Vivaglobin is an Immune Globulin Subcutaneous (Human) (IGSC), 16% Liquid indicated as replacement therapy for primary humoral immunodeficiency (PI). This includes, but is not limited to, the primary immunodeficiency in common variable immunodeficiency (CVID), X-linked agammaglobulinemia, congenital agammaglobulinemia, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.
Vivaglobin Dosage and Administration
For subcutaneous infusion only. DO NOT INJECT INTO A BLOOD VESSEL.
Self-Administration
Self-administration is appropriate for some patients. If self-administration is planned, the healthcare professional should provide the patient with instructions and training for subcutaneous infusion in the home or other appropriate setting (see Patient Counseling Information [17.1] and the FDA-Approved Patient Labeling).
Preparation and Handling
Vivaglobin is a colorless to light brown solution. Do not use if the solution is cloudy (turbid) or contains particulates.
- Prior to administration, bring the Vivaglobin vial(s) to room temperature. Then, visually inspect each vial for particulate matter by gently swirling the vial, and check for discoloration by holding it up to the light.
- Check the product expiration date on the vial label. Do not use beyond the expiration date.
- Do not mix Vivaglobin with other products.
- Do not shake the Vivaglobin vial.
- Use aseptic technique when preparing and administering Vivaglobin.
- The Vivaglobin vial is for single-use only. Discard all administration equipment and any unused product immediately after each infusion in accordance with local requirements.
Dosage
The dose should be individualized based on the patient's clinical response to Vivaglobin therapy and serum immunoglobulin (IgG) trough levels.
Begin treatment with Vivaglobin one week after the patient has received a regularly scheduled Immune Globulin Intravenous (Human) (IGIV) infusion. Prior to receiving treatment with Vivaglobin, patients need to have been receiving IGIV treatment for at least 3 months at dosing intervals of either every 3 weeks or every 4 weeks.
The initial weekly dose of Vivaglobin is established by converting the monthly IGIV dose into a weekly equivalent and increasing it using a dose adjustment factor (see Initial Weekly Dose). The goal is to achieve a systemic serum IgG exposure (area under the concentration-time curve [AUC]) not inferior to the AUC of the previous IGIV treatment (see Pharmacokinetics [12.3]).
Prior to switching treatment from IGIV to Vivaglobin, obtain the patient's serum IgG trough level to guide subsequent dose adjustment (see Dose Adjustment). After 2 to 3 months, weekly administration of Vivaglobin will lead to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared with monthly IGIV treatment.
Initial Weekly Dose
To calculate the initial weekly dose of Vivaglobin, multiply the previous IGIV dose in grams (g) by the dose adjustment factor of 1.37, then divide this dose by the number of weeks between doses during the patient's previous IGIV treatment (i.e., 3 or 4).
| IGSC weekly dose (g) = | 1.37 × previous IGIV dose (g) |
| Number of weeks between IGIV doses |
To convert the Vivaglobin dose (g) to milliliters (mL), divide the dose in grams (g) by 0.16.
Dose Adjustment
Over time, the dose may need to be adjusted to achieve the desired clinical response and serum IgG trough level. To determine if a dose adjustment should be considered, measure the patient's serum IgG trough level on IGIV prior to switching to Vivaglobin and every 2 to 3 months after switching from IGIV to Vivaglobin.
To achieve the same AUC with Vivaglobin as with the previous IGIV treatment, follow these steps:
- Estimate the target serum IgG trough level on weekly Vivaglobin treatment, which is derived as follows:
Target concentration (mg/dL) during Vivaglobin treatment = the last trough level during prior IGIV treatment + 180 mg/dL - In Table 1, find the additional Vivaglobin dose to be administered, based on the patient's body weight, and the difference between the target IgG concentration (mg/dL) and the observed trough level during Vivaglobin treatment.
Additional dosage increments may be indicated based on the patient's clinical response (infection frequency and severity).
| Difference From Target IgG Trough Level* (mg/dL) | Body Weight (kg) | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 10 | 15 | 20 | 30 | 40 | 50 | 60 | 70 | 80 | 90 | 100 | 110 | 120 | |
| Dose Adjustment (mL per Week)† | |||||||||||||
| |||||||||||||
| 100 | 1 | 2 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| 150 | 2 | 2 | 3 | 5 | 6 | 8 | 9 | 11 | 12 | 14 | 15 | 17 | 18 |
| 200 | 2 | 3 | 4 | 6 | 8 | 10 | 12 | 14 | 16 | 18 | 20 | 23 | 25 |
| 250 | 3 | 4 | 5 | 8 | 10 | 13 | 15 | 18 | 20 | 23 | 26 | 28 | 31 |
| 300 | 3 | 5 | 6 | 9 | 12 | 15 | 18 | 22 | 25 | 28 | 31 | 34 | 37 |
| 350 | 4 | 5 | 7 | 11 | 14 | 18 | 22 | 25 | 29 | 32 | 36 | 39 | 43 |
| 400 | 4 | 6 | 8 | 12 | 16 | 20 | 25 | 29 | 33 | 37 | 41 | 45 | 49 |
| 450 | 5 | 7 | 9 | 14 | 18 | 23 | 28 | 32 | 37 | 41 | 46 | 51 | 55 |
| 500 | 5 | 8 | 10 | 15 | 20 | 26 | 31 | 36 | 41 | 46 | 51 | 56 | 61 |
For example, if a patient with a body weight of 70 kg has an actual IgG trough level of 900 mg/dL and the target trough level is 1000 mg/dL, this results in a difference of 100 mg/dL. Therefore, increase the weekly dose of Vivaglobin by 7 mL.
Monitor the patient's clinical response, and repeat the dose adjustment process as needed.
Administration
Vivaglobin is for subcutaneous infusion only. DO NOT INJECT INTO A BLOOD VESSEL.
Vivaglobin is for subcutaneous infusion, preferably in the abdomen, thigh, upper arm, and/or lateral hip. Multiple injection sites should be at least two inches apart, and the actual point of injection should be changed with each weekly administration.
- Infusion volume – Do not exceed 15 mL per site. Divide doses greater than 15 mL and infuse into a maximum of three simultaneous sites for children weighing less than 45 kg (99 pounds), a maximum of six simultaneous sites for adults up to age 65, and a maximum of four simultaneous sites for patients 65 years of age and older. If necessary, additional sites can be used consecutively during an infusion.
- Infusion rate – The maximum recommended infusion rate is 20 mL per hour per site and should not exceed a total of 3.0 mg/kg/minute (1.13 mL/kg/hour) for all simultaneous injection sites combined.
Ensure that patients are not volume depleted.
Follow the steps below and use aseptic technique to administer Vivaglobin. For information about subcutaneous infusion in the home or other appropriate setting, see Patient Counseling Information (17.1).
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After administration, immediately discard any unused product and administration equipment in accordance with local procedures.
Dosage Forms and Strengths
Vivaglobin is a solution containing 16% IgG (160 mg/mL) for subcutaneous infusion.
Contraindications
Vivaglobin is contraindicated in patients who have had an anaphylactic or severe systemic reaction to the administration of Immune Globulin (Human).
Vivaglobin is contraindicated in IgA-deficient patients with antibodies against IgA or a history of hypersensitivity (see Description [11]).
Warnings and Precautions
Hypersensitivity Reactions
Severe hypersensitivity reactions may occur (see Patient Counseling Information [17.2]). In case of hypersensitivity, discontinue the Vivaglobin infusion immediately and institute appropriate treatment. Epinephrine should be immediately available to treat any acute severe hypersensitivity reactions.
Individuals with IgA deficiency can develop anti-IgA antibodies and anaphylactic reactions (including anaphylaxis and shock) after administration of blood components containing IgA. Patients with known antibodies to IgA may have a greater risk of developing potentially severe hypersensitivity and anaphylactic reactions. Vivaglobin contains ≤1.7 mg/mL IgA (see Description [11]). The minimum concentration of IgA that will provoke a hypersensitivity reaction is not known; therefore all IgG preparations carry the risk of inducing an anaphylactic reaction to IgA.
Aseptic Meningitis Syndrome (AMS)
AMS has been reported to occur infrequently with IGIV treatment5 and with Vivaglobin treatment. The syndrome usually begins within several hours to 2 days following IGIV treatment. AMS is characterized by signs and symptoms including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, nausea, and vomiting. Cerebrospinal fluid (CSF) studies frequently show pleocytosis up to several thousand cells per cubic millimeter, predominantly from the granulocytic series, and with elevated protein levels up to several hundred mg/dL. AMS may occur more frequently in association with high doses (2 g/kg) and/or rapid infusion of IGIV.
Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. Discontinuation of IGIV treatment has resulted in remission of AMS within several days without sequelae.
Reactions Reported with IGIV Treatment
The following reactions have been reported to occur with IGIV treatment and may occur with IGSC treatment.
Renal Dysfunction/Failure
Renal dysfunction/failure, osmotic nephropathy, and death may occur with use of human immune globulin products. Ensure that patients are not volume depleted and assess renal function, including measurement of blood urea nitrogen (BUN) and serum creatinine, before the initial infusion of Vivaglobin and at appropriate intervals thereafter.
Periodic monitoring of renal function and urine output is particularly important in patients judged to have a potential increased risk of developing acute renal failure.1 If renal function deteriorates, consider discontinuing Vivaglobin. For patients judged to be at risk of developing renal dysfunction because of pre-existing renal insufficiency or predisposition to acute renal failure (such as those with diabetes mellitus or hypovolemia, those who are overweight or use concomitant nephrotoxic medicinal products, or those who are over 65 years of age), administer Vivaglobin at the minimum rate practicable.
Thrombotic Events
Thrombotic events may occur with use of human immune globulin products.2-4 Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, hypercoagulable disorders, prolonged periods of immobilization, and/or known or suspected hyperviscosity. 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. For patients judged to be at risk of developing thrombotic events, administer Vivaglobin at the minimum rate practicable.
Hemolysis
Vivaglobin may contain blood group antibodies that may act as hemolysins and induce in vivo coating of red blood cells (RBCs) with immunoglobulin, causing a positive direct antiglobulin (Coombs') test result and hemolysis.6-8 Delayed hemolytic anemia can develop subsequent to immune globulin therapy due to enhanced RBC sequestration, and acute hemolysis, consistent with intravascular hemolysis, has been reported.9
Monitor recipients of Vivaglobin for clinical signs and symptoms of hemolysis. If these are present after Vivaglobin infusion, perform appropriate confirmatory laboratory testing. If transfusion is indicated for patients who develop hemolysis with clinically compromising anemia after receiving Vivaglobin, perform adequate cross-matching to avoid exacerbating on-going hemolysis.
Transfusion-Related Acute Lung Injury (TRALI)
Noncardiogenic pulmonary edema may occur in patients administered human immune globulin products.10 TRALI is characterized by severe respiratory distress, pulmonary edema, hypoxemia, normal left ventricular function, and fever. Typically, it occurs within 1 to 6 hours following transfusion. Patients with TRALI may be managed using oxygen therapy with adequate ventilatory support.
Monitor recipients of Vivaglobin for pulmonary adverse reactions. If TRALI is suspected, perform appropriate tests for the presence of anti-neutrophil antibodies in both the product and patient's serum.
Transmissible Infectious Agents
Because Vivaglobin is made from human plasma, it may carry a risk of transmitting infectious agents, e.g., viruses and, theoretically, the Creutzfeldt-Jakob (CJD) agent. No cases of transmission of viral diseases or CJD have been associated with the use of Vivaglobin. Report all infections thought possibly to have been transmitted by Vivaglobin to the CSL Behring Pharmacovigilance Department at 1-866-915-6958 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The physician should discuss the risks and benefits of this product with the patient before prescribing or administering it to the patient (see Patient Counseling Information [17.2]).
Laboratory Tests
After infusion of IgG, the transitory rise of the various passively transferred antibodies in the patient's blood may yield positive serological testing results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens (e.g., A, B, and D) may cause a positive direct or indirect antiglobulin (Coombs') test.
Adverse Reactions
The most common adverse reactions (those AEs considered by the investigator to be at least possibly related to Vivaglobin administration) observed in ≥5% of study subjects receiving Vivaglobin were local injection-site reactions (swelling, redness, and itching), headache, nausea, rash, asthenia, and gastrointestinal disorder.
Clinical Studies Experience
Because clinical studies 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.
US-Canada Study
The safety of Vivaglobin was evaluated in a clinical study in the US and Canada for 12 months in 65 subjects with PI who had been previously treated with IGIV every 3 or 4 weeks (see Clinical Studies [14.1]). After 3 months, subjects were switched from IGIV to weekly subcutaneous administration of Vivaglobin for 12 months. Subjects were treated weekly with Vivaglobin at a mean dose of 158 mg/kg body weight (range: 34 to 352 mg/kg). The 65 subjects received a total of 3,656 infusions of Vivaglobin.
Table 2 shows the number of subjects who withdrew from the US-Canada study due to adverse events (AEs) and the AEs leading to discontinuation.
| AEs | Subjects with AEs At Least Possibly Related | Subjects with AEs Irrespective of Causality | Total Number (%) of Subjects |
|---|---|---|---|
| |||
| Subjects with at least 1 AE leading to discontinuation | 4 | 1 | 5 (8%) |
| Injection-site reaction | 3 | – | 3 (5%) |
| Intestinal obstruction | – | 1 | 1 (2%) |
| Hyperventilation | 1* | – | 1 (2%) |
| Tachycardia | 1* | – | 1 (2%) |
Table 3 summarizes the most frequent AEs (experienced by more than 5% of subjects), irrespective of causality. It includes all AEs and those considered temporally associated with the Vivaglobin infusion, i.e., occurring during the infusion or within 72 hours after the end of the infusion.
| Table 3: Incidence of Subjects With Adverse Events (AEs)* (Experienced by >5% of Subjects) and Rate† per Infusion, Irrespective of Causality, in the US-Canada Study | ||||
|---|---|---|---|---|
| All AEs | AEs Occurring During or Within 72 Hours of Infusion | |||
| AEs* (>5% of Subjects) | Number (%) of Subjects (n=65) | Number (Rate†) of AEs per Infusion (n=3656) | Number (%) of Subjects (n=65) | Number (Rate†) of AEs per Infusion (n=3656) |
| ||||
| AEs at the injection site‡ | 60 (92%) | 1789 (0.49) | 60 (92%) | 1767 (0.4848) |
| Other AEs | ||||
| Headache | 31 (48%) | 159 (0.04) | 30 (46%) | 104 (0.033) |
| Gastrointestinal disorder | 24 (37%) | 35 (0.01) | 18 (28%) | 24 (0.007) |
| Fever | 16 (25%) | 28 (0.008) | 12 (8%) | 20 (0.005) |
| Nausea | 12 (18%) | 18 (0.005) | 11 (17%) | 15 (0.004) |
| Rash | 11 (17%) | 22 (0.006) | 10 (15%) | 16 (0.004) |
| Sore throat | 10 (15%) | 17 (0.005) | 8 (12%) | 11 (0.003) |
| Allergic reaction | 7 (11%) | 8 (0.002) | 5 (8%) | 5 (0.001) |
| Pain | 6 (9%) | 8 (0.002) | 4 (6%) | 4 (0.001) |
| Diarrhea | 6 (9%) | 6 (0.002) | 5 (8%) | 5 (0.001) |
| Cough increased | 6 (9%) | 6 (0.002) | 5 (8%) | 5 (0.001) |
| Gastrointestinal pain | 5 (8%) | 6 (0.002) | 4 (6%) | 5 (0.001) |
| Migraine | 5 (8%) | 5 (0.001) | 2 (3%) | 2 (0.001) |
| Skin disorder | 5 (8%) | 7 (0.002) | 3 (5%) | 5 (0.001) |
| Asthma | 5 (8%) | 8 (0.002) | 3 (5%) | 4 (0.001) |
| Arthralgia | 4 (6%) | 4 (0.001) | 3 (5%) | 3 (0.001) |
| Asthenia | 4 (6%) | 4 (0.001) | 2 (3%) | 2 (0.001) |
| Malaise | 4 (6%) | 5 (0.001) | 2 (3%) | 2 (0.001) |
The total number of AEs, irrespective of causality, including injection-site reactions, that began during or within 72 hours after the end of an infusion was 2262 (a rate of 0.62 AEs per infusion); excluding injection-site reactions, the rate of AEs per infusion was 0.14.
Table 4 summarizes the severity of local AEs by infusion, irrespective of causality.
| Table 4: Severity of Local Adverse Events (AEs) by Infusion, Irrespective of Causality, in the US-Canada Study | ||
|---|---|---|
| AEs | Number (Rate*) of AEs | Number (Rate*) of AEs Occurring During or Within 72 Hours of Infusion |
| (Number of infusions: 3656) | ||
| ||
| AEs at the injection site | 1789 (0.49) | 1767 (0.48) |
| Mild† | 1112 (0.30) | 1100 (0.30) |
| Moderate‡ | 601 (0.16) | 593 (0.16) |
| Severe§ | 65 (0.02) | 64 (0.02) |
| Unknown severity | 11 (<0.01) | 10 (<0.01) |
| Discontinuations due to AEs at the injection site | 3 subjects | |
Of the three subjects who discontinued the study due to injection-site reactions, one withdrew on Day 1 (Infusion 1) of the wash-in/wash-out period after a moderate injection-site reaction and a mild headache; one withdrew on Day 22 (Infusion 4) of the wash-in/wash-out period following severe injection-site reactions for two weeks; and one withdrew on Day 78 following a mild injection-site reaction.
Local reactions decreased substantially after repeated use.
Table 5 summarizes the most frequent adverse reactions (experienced by at least 3% of subjects) and considered by the investigator to be at least possibly related to Vivaglobin administration.
| Related Adverse Reactions (≥3% Subjects) | Number (%) of Subjects (n=65) | Number (Rate*) of Adverse Reactions per Infusion (n=3656) |
|---|---|---|
| ||
| Adverse reactions at the injection site† | 60 (92%) | 1787 (0.49) |
| Other Adverse reactions | ||
| Headache | 21 (32%) | 59 (0.016) |
| Nausea | 7 (11%) | 9 (0.002) |
| Rash | 4 (6%) | 9 (0.002) |
| Asthenia | 3 (5%) | 3 (0.001) |
| Gastrointestinal disorder | 3 (5%) | 3 (0.001) |
| Fever | 2 (3%) | 2 (0.001) |
| Skin disorder | 2 (3%) | 3 (0.001) |
| Tachycardia | 2 (3%) | 2 (0.001) |
| Urine abnormality | 2 (3%) | 3 (0.001) |
Europe-Brazil Study
In a clinical study conducted in Europe and Brazil, the efficacy and safety of Vivaglobin were evaluated for 10 months in 60 subjects with PI. Subjects were treated weekly with Vivaglobin at a mean dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was 101% of their previous weekly IGIV or IGSC dose (see Clinical Studies [14.2]). Study subjects received a total of 2,297 infusions of Vivaglobin.
The AEs and their rates reported in this study were similar to those reported in the US-Canada study, with two exceptions: no episodes of headache were reported; and 18 (a rate of 0.008 per infusion) episodes of fever were judged to be related to the administration of Vivaglobin. One subject discontinued due to repeated local reactions of moderate severity.
Postmarketing Experience
Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions or establish a causal relationship to product exposure.
Vivaglobin
Adverse reactions identified during worldwide postmarketing use of Vivaglobin for treatment of PI are allergic-anaphylactic reactions (including dyspnea, pruritus, urticaria, rash, edema and other cutaneous reactions, wheezing, syncope, hypotension, and throat swelling), generalized reactions (including flu-like symptoms, myalgia, chills, fever, tachycardia, arthralgia, nausea and vomiting, diarrhea, gastrointestinal cramping, stomach pain, back pain, headache, headache possibly caused by increased blood pressure, and chest tightness), migraine, and injection-site reactions.
General
The following adverse reactions have been identified and reported during the postmarketing use of IGIV products11:
- 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, bullous dermatitis
- Hematologic: Pancytopenia, leukopenia, hemolysis, positive direct antiglobulin (Coombs') test
- General/Body as a Whole: Pyrexia, rigors
- Musculoskeletal: Back pain
- Gastrointestinal: Hepatic dysfunction, abdominal pain
Drug Interactions
Live Virus Vaccines
The passive transfer of antibodies with immunoglobulin administration may interfere with the response to live virus vaccines such as measles/mumps/rubella and varicella (see Patient Counseling Information [17.2]).
Serological Testing
Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.
USE IN SPECIFIC POPULATIONS
Pregnancy
Pregnancy Category C. Animal reproduction studies have not been conducted with Vivaglobin. It is also not known whether Vivaglobin can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Vivaglobin should be given to a pregnant woman only if clearly needed.
Nursing Mothers
Vivaglobin has not been evaluated in nursing mothers.
Pediatric Use
- In the US-Canada study, Vivaglobin was evaluated in 6 children (ages 5 through 11) and 4 adolescents (ages 13 through 16). In the Europe-Brazil study, Vivaglobin was evaluated in 16 children (ages 3 through 11) and 6 adolescents (ages 13 through 16).
- The safety and efficacy of Vivaglobin were not studied in pediatric subjects under 2 years of age.
- There were no differences in the safety and efficacy profiles as compared with adult subjects.
- No pediatric-specific dosing requirements were necessary to achieve the desired serum IgG levels.
- For recommendations on the number of simultaneous injection sites for pediatric patients who weigh less than 45 kg (99 pounds), see Administration (2.4).
Geriatric Use
The clinical studies of Vivaglobin did not include sufficient numbers of subjects 65 years of age and older to determine whether they respond differently from younger subjects. For recommendations on the number of simultaneous injection sites for geriatric patients, see Administration (2.4).
Vivaglobin Description
Vivaglobin is a sterile solution consisting of pasteurized, polyvalent immune globulin for subcutaneous administration. Vivaglobin is manufactured from large pools of human plasma by cold alcohol fractionation and is not chemicall
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