2.1 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).

2.2 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.

2.3 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.

2.4 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).

1. Assemble supplies – Place the Vivaglobin vial(s) and all supplies needed for the infusion on a clean, flat surface.
2. Thoroughly wash and dry hands – The use of gloves when preparing and administering Vivaglobin is optional.
3. Clean the vial stopper – Remove the protective cap from the vial to expose the central portion of the rubber stopper. Clean the stopper with alcohol and allow it to dry.
4. Prepare and fill the syringe(s) – Using a sterile syringe and needle, pull back on the plunger to draw air into the syringe that is equal to the amount of Vivaglobin to be withdrawn. Then, insert the needle into the vial stopper and inject the air into the vial. Finally, withdraw the desired volume of Vivaglobin. If multiple vials are required to achieve the desired dose, repeat this step with another syringe.
5. Fill and prime the infusion pump – Follow the manufacturer's instructions for filling the pump reservoir and for preparing the pump, 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.
6. Select the injection site(s) – The number and location of injection sites depends on the volume of the total dose. Doses greater than 15 mL should be divided and infused into multiple sites that are at least two inches apart. The recommended number of simultaneous injection sites is up to six for adults, up to three for children who weigh less than 45 kg (99 pounds) and up to four for patients ages 65 and over. If necessary, additional injection sites can be used consecutively.
7. Clean the injection site(s) – Using an antiseptic solution, clean each site beginning at the center and working outward in a circular motion. Allow each site to dry before proceeding.
8. Insert the needle – Based on the patient's body mass, grasp or spread the skin; then insert the needle into the subcutaneous tissue.
9. Check for proper placement of the needle. Vivaglobin must not be injected into a blood vessel – After inserting each needle into the subcutaneous tissue and before starting the infusion, test to make sure that a blood vessel has not been accessed accidentally. To do this, attach a sterile syringe to the end of the primed administration tubing, gently pull back on the plunger, and see if any blood is flowing back into the tubing. If blood is present, remove and discard the needle and administration tubing. Repeat steps 5 and 8 (priming and needle insertion) using a new needle, new administration tubing, and a different injection site.
10. Secure the needle to the skin – Apply sterile gauze or transparent dressing over each site to hold the needle in place. If using multiple, simultaneous injection sites, secure the Y-site connection tubing to the administration tubing.
11. Infuse Vivaglobin – Follow the manufacturer's instructions to turn on the pump.
12. Record the infusion – Remove the peel-off portion of the label from each vial used, and affix it to the patient record.

After administration, immediately discard any unused product and administration equipment in accordance with local procedures.

5.1 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.

5.2 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.

5.3 Reactions Reported with IGIV Treatment

The following reactions have been reported to occur with IGIV treatment and may occur with IGSC treatment.

5.4 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]).

5.5 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.

6.1 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.

6.2 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.

7.1 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]).

7.2 Serological Testing

Various passively transferred antibodies in immunoglobulin preparations may lead to misinterpretation of the results of serological testing.

8.1 Pregnancy

8.3 Nursing Mothers

Vivaglobin has not been evaluated in nursing mothers.

8.4 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).

8.5 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).

12.1 Mechanism of Action

Vivaglobin supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents. The mechanism of action in PI has not been fully elucidated.

12.3 Pharmacokinetics

The bioavailability of Vivaglobin is approximately 73% compared with IGIV, but can vary significantly among patients (see Clinical Studies [14.1]). With Vivaglobin, peak serum IgG levels are lower than those achieved with IGIV. Subcutaneous administration results in relatively stable steady-state serum IgG levels when the product is dosed on a weekly basis.12-13

The pharmacokinetics (PK) of Vivaglobin were evaluated in the clinical study conducted in the US and Canada (see Clinical Studies [14.1]). Subjects previously treated with IGIV were switched to weekly subcutaneous treatment with Vivaglobin. After a 3-month wash-in/wash-out period, doses were adjusted individually aiming to provide an IgG systemic exposure (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 dose adjustment for Vivaglobin was 137% ± 21% SD (range: 103% to 192%) of the previous weekly-equivalent IGIV dose. Following 10 to 12 weeks of treatment with Vivaglobin at this individually adjusted dose, the final steady-state AUC determinations were made in 17 of the 19 per-protocol subjects. The geometric mean ratio of the steady-state AUCs, standardized to a weekly treatment period, for Vivaglobin versus IGIV treatment, was 94.5% (range: 71.4% to 110.1%) with a lower 95% confidence limit of 89.8% for the 17 subjects.

Table 7 summarizes additional pharmacokinetic parameters for this study including dosing and serum IgG peak and trough levels following treatment with IGIV and Vivaglobin.

The 6-month clinical study conducted in Europe and Brazil in 60 subjects with PI also included a PK evaluation. 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]). After the subjects had reached steady state with weekly administration of Vivaglobin, peak serum IgG levels were observed after a mean of 2.5 days (range: 0 to 7 days) in 41 subjects.

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

14.1 US-Canada Study

The open-label, prospective, multicenter clinical study conducted in the US and Canada evaluated the pharmacokinetics, efficacy, safety, and tolerability of Vivaglobin in 65 (51 per-protocol) adult and pediatric subjects with PI. Subjects previously receiving monthly treatment with IGIV were switched to weekly subcutaneous administration of Vivaglobin for 12 months, after a 3-month wash-in/wash-out period.

The study evaluated the annual rate of serious bacterial infections (defined as bacterial pneumonia, meningitis, sepsis, osteomyelitis, and visceral abscesses). The annual rate of any infections was also evaluated.

In this study, the volume of Vivaglobin infused (using administration tubing and an infusion pump) did not exceed 15 mL per injection site at a rate of 20 mL per hour per site. Doses greater than 15 mL were divided and infused into multiple sites using Y-site connection tubing. For recommendations on the number of simultaneous injection sites for pediatric patients weighing less than 45 kg (99 pounds), see Administration (2.4).

Table 8 summarizes the dosing and annual rate of infections for the 51 per-protocol subjects in efficacy phase of the US-Canada study.

Table 9 provides a summary of missed school or work and hospitalization due to infection, which were also evaluated in the efficacy phase of the study.

14.2 Europe-Brazil Study

In a clinical study of Vivaglobin conducted in Europe and Brazil, 60 adult and pediatric subjects with PI were switched to weekly subcutaneous administration of Vivaglobin for 6 months. Forty-nine (49) subjects had been on IGIV, and 11 subjects had been treated long-term with another IGSC before entering the study. The 47 per-protocol subjects received a weekly mean dose of 89 mg/kg body weight of Vivaglobin (range: 51 to 147 mg/kg), which was 101% (range: 81% to 146%) of their previous immune globulin treatment.

The annualized rate of serious bacterial infections was 0.04 infections per subject year (one-sided upper 99% confidence interval: 0.21). The annualized rate of any infections was 4.3 infections per subject year).

16.1 How Supplied

Vivaglobin is supplied in a single-use, tamper-evident vial containing 160 mg protein per mL of preservative-free liquid. Each vial label contains a peel-off strip with the vial size and product lot number for use in recording doses in a patient treatment record. The components used in the packaging for Vivaglobin are latex-free.

The following dosage forms are available:

16.2 Storage and Handling

Store in the refrigerator at 2–8°C (36–46°F). Vivaglobin is stable for the period indicated by the expiration date on its label. Do not freeze. Do not use product that has been frozen. Do not shake. Keep Vivaglobin in its original carton to protect it from light.

17.1 Self-Administration

If self-administration is appropriate, ensure that the patient receives instructions and training on subcutaneous administration in the home setting. This should include the type of equipment to be used and information on its maintenance, demonstration of proper infusion techniques, selection of appropriate infusion sites (e.g., abdomen, thigh, upper arm, and/or lateral hip), maintenance of a treatment diary/log book, and measures to be taken in case of adverse reactions.

Make sure your patients understand how important it is that they adhere to the weekly administration schedule for Vivaglobin in order to maintain the steady levels of IgG in their blood. It is recommended that patients keep their treatment diary/log book current by recording, after each infusion, the time, date, dose, and any reactions, and by removing the peel-off portion of the label (containing the lot number) from the product vial and placing it in the treatment diary/log book.

Tell your patients that mild to moderate local injection-site reactions (e.g., swelling, redness, and itching) are a common side effect of subcutaneous therapy, but to contact their healthcare professional if a local reaction lasts longer than 4 days or is severe. With subcutaneous infusions, it is important that the needle is long enough to reach the subcutaneous tissue and that the actual point of injection be changed with each infusion.

17.2 Additional Information for Patients

• Dose adjustments – Tell patients that they may be tested regularly to make sure they have the correct levels of Vivaglobin (IgG) in their blood. These tests may result in adjustments to their dose.
• Hypersensitivity reactions – Inform patients of the early signs of hypersensitivity reactions to Vivaglobin (including hives, generalized urticaria, tightness of the chest, wheezing, hypotension, and anaphylaxis). Advise them of appropriate actions to take in the event of a hypersensitivity reaction.
• Interference with vaccines – Inform patients that administration of immunoglobulin may interfere with the response to live virus vaccines (e.g., measles, mumps, rubella, and varicella) and to notify their immunizing physician of recent therapy with Vivaglobin.
• Aseptic meningitis syndrome (AMS) – Inform patients of the symptoms of AMS, including severe headache, neck stiffness, drowsiness, fever, sensitivity to light, painful eye movements, nausea, and vomiting.
• Reactions reported with IGIV treatment – Advise patients to be aware of and immediately report the following signs and symptoms to their healthcare professional:
  • Decreased urine output, sudden weight gain, fluid retention/edema, and/or shortness of breath, which may suggest kidney problems.
  • Shortness of breath, changes in mental status, chest pain, and other manifestations of thrombotic and embolic events.
  • Fatigue, increased heart rate, yellowing of the skin or eyes, and dark-colored urine, which may suggest hemolysis.
  • Severe breathing problems, lightheadedness, drops in blood pressure, and fever, which may suggest TRALI (a condition typically occurring within one to six hours following transfusion).
• Transmissible infectious agents – Inform patients that Vivaglobin is made from human plasma (part of the blood) and may contain infectious agents that can cause disease.

The attached Vivaglobin "Information for Patients" contains more detailed instructions for patients who will be self-administering Vivaglobin.

FDA-Approved Patient Labeling