not fasted.

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 9,000 Units per kg dosage group experienced syncope.

There was a lower incidence of adverse reactions when VIGIV (9,000 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.

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. This is also the case with literature reports authored independently.

There has been a case of severe vaccinia infection that developed intravascular hemolysis, leukopenia and thrombocytopenia while receiving VIGIV. However, the hemolysis did not reoccur with continued VIGIV dosing.

The following is a list of adverse reactions that have been identified and reported during the postapproval use of other IGIV products:

  • Infusion reactions: Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
  • Renal: Acute renal dysfunction/failure, osmotic nephropathy
  • Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
  • Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
  • Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
  • Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
  • Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test
  • Gastrointestinal: Hepatic dysfunction, abdominal pain
  • General/Body as a Whole: Pyrexia, rigors

Overdose

No Information Provided

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 Clinical Studies]. In addition, infusions of VIGIV of up to 24,000 Units per kg were well 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. tolerated [see 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 (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 doseproportionality (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 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
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 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,

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)
*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

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 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 (AUEC4-32) 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.

Side effects

Drug exposure to date has primarily been evaluated in healthy volunteers. The most common adverse reactions to VIGIV treatment (>10%) include headache, nausea, rigors and dizziness in clinical trials involving VIGIV. Although there were no serious adverse events reported in VIGIV clinical trials, there has been a post-marketing case of severe vaccinia infection that developed intravascular hemolysis, leukopenia and thrombocytopenia during VIGIV treatment.

Clinical Trials Experience

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug.

In a safety/pharmacokinetics study, 60 healthy male and female volunteers received a single intravenous dose of either 6,000 Units per kg or 9,000 Units per kg VIGIV. The population consisted of vaccinia vaccination-naive 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 (9,000 Units per kg) 4 days prior to vaccinia vaccination (n=10), or VIGIV (9,000 Units per kg) concurrent with vaccinia vaccination (n=12). The population consisted of vaccinia vaccination-naive 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 9,000 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-naive 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%)

SYSTEM ORGAN CLASS PREFERRED TERM CNJ-016 (%) PLACEBO†
N=32 (%)
6,000 U/kg‡
N=31
9,000 U/kg§
N=39
9,000 U/kg¶
N=20
24,000 U/kg¶
N=20
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) 0 (0.0)
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)
* Adverse events that occurred during or within 3 days of VIGIV or placebo administration.
† 0.9% NaCl infused at 2 mL/min.
‡ Infusion rate: 4 mL/min; subjects were fasted.
§ Infusion rate: 4 mL/min or 2 mL/min; subjects were fasted.
¶ Infusion rate: 2 mL/min; subjects were not fasted.

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 9,000 Units per kg dosage group experienced syncope.

There was a lower incidence of adverse reactions when VIGIV (9,000 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.

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. This is also the case with literature reports authored independently.

There has been a case of severe vaccinia infection that developed intravascular hemolysis, leukopenia and thrombocytopenia while receiving VIGIV. However, the hemolysis did not reoccur with continued VIGIV dosing.

The following is a list of adverse reactions that have been identified and reported during the postapproval use of other IGIV products:

  • Infusion reactions: Hypersensitivity (e.g., anaphylaxis), headache, diarrhea, tachycardia, fever, fatigue, dizziness, malaise, chills, flushing, urticaria or other skin reactions, wheezing or other chest discomfort, nausea, vomiting, rigors, back pain, myalgia, arthralgia, and changes in blood pressure
  • Renal: Acute renal dysfunction/failure, osmotic nephropathy
  • Respiratory: Apnea, Acute Respiratory Distress Syndrome (ARDS), TRALI, cyanosis, hypoxemia, pulmonary edema, dyspnea, bronchospasm
  • Cardiovascular: Cardiac arrest, thromboembolism, vascular collapse, hypotension
  • Neurological: Coma, loss of consciousness, seizures, tremor, aseptic meningitis syndrome
  • Integumentary: Stevens-Johnson syndrome, epidermolysis, erythema multiforme, dermatitis (e.g., bullous dermatitis)
  • Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs’) test
  • Gastrointestinal: Hepatic dysfunction, abdominal pain
  • General/Body as a Whole: Pyrexia, rigors

Read the entire FDA prescribing information for CNJ-016 (Vaccinia Immune Gobulin (Human) Injection )

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