Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? is a pasteurized, polyvalent human normal immunoglobulin for subcutaneous infusion. Vivaglobin^Ã? is manufactured from large pools of human plasma by cold alcohol fractionation and is not chemically altered or enzymatically degraded.

Vivaglobin^Ã? is supplied as a sterile liquid to be administered by the subcutaneous route. Vivaglobin^Ã? is a 16% (160 mg/mL) protein solution, with a content of at least 96% immunoglobulin G (IgG). The distribution of IgG subclasses is similar to that present in normal human plasma. Vivaglobin^Ã? contains 2.25% glycine, 0.3% sodium chloride, and water for injection, U.S.P. The pH of Vivaglobin^Ã? is 6.4 to 7.2. Vivaglobin^Ã? contains no preservative.

All plasma used in the manufacture of Vivaglobin^Ã? is tested using FDA-licensed serological assays for hepatitis B surface antigen and antibodies to hepatitis C virus (HCV) and human immunodeficiency virus types 1 and 2 (HIV-1/2) as well as FDA-licensed Nucleic Acid Testing (NAT) for HCV and HIV-1 and found to be nonreactive (negative). For hepatitis B virus (HBV), an investigational NAT procedure is used and the plasma found to be negative. However, the significance of a negative result has not been established. In addition, the plasma has been tested by NAT for hepatitis A virus (HAV) and parvovirus B19 (B19). Only plasma that passed virus-screening is used for production and the limit for B19 in the fractionation pool is set not to exceed 10⁴ IU of B19 DNA per mL.

The manufacturing procedure for Vivaglobin^Ã? includes multiple processing steps that reduce the risk of virus transmission. The virus reduction capacity of two steps was evaluated in a series of in vitro spiking experiments; the steps were ethanol - fatty alcohol / pH precipitation and pasteurization in aqueous solution at 60° C for 10 hours. Total mean cumulative virus reductions ranged from 9.0 to ≥ 14.1 log₁₀ as shown in Table 1.

Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? is indicated for the treatment of patients with primary immune deficiency (PID).

Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? contains no preservative. Therefore, discard unused product immediately after use.

Vivaglobin^Ã? must not be mixed with other products.

Vivaglobin^Ã? is to be injected subcutaneously, preferentially in the abdomen, thighs, upper arms, and/or lateral hip.

All subjects who received Vivaglobin^Ã? in the clinical trials had previously been treated with immune globulin. It is recommended that the patient start treatment with Vivaglobin^Ã? one week after receiving a regularly scheduled IGIV infusion.

The initial weekly Vivaglobin^Ã? dose can be calculated by multiplying the previous IGIV dose by 1.37, then dividing this dose into weekly doses based on the patientsevious IGIV treatment interval; for example, if IGIV was administered every three weeks, divide by 3. This dose of Vivaglobin^Ã? will provide a systemic IgG exposure (AUC) comparable to that of the previous

IGIV treatment. Weekly administration of this dose will lead to stable steady-state serum IgG levels with lower IgG peak levels and higher IgG trough levels compared to monthly IGIV treatment (see Table 2 for trough levels).

The recommended weekly dose of Vivaglobin^Ã? is 100 to 200 mg/kg body weight administered subcutaneously. Doses may be adjusted over time to achieve the desired clinical response and serum IgG levels. As there can be differences in the half-life of IgG among patients with primary immune deficiencies, the dose and dosing interval of immunoglobulin therapy may vary.

The minimum serum concentration of IgG necessary for protection against infections has not been established in randomized and controlled clinical studies. However, based on clinical experience, a target serum IgG trough level (i.e., prior to the next infusion) of at least 500 mg/dL has been proposed in the literature for IGIV therapy.⁴

Serum IgG levels can be sampled at any time during routine weekly treatment. Subjects on Vivaglobin^Ã? therapy maintained relatively constant IgG levels, rather than the peak and trough pattern observed with monthly IGIV therapy.

In the clinical study with Vivaglobin^Ã?, a volume of 15 mL per injection site at a rate of 20 mL per hour per site was not exceeded. Doses over 15 mL were divided and infused into several sites using an infusion pump. Multiple simultaneous injections were enabled by administration tubing and Y-site connection tubing (CADD-Legacy^Ã? pumps were used in the study conducted in the US and Canada). Injection sites were at least two inches apart.

The following areas were used for subcutaneous injection of Vivaglobin^Ã?: abdomen, thighs, upper arms, and/or lateral hip. The actual point of injection was changed with each weekly administration.

Prior to use, allow the solution to reach ambient room temperature. Vivaglobin^Ã? should be inspected visually for discoloration and particulate matter prior to administration. DO NOT SHAKE. The appearance of Vivaglobin^Ã? can vary from colorless to light brown. Do not use if the solution is cloudy or has particulates. Check the product expiration date on the vial. Do not use beyond the expiration date.

1. Use aseptic technique when preparing and administering Vivaglobin^Ã? for injection.

2. Remove the protective cap from the vial to expose the central portion of the rubber stopper.

3. Wipe the rubber stopper with alcohol and allow to dry.

4. Using a sterile syringe and needle, prepare to withdraw Vivaglobin^Ã? by first injecting air into the vial that is equivalent to the amount of Vivaglobin^Ã? to be withdrawn. Then withdraw the desired volume of Vivaglobin^Ã?. If multiple vials are required to achieve the desired dose, repeat this step. (Fig. 2)

5. Follow the manufacturers illing the pump reservoir and preparing the pump,instructions administration tubing and Y-site connection tubing, if needed. Be sure to prime the administration tubing to ensure that no air is left in the tubing or needle by filling the tubing/needle with Vivaglobin^Ã?.

6. Select the number and location of injection sites depending on the volume of the total dose. Note: In clinical studies with Vivaglobin^Ã?, a volume of 15 mL per injection site was not exceeded. (Fig. 3)

7. Cleanse the injection site(s) with antiseptic solution using a circular motion working from the center of the site and moving to the outside. Sites should be clean, dry, and at least two inches apart. (Fig. 4)

8. Grasp the skin between two fingers and insert the needle into the subcutaneous tissue. (Fig. 5)

9. Vivaglobin^Ã? must not be injected into a blood vessel. After each needle is inserted into the tissue, test to make sure that a blood vessel has not been accidentally accessed. This must be done prior to starting the infusion. To do this, attach a sterile syringe to the end of the primed administration tubing, gently pull back on the syringe plunger and look to see if any blood is flowing back into the administration tubing. If you see any blood, remove and discard the needle and administration tubing. Repeat priming and needle insertion steps using a new needle, administration tubing and a new infusion site. Secure the needle in place by applying sterile gauze or transparent dressing over the site. (Fig. 6)

10. If using multiple, simultaneous injection sites, use Y-site connection tubing and secure to the administration tubing.

11. Infuse Vivaglobin^Ã? following the manufacturersructions for the pump. (Fig. 7)

12. Remove the peel-off label with the product lot number and expiration date from the Vivaglobin^Ã? vial and use this to complete the patient record.

After administration, discard any unused solution and administration equipment in accordance with biohazard procedures.

If the physician believes that home administration is appropriate, the physician or health professional should provide the patient with instructions on subcutaneous infusion for home treatment. This should include the type of equipment to be used along with its maintenance, proper infusion techniques, selection of appropriate infusion sites (e.g., abdomen, thighs, upper arms, and/or lateral hip), maintenance of a treatment diary, and measures to be taken in case of adverse reactions.

Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? is supplied in single-use vials containing 160 mg IgG per mL. The following dosage forms are available:

STORAGE

Store in the refrigerator at 2 - 8°C (36 - 46° F). Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? is stable for the period indicated by the expiration date on its label. Do not freeze. Keep vials in storage box until use.

REFERENCES

4. Roifmann CM, Levison H, Gelfand EW. High-dose versus low-dose intravenous immunoglobulin in hypogammaglobuli-naemia and chronic lung disease. Lancet 1987;1(8451):1075-7.

In clinical studies, administration of Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? has been shown to be safe and well tolerated in both adult and pediatric subjects. Reactions similar to those reported with administration of other immune globulin products may also occur with Vivaglobin^Ã?. Rarely, immediate anaphylactoid and hypersensitivity reactions may occur. In exceptional cases, sensitization to IgA may result in an anaphylactic reaction (see CONTRAINDICATIONS).

Should evidence of an acute hypersensitivity reaction be observed, the infusion should be stopped promptly, and appropriate treatment and supportive therapy should be administered.

In the US and Canada clinical study, the safety of Vivaglobin^� was evaluated for 15 months (3­month wash-in/wash-out period followed by 12-month efficacy period) in 65 subjects with PID. The most frequent adverse reaction was local reaction at the injection site. Table 5 summarizes the most frequent adverse events by subject reported in the clinical study, and Table 6 summarizes the most frequent adverse events by infusion.

Table 7 summarizes the most frequent related adverse events by subject reported in the clinical study, and Table 8 summarizes the most frequent related adverse events by infusion.

In the non-IND Europe and Brazil clinical study, the safety of Vivaglobin^Ã? was evaluated for 10 months in 60 subjects with PID. The adverse events and their rates reported in this study were similar to those reported in the US and Canada study, with two notable exceptions for the related adverse events. These events were 59 episodes of headache (1.6%) and 2 episodes of fever (0.1%) in the US and Canada study and no episodes of headache and 18 episodes of fever (0.8%) in the Europe and Brazil study.

Local injection site reactions consisting of mostly mild or moderate swelling, redness and itching, have been observed with the use of Vivaglobin^Ã?. No serious local site reactions were observed. The majority of injection site reactions resolved within four days. Additionally, the number of subjects reporting local injection site reactions decreased substantially after repeated use (see Figure 1). Only three subjects in the US and Canada study and one subject in the Europe and Brazil study discontinued due to local site reactions.

Immunoglobulin administration can transiently impair the efficacy of live attenuated virus vaccines such as measles, mumps and rubella. The immunizing physician should be informed of recent therapy with Immune Globulin Subcutaneous (Human), Vivaglobin^Ã?, so that appropriate precautions can be taken.

Vivaglobin^Ã? should not be mixed with other medicinal products.

Patients who receive immune globulin therapy for the first time, who are switched from another brand of immune globulin, or who have not received immune globulin therapy within the preceding eight weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting. On rare occasions, these reactions may lead to shock. Such patients should be monitored for these reactions in a clinical setting during the initial administration of Immune Globulin Subcutaneous (Human), Vivaglobin^Ã?.

If anaphylactic or anaphylactoid reactions are suspected, discontinue administration immediately. Treat any acute anaphylactoid reactions as medically appropriate.

Vivaglobin^Ã? is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, that can cause disease. Because Vivaglobin^Ã? is made from human blood, it may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the CJD agent. The risk that such plasma-derived 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 manufacture (see DESCRIPTION section for virus reduction measures). Stringent procedures utilized at plasma collection centers, plasma-testing laboratories and fractionation facilities are designed to reduce the risk of virus transmission. The primary virus reduction steps of the Vivaglobin^Ã? manufacturing process are pasteurization (heat treatment of the aqueous solution at 60° C for 10 hours) and ethanol - fatty alcohol / pH precipitation. Additional purification procedures used in the manufacture of Vivaglobin^Ã? also potentially provide virus reduction. Despite these measures, such products may still potentially contain human pathogenic agents, including those not yet known or identified. Thus, the risk of transmission of infectious agents cannot be totally eliminated. Any infections thought by a physician to have been possibly transmitted by this product should be reported by the physician or other healthcare provider to ZLB Behring at 800-504-5434 (in the US and Canada). The physician should discuss the risks and benefits of this product with the patient.

During clinical trials, no cases of infection due to hepatitis A, B, or C virus, parvovirus B19, or HIV were reported with the use of Vivaglobin^Ã?.

Administer Immune Globulin Subcutaneous (Human), Vivaglobin^Ã?, subcutaneously. Do not administer this product intravenously. The recommended infusion rate and amount per injection site stated under DOSAGE AND ADMINISTRATION should be followed. When initiating therapy with Vivaglobin^Ã?, patients should be monitored for any adverse events during and after the infusion.

After injection of immunoglobulins, the transitory rise of the various passively transferred antibodies in the patients results, with the potential for misleading interpretation. Passive transmission of antibodies to erythrocyte antigens, e.g., A, B, D may cause a positive direct or indirect antiglobulin test.

Animal reproduction studies have not been conducted with Immune Globulin Subcutaneous (Human), Vivaglobin^Ã?. It is also not known whether Vivaglobin^Ã? can cause fetal harm when administered to a pregnant woman, or can affect reproduction capacity. Vivaglobin^Ã? should be given to a pregnant woman only if clearly needed.

Vivaglobin^Ã? was evaluated in 6 children and 4 adolescents in the US and Canada study and in 16 children and 6 adolescents in the non-IND study. There were no apparent differences in the safety and efficacy profiles as compared to adult subjects. No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. The safety and efficacy of Vivaglobin^Ã? was not studied in pediatric subjects under two years of age.

The clinical study of Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.

No information provided.

As with all immune globulin products, Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A (IgA) deficiency (serum IgA <0.05 g/L) who have known antibody against IgA.

Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents.

Vivaglobin^Ã? is to be administered by injection into the subcutaneous tissue. Subcutaneous administration of immune globulin decreases bioavailability compared to intravenous administration.¹ The bioavailability of Vivaglobin^Ã? is approximately 73% compared to IGIV. Various factors, such as the site of administration and IgG catabolism, can affect absorption.^1,2 With Vivaglobin^Ã? administration, peak serum IgG levels are lower than those achieved with immune globulin intravenous (IGIV). Subcutaneous administration results in relatively stable steady-state serum IgG levels when administered on a weekly basis.^2,3 This serum IgG profile is representative of that seen in a normal population.

The pharmacokinetics (PK) of Vivaglobin^Ã? was evaluated in the PK phase of a pivotal 12-month clinical study conducted in the United States and Canada in subjects with primary immune deficiency (PID) (see CLINICAL STUDIES). Subjects who were previously treated with IGIV were switched over to weekly Vivaglobin^Ã? subcutaneous treatment and, after a 3-month wash-in/wash-out period, doses were individually adjusted to provide an IgG systemic exposure (area under the curve; AUC) that was not inferior to the AUC of the previous weekly-equivalent IGIV dose. For the 19 per-protocol subjects completing the wash-in/wash-out period, the average Vivaglobin^Ã? dose adjustment was 137% (range: 103 to 192%) of the previous weekly-equivalent IGIV dose. Following 10 to 12 weeks of treatment with Vivaglobin^Ã? at this adjusted dose, the final steady-state AUC determinations were made. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Vivaglobin^Ã? versus IGIV treatment was 94.5% (range: 71.4 to 110.1%) with a lower 95% confidence limit of 89.8% for the per-protocol population (n = 17). Table 2 summarizes additional pharmacokinetic parameters for this study including dosing and serum IgG peak and trough levels following treatment with IGIV and Vivaglobin^Ã?.

A non-IND 6-month clinical study was conducted in Europe and Brazil in 60 subjects with PID. After the subjects had reached steady state with weekly Vivaglobin^Ã? administration, peak serum IgG levels were observed after a mean of 2.5 days (range 0 to 7 days) in 41 subjects.

In contrast to serum IgG levels observed with monthly IGIV treatment (rapid peaks followed by a slow decline), the serum IgG levels in subjects receiving weekly subcutaneous Vivaglobin^Ã?therapy were relatively stable in both studies.

The pivotal open-label, prospective, multicenter clinical study conducted in the United States and Canada evaluated the pharmacokinetics, efficacy, safety and tolerability of Immune Globulin Subcutaneous (Human), Vivaglobin^Ã? in adult and pediatric subjects with primary immune deficiency (PID). In this study, 65 adult and pediatric PID subjects previously treated monthly with IGIV were switched to weekly subcutaneous administrations of Vivaglobin^Ã? for 12 months. The per-protocol efficacy analysis included 51 subjects. Subjects received a weekly mean Vivaglobin^Ã? dose of 158 mg/kg body weight (range: 34 to 352 mg/kg), which was 136% (range: 99 to 188%) of their previous weekly-equivalent IGIV dose.

The annual rate of serious bacterial infections (defined as bacterial pneumonia, meningitis, sepsis, osteomyelitis, and visceral abscesses), the primary endpoint, was 0.04 infections per subject per year (one-sided upper 99% confidence interval: 0.14) for the per-protocol set (n = 51). Pneumonia was reported in two subjects. The annual rate of any infections, a secondary endpoint, was 4.4 infections per subject per year.

The IgG subclass levels observed in this study were consistent with a physiologic distribution pattern (mean values) IgG₁: 703 mg/dL, IgG₂: 278 mg/dL, IgG₃: 36 mg/dL, and IgG₄: 30 mg/dL.

Table 3 summarizes the dosing and annual rate of infections for the efficacy phase of this study.

Table 4 provides a summary of missed school or work and hospitalization due to infection, which were secondary endpoints.

In a non-IND clinical study of Vivaglobin^Ã? conducted in Europe and Brazil, 60 adult and pediatric subjects with PID were switched to weekly subcutaneous administration of Vivaglobin^Ã? for six months. Forty-nine (49) subjects had been on IGIV and 11 subjects had been treated long-term with another brand of Immune Globulin Subcutaneous (Human) replacement therapy before entering the study. The forty-seven (47) per-protocol subjects received a weekly mean Vivaglobin^Ã? dose of 89 mg/kg body weight (range: 51 to 147 mg/kg), which was 101% (range: 81 to 146%) of their previous immune globulin treatment. The annualized rates of serious bacterial infections (0.04 infections/subject year, one-sided upper 99% confidence interval: 0.21) and any infections (4.3 infections/subject year) were similar to those reported in the study conducted in the US and Canada.

1. Smith GN, Griffiths B, Mollison D, Mollison PL. Uptake of IgG after intramuscular and subcutaneous injection. Lancet 1972;1:1208-12.

2. Waniewski I, Gardulf A, Hammarström L. Bioavailability of g -Globulin after subcutaneous infusions in patients with common variable immunodeficiency. J Clin Immunol 1994;14(2):90-7.

3. Data on file.

No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.