CNJ-016: Package Insert and Label Information

CNJ-016- human vaccinia virus immune globulin injection
Emergent BioSolutions Canada Inc.

WARNING: INTERACTIONS WITH GLUCOSE MONITORING SYSTEMS

Blood glucose measurement in patients receiving VIGIV must be done with a glucose-specific method (monitor and test strips) to avoid interference by maltose contained in VIGIV. Glucose dehydrogenase pyrroloquinolinequinone (GDH-PQQ) or glucose-dye-oxidoreductase method (monitor and test strips) must not be used for blood glucose testing in patients receiving VIGIV, since maltose in IGIV products has been shown to give falsely high blood glucose levels in these testing systems. This could result in the inappropriate administration of insulin, resulting in life-threatening hypoglycemia. Cases of true hypoglycemia may go untreated if the hypoglycemic state is masked by falsely elevated glucose readings.

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 [see 5.3 Blood Glucose Monitoring ].

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.

2 DOSAGE AND ADMINISTRATION

For intravenous use only.

2.1 Dosage for Treatment of Severe Complications of Vaccinia Vaccination

Administer VIGIV at a dose of 6000 Units per kg, as soon as symptoms appear and are judged to be due to severe vaccinia-related complication. Consider repeat dosing, depending on the severity of the symptoms and response to treatment; however, clinical data on repeat doses are lacking. Consider higher doses (e.g. 9000 Units per kg) if the patient does not respond to the initial 6000 Units per kg dose. Doses up to 24,000 Units per kg administered to healthy volunteers were well tolerated in clinical trials [see 14 CLINICAL STUDIES].

2.2 Preparation

Bring VIGIV vials to room temperature prior to dosing.
If frozen, thaw vial by placing in a refrigerator at 36 to 46°F (2 to 8°C) until the contents are thawed for approximately 14 hours. Product can be thawed rapidly by placing at room temperature for one hour followed by a water bath at 98.6°F (37°C) until thawed.
Do not thaw this product in a microwave oven.
Do not refreeze the vial.
DO NOT SHAKE VIAL. SHAKING VIAL MAY CAUSE FOAMING.
Remove the entire contents of the vial to obtain the labeled dosage of VIGIV. If partial vials are required for the dosage calculation, withdraw the entire contents of the vial to ensure accurate calculation of the dosage requirement.
VIGIV is compatible with 0.9% Sodium Chloride USP. No other drug interactions or compatibilities have been evaluated. If a pre-existing catheter must be used, flush the line with 0.9% Sodium Chloride USP before use. VIGIV may be administered either undiluted or diluted no more than 1:2 (v/v).
VIGIV vial is for single use only. Do not reuse or save VIGIV for future use.
VIGIV contains no preservatives. Discard partially used vials.

2.3 Administration

Inspect the product prior to use and do not use if solution is cloudy, discolored or contains particulates.
Administer VIGIV intravenously through a dedicated intravenous line with the rate of infusion of no greater than 2 mL/min.
For patients weighing less than 50 kg, infuse the product at a rate no greater than 0.04 mL/kg/minute (133.3 Units per kg/minute).
Adverse drug reactions may be related to the rate of infusion. Slower infusion rate may be needed for patients who develop a minor adverse reaction (e.g. flushing) or for patients with risk factors for thrombosis/thromboembolism.
Closely monitor and carefully observe patients and their vital signs for any symptoms throughout the infusion period and immediately following an infusion.
For patients with pre-existing renal insufficiency, or at increased risk of acute kidney injury, thrombosis, or volume overload, do not exceed the recommended infusion rate and follow the infusion schedule closely.
For patients with risk factors for thrombosis, the maximum daily dose of VIGIV should not exceed 12,000 Units per kg [see 5.4 Thrombosis]

3 DOSAGE FORMS AND STRENGTHS

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

4 CONTRAINDICATIONS

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).

5 WARNINGS AND PRECAUTIONS

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. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis up to several thousand cells per cubic millimeter, predominately from the granulocytic series, and with elevated protein levels up to several hundred mg/dL, but negative culture results. Conduct a thorough neurological examination in patients exhibiting such symptoms and signs, including CSF studies, to rule out other causes of meningitis.

AMS may occur more frequently in association with high total doses (2 g/kg) of IGIV treatment. For VIGIV, at the recommended dosage of 6000 Units per kg, a patient may be exposed to up to 0.18 g/kg protein after VIGIV administration.

5.7 Transfusion-related Acute Lung Injury (TRALI)

Noncardiogenic pulmonary edema may occur in patients administered IGIV. TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever and typically occurs within one to six hours after transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.

Monitor VIGIV recipients for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient serum.

5.8 Transmissible Infectious Agents

Because this product is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, the variant Creutzfeldt‐Jakob disease (vCJD) agent and, theoretically, the Creutzfeldt‐Jakob disease (CJD) agent.

All infections thought to have been possibly transmitted by this product should be reported by the physician or other health care provider to Emergent BioSolutions Canada Inc. at 1 800-768-2304.

5.9 Monitoring: Laboratory Tests

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 BUN and serum creatinine, before the initial infusion of VIGIV and at appropriate intervals thereafter.
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.
If signs and/or symptoms of hemolysis are present after an infusion of VIGIV, perform appropriate laboratory testing for confirmation.
If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient’s serum.

6 ADVERSE REACTIONS

The adverse reactions to VIGIV treatment in clinical trials (>10%) include headache, nausea, rigors and dizziness.

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.
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.

SYSTEM ORGAN CLASS

PREFERRED TERM

VIGIV (%)

PLACEBO N=32 (%)

6000 U/kg N=31

9000 U/kg § N=39

9000 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)

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.

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