For additional clinical information, contact Medical Affairs at 1-800-504-5434.
For additional reimbursement information or to order Vivaglobin®, contact the Vivaglobin® Resource Center at 1-877-VIVAGLOBIN (1-877-848-2456).
Clinical
How does subcutaneous (Sub-Q) infusion of Vivaglobin® work?
Vivaglobin
® is infused into the subcutaneous tissue using a portable infusion pump. The drug is infused into one or more sites, generally the abdomen, thighs, upper arms and hips. No more than 15 mL is recommended per each site. Once inside the tissue, the immunoglobulin G (IgG) diffuses or is absorbed slowly into the blood. With weekly administration, the IgG levels reach a stable, steady state. The subcutaneous administration serum profile is more representative of that of the normal population with less variation in immunoglobulin (Ig) trough levels once steady state is reached.
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Is Sub-Q administration of Ig a new practice?
No. In the 1950s, Bruton, Janeway and Gitlin pioneered the use of Ig therapy for treatment in some of the first patients diagnosed with primary immunodeficiency (PI), using both the intramuscular and subcutaneous routes. Intravenous administration ultimately became the standard, but subcutaneous infusion grew in popularity in Europe during the 1990s.
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Where can further clinical information about subcutaneous administration be accessed?
A compilation of peer-reviewed articles can be accessed
here.
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Product Description
What is Vivaglobin®?
Vivaglobin
® is a pasteurized, polyvalent human normal immunoglobulin for subcutaneous infusion supplied as a 16% sterile protein solution. Vivaglobin
® is manufactured from large pools of human plasma by cold alcohol fractionation and is not chemically altered or enzymatically degraded. Vivaglobin
® supplies a broad spectrum of opsonizing and neutralizing IgG antibodies against a wide variety of bacterial and viral agents.
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What is the FDA-approved indication for Vivaglobin®?
Vivaglobin
® is indicated for the treatment of patients with primary immunodeficiency (PI).
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What excipients are contained in Vivaglobin®?
Vivaglobin
® is supplied as a sterile liquid 16% (160 mg/mL) protein solution, with a content of at least 96% immunoglobulin G (IgG). Vivaglobin
® contains 2.25% glycine, 0.3% sodium chloride, and water for injection, USP. Vivaglobin
® contains no preservatives.
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What stabilizers are used in Vivaglobin®?
The stabilizer used in Vivaglobin
® is glycine. Glycine (alpha amnioacetic acid) is a nonessential amino acid normally present in the body. Glycine is used in intravenous nutritional supplements. It has been used as a stabilizer in several intravenous immunoglobulin products since 1992.
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Does Vivaglobin® contain preservatives?
There are no preservatives in Vivaglobin
®.
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Does Vivaglobin® contain mercury?
There is no mercury in Vivaglobin
®.
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Do the stoppers for Vivaglobin® contain latex?
There is no latex in Vivaglobin
® or its packaging.
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What is the normal color of Vivaglobin®?
Vivaglobin
® is a clear solution that can vary from colorless to light brown.
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What is the pH of Vivaglobin®?
The pH of Vivaglobin
® is 6.4 to 7.2.
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What is the IgG level in Vivaglobin®?
Vivaglobin
® is supplied as a sterile liquid 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.
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What is the concentration of Vivaglobin®?
It is a 16% (160 mg/mL) protein solution.
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Is Vivaglobin® as safe as IVIg?
Vivaglobin
® is prepared using the same rigorous donor selection and testing processes that are used in the manufacturing of IVIg. The manufacturing procedure for Vivaglobin
® includes multiple processing steps that reduce the risk of virus transmission. The virus reduction capacity of the two steps has been evaluated in a series of in vitro spiking experiments; the steps were alcohol/pH precipitation and pasteurization in aqueous solution at 60
o C for 10 hours.
As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.
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Are there any contraindications for Vivaglobin®?
As with all immune globulin products, Vivaglobin
® is contraindicated in individuals with a history of anaphylactic or severe systemic response to immune globulin preparations and in persons with selective immunoglobulin A deficiency who have known antibody against IgA. If anaphylactic or anaphylactoid reactions are suspected, discontinue administration immediately and treat as medically appropriate.
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Manufacturing Process/Safety
Where is the plasma for Vivaglobin® collected?
The plasma used for fractionation of Vivaglobin
® is currently obtained from FDA-licensed centers in the United States, which are also inspected regularly by CSL Behring.
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What specific tests are conducted on donor plasma?
All plasma used in the manufacturing of Vivaglobin
® is tested using FDA-licensed serological assays for hepatitis B surface antigen, antibodies to hepatitis C virus (HCV), human immunodeficiency virus type 1 (HIV-1), and Nucleic Acid Testing for HCV and HIV-1 and found to be nonreactive (negative).
As with all plasma-derived products, the risk of transmission of infectious agents, including viruses and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent, cannot be completely eliminated.
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What viral safety steps are used in manufacturing Vivaglobin®?
The manufacturing procedure of Vivaglobin
® includes established multiple processing steps that reduce the risk of virus transmission. These steps have been used in the manufacturing of intravenous immunoglobulins. The main virus reduction step of the Vivaglobin
® manufacturing process is a pasteurization technique, which involves heating the product at 60
o C for 10 hours. Vivaglobin
® also uses an additional alcohol/pH precipitation process to further reduce the risk of viral transmission. The total mean cumulative virus reductions ranged from 9.0 log
10 to 14.1 log
10. As with all products manufactured from human plasma, the risk of transmitting infectious agents cannot completely be eliminated. However, during clinical trials, no cases of hepatitis A, B, C virus, parvovirus B19 or HIV were reported with the use of Vivaglobin
®.
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Clinical Data
Efficacy
Is Vivaglobin® as effective as IVIg?
Vivaglobin
® was shown to be as effective as IVIg in two prospective studies, one in the US and Canada, the other a non-IND (investigational new drug) study in Europe and Brazil. The North American (NA) Phase 2/3 study was designed to include open-label, prospective, multicenter trials with 3 sites in Canada and 16 sites in the US. The pharmacokinetics (PK) were measured to compare the area under the curve (AUC) of IVIg with that of Vivaglobin
®. The subjects in the PK study were then assessed and doses adjusted. The primary endpoint of the study was to assess the efficacy via annual serious bacterial infections (SBIs); the secondary endpoints included annual infections and IgG trough levels. The treatment portion of the trial was a 12-week wash-in/wash-out phase followed by a
52 (+/- 2)-week efficacy phase.
The subjects received a mean weekly dose of 158 mg/kg during the efficacy phase of the NA study. Prior to the start of this study, there was a retrospective collection of IgG trough levels, which included 2 values within the last two months. If one of the values was >4.5 g/L and
<5 g/L, a retrospective collection of all IgG trough levels documented within the past 6 months was completed.
In the non-IND efficacy substudy 3002, the subjects underwent a similar start and treatment process as in the NA study. The subjects began Sub-Q Ig therapy one week after their last IVIg infusion, with a mean weekly dose of 89 mg/kg and entered a 3-month wash-in/wash-out period, followed a 6-month efficacy period.
Two SBIs were reported during the efficacy phase of the NA study and one in the non-IND EU study. In the NA study, the rate of SBIs per subject year was 0.04, and the annual rate for any infection was 4.4 per subject year.
The annualized rate of SBIs in the non-IND study was also 0.04 per subject year, with an annualized rate of any kind of infection of 4.3 per subject year.
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How can the therapeutic effectiveness of Vivaglobin® be assessed?
Patients on any immunoglobulin therapy for PI are assessed via frequency and severity of infections and monitoring of serum IgG trough levels. 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 (prior to the next infusion) of at least 500 mg/dL has been proposed in the literature for IVIg therapy. Doses may be adjusted over time to achieve the desired clinical response and serum IgG levels. Serum IgG levels can be sampled at any time during routine weekly treatment.
Selection of appropriate patients for subcutaneous administration is important to successful treatment. Specialty pharmacy providers and home healthcare providers should carefully monitor the patients for compliance and communicate regularly with the prescribing physician. Patients and their caregivers should be adequately trained, willing to administer the medication, and able to obtain adequate clinical support.
Identifying patients who are good candidates for Vivaglobin® therapy
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Tolerability
What are the possible side effects of Vivaglobin®?
In clinical studies, Vivaglobin
® has been shown to be safe and well tolerated in patients. As with any medication, side effects may accompany treatment. The frequency of side effects was based on a review of more than 5,900 infusions given during the clinical trials. The most frequently reported side effect was injection-site reaction, generally consisting of mild or moderate swelling, redness, and itching at the site of infusion. In clinical trials, these reactions tended to decrease substantially over time. Other side effects may include: headache, gastrointestinal disorder, fever, nausea, sore throat, rash, allergic reaction, increased cough, pain, and diarrhea.
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What are the warnings for Vivaglobin®?
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 8 weeks may be at risk for developing reactions including fever, chills, nausea, and vomiting. On rare occasions, these reactions may lead to shock. These patients should be monitored for these reactions in a clinical setting during the initial administration of Vivaglobin
®.
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How long will the injection-site irritation last?
In the clinical trials, the majority of injection-site reactions resolved within four days. The number of subjects reporting local injection-site reactions decreased substantially after repeated use. These local injection-site reactions consisted of mostly mild or moderate swelling, redness and itching.
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Administration/Patient Selection
What is the youngest patient to whom Vivaglobin® can be administered?
Vivaglobin
® has been approved by the FDA for use in adults and children ages 2 or older. In the Vivaglobin
® clinical trials, both males and females of at least 2 years of age, with a body weight of at least 10 kg and diagnosed with PI were included. Safety and efficacy of Vivaglobin
® have not been established in children younger than two years of age.
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Is there a specific pediatric dose of Vivaglobin®?
No pediatric-specific dose requirements were necessary to achieve the desired serum IgG levels. Dosing is based on body weight and adjusted according to clinical response and serum IgG levels.
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How long will the injection-site irritation last?
In the clinical trials, the majority of injection-site reactions resolved within four days. The number of subjects reporting local injection-site reactions decreased substantially after repeated use. These local injection-site reactions consisted of mostly mild or moderate swelling, redness and itching.
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Dosing
What is the recommended dosing for Vivaglobin®?
The recommended weekly dose of Vivaglobin
® is 100 mg/kg 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 immunodeficiency, the dose and dosing interval of immunoglobulin therapy may vary.
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How should a patient’s dosing be transitioned from IVIg to Sub-Q Ig?
It is recommended that the patient start treatment with Vivaglobin® one week after receiving a regularly scheduled IVIg infusion. The initial weekly Vivaglobin® dose can be calculated by multiplying the previous IVIg dose by 1.37, then dividing this dose into weekly doses based on the patient's previous IVIg treatment interval; for example, if IVIg was administered every three weeks, divide by 3. This dose of Vivaglobin® will provide a systemic IgG exposure (AUC) comparable to that of the previous IVIg treatment. Doses may be adjusted over time to achieve the desired clinical response and serum IgG levels.
As with all immune globulin (Ig) products, patients receiving Ig therapy for the first time, receiving a new product, or not having received Ig 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 in a clinical setting during the initial administration.
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What is the maximum amount of Vivaglobin® to be infused per site?
In the clinical study with Vivaglobin
®, a volume of 15 mL per infusion site was not exceeded. Doses over 15 mL were divided and infused into several sites using an infusion pump. Multiple simultaneous infusions were enabled by administration tubing and Y-site connection tubing.
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How frequently can Sub-Q Ig infusions be given?
Vivaglobin
® was administered on a weekly basis during the clinical trials. However, as there can be differences in the half-life of IgG among patients with primary immunodeficiency, the dose and dosing interval of immunoglobulin therapy may vary at the discretion of the prescriber. Serum IgG levels can be sampled at any time during routine weekly treatment.
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At how fast a rate can Vivaglobin® be infused?
Vivaglobin
® can be infused up to 20 mL per hour.
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Will premedication be necessary?
Premedication is sometimes used in administration of IVIg to reduce systemic adverse events. Subcutaneous dosing allows for a slow administration and gradual adsorption. This may prevent rapid large swings in serum IgG and the adverse events they may cause. Generally, there have been fewer reported systemic events with subcutaneous administration. No serious adverse events were reported during clinical trial. Stiehm reports using premedication in patients with prior anaphylactic reactions. It will be up to the clinician to determine whether premedication is needed on an individual basis.
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Lifestyle
How does Vivaglobin® affect patients’ lifestyles?
Intravenous immunoglobulin (IVIg) therapy makes regular demands on patients’ time—3.5 hours on average per infusion every 3 to 4 weeks. That’s time taken away from work or school, family life, and social activities.
Today, Ig therapy doesn’t have to slow patients down, interrupt their routines, or interfere with their busy lives. Patients don’t have to be tied to an IV pole. The portable pumps used with Vivaglobin® therapy allow greater freedom and flexibility.
With Vivaglobin® and proper training, your patients have control over their treatment schedule—for example, choosing to infuse weekly during a favorite prime time TV show rather than during an infusion clinic’s business hours. Because Vivaglobin® uses a small portable pump, it allows patients to infuse their Ig in the comfort of their home—or while traveling on business or vacation. In other words, self-administered Vivaglobin® gives patients greater freedom and flexibility, allowing them to infuse their treatment when and where they want it.
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Who can benefit from the Sub-Q way?
Patients who move to the Sub-Q way come from many walks of life, and no one patient group (ages 2 or older) can be excluded from consideration for Sub-Q Ig therapy. However, research studies and experience have identified patient characteristics that may indicate which patients may be most successful going beyond IV and moving to the Sub-Q way.
More than 2,500 US patients and/or their caregivers have been taught to self-administer Vivaglobin®.1 Many patients (or their caregivers) can easily learn to administer Sub-Q Ig therapy—often in just 4 to 6 training sessions.
Identifying patients who are good candidates for Vivaglobin®
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What do patients like about the Sub-Q way?
Several studies have reported on lifestyle and treatment satisfaction with Vivaglobin® subcutaneous (Sub-Q) Ig therapy in the management of primary immunodeficiency (PI).
In a multinational European study, Gardulf et al implemented a validated health-related quality of life (HRQOL) index in children and adults who moved from hospital IV therapy to home administration of Vivaglobin®. In both age groups, the sum score of the HRQOL index increased significantly from baseline to 10 months of home Sub-Q Ig therapy.
Similarly, in a prospective, North American study, Nicolay et al conducted a longitudinal study of adult patients with PI. The study investigated the impact of Sub-Q Vivaglobin® therapy on two groups of patients who moved from intravenous immunoglobulin (IVIg) therapy to the Sub-Q way:
- Group A: received IVIg at the hospital/clinic prior to initiating Sub-Q Ig therapy at home
- Group B: received IVIg at home prior to beginning Sub-Q Ig therapy at home
Results were as follows:
- 91% to 92% of patients preferred home therapy
- Vast majority of patients in both groups (81% of Group A ; 69% of Group B) preferred moving to the Sub-Q way
Greater freedom, enhanced independence, and scheduling flexibility were advantages reported by patients in these studies.
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Do steady-state IgG levels improve patient vitality?
Nicolay et al, Gardulf et al, and others have noted improvement in patient vitality on Sub-Q Ig therapy. It has been suggested that stable and consistently high serum IgG levels not only provide consistent protection against infection, but also might contribute to an enhanced energy level, particularly in patients who complain of fatigue prior to receiving their next IVIg infusion.
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Do weekly infusions of Vivaglobin® fit patients’ lifestyles?
Ensuring that patients understand how Sub-Q Ig therapy is administered may help to set realistic expectations and create greater success in initiating and sustaining Vivaglobin
® therapy. For example, visiting the Vivaglobin
® Web site or viewing the Vivaglobin
® patient DVD are two simple, yet effective, strategies for helping patients understand how Vivaglobin
® can fit their lifestyles.
This helps patients to be more prepared for training and potentially for self-administration. Many patients (or their caregivers) can easily learn to administer Sub-Q Ig therapy — often in just 4 to 6 training sessions.1-3
In a European study, Kittner et al identified characteristics of patients who were more likely to successfully move to the Sub-Q way. For example, patients who expressed high levels of anxiety and emotional lability were less likely to choose to go beyond IV. By contrast, patients who chose to move to the Sub-Q way tended to be more active, more independent, and/or preferred the flexibility of Sub-Q Ig therapy.4
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General/Other
What was the distribution of IgG subclasses during the clinical trial of Vivaglobin®?
The IgG subclass levels observed in the Vivaglobin
® 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.
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Can Vivaglobin® be mixed with other brands of immunoglobin?
It is not recommended that Vivaglobin
® be mixed with any other drugs including intravenous or intramuscular immunoglobulins. Source: 1. PI line 407
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Can Vivaglobin® be mixed with other medications?
Other products must not be mixed with the Vivaglobin
® solution.
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Will Vivaglobin® interfere with any other medication?
As with all immunoglobin products, Vivaglobin
® can impair the efficacy of certain virus vaccines, such as measles, mumps and rubella (also known by its abbreviation "MMR"). The immunizing physician should be informed of recent treatment with Vivaglobin
® so appropriate precautions can be taken.
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Will Vivaglobin® interfere with any lab tests?
After infusion of immunoglobulins, 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, D) may cause a positive direct or indirect antiglobulin (Coombs) test.
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Can Vivaglobin® be used in a lesser concentration?
Vivaglobin
® is concentrated to 16%. There is no data to support dilution of Vivaglobin
® to a lesser concentration.
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Can Vivaglobin® be used during pregnancy?
Vivaglobin
® falls under Category C. Animal reproduction studies have not been conducted with Immune Globulin Subcutaneous (Human), 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.
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References
- Bruton OC. Agammaglobulinemia. Pediatrics. 1952;9:722-728.
- Berger M. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin Immunol. 2004;112:1-7.
- Williams DA, Lemke TL. Foye’s Principles of Medicinal Chemistry. 5th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002.
- Ochs HD, Gupta S, Kiessling P, et al. Safety and efficacy of self-administered subcutaneous immunoglobulin in patients with primary immunodeficiency diseases. J Clin Immunol. 2006;26:265-273.
- Gardulf A, Nicolay U, Asensio O, et al. Rapid subcutaneous IgG replacement therapy is effective and safe in children and adults with primary immunodeficiencies—prospective, multi-national study. J Clin Immunol. 2006;26:177-185.
- Eijkhout, HW, van der Meer JW, Kallenberg CG, et al. The effect of two different dosages on the incidence of recurrent infections in patients with primary hypogammaglobulinemia; a randomized, double-blind, crossover multicenter trial. Ann Intern Med. 2001;135:165-174.
- Stiehm ER, Casillas AM, Finkelstein JZ, et al. Slow subcutaneous human intravenous immunoglobulin in the treatment of antibody immunodeficiency: use of an old method with a new product. J Allergy Clin Immunol. 1998:101:848-849.
- Gardulf A, Nicolay U, Math D, et al. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol. 2004;114:936-942.
- Nicolay U, Kiessling P, Berger M, et al. Health-related quality of life and treatment satisfaction in North American patients with primary immunedeficiency diseases receiving subcutaneous IgG self-infusions at home. J Clin Immunol. 2006;26:65-72.
- Kittner JM, Grimbacher B, Wulfe W, Jäger B, Schmidt RE. Patients’ attitude to subcutaneous immunoglobulin substitution as home therapy. J Clin Immunol. 2006;26:400-405.
- Data on file, CSL Behring 2006
- Treatment Experiences and Preferences of Patients With Primary Immune Deficiency: First National Survey. Immune Deficiency Foundation. June 20, 2003.
