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 Everything you want to know about Gamunex®.

Introduction

Efficacy

Tolerability

Safety

Reliability

Convenience

Trust

Introduction

  • What is Gamunex®?


    • Gamunex® is a ready-to-use 10% sterile solution of human immune globulin protein for intravenous administration.1
    • The Gamunex® advanced product features and composition are rooted in a new revolutionary caprylate/chromatography-based purification process.

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  • How does the Gamunex® manufacturing process compare to the Gamimune® N, 10% manufacturing process?


    • We have developed a revolutionary new purification process that is shorter, more efficient, and gentler to the fragile immunoglobulins. The new process is the advanced product profile platform for Gamunex®.
    • To improve supply reliability, Gamunex® is produced in a new, dedicated, fully automated, state-of-the-art manufacturing facility in Clayton, North Carolina.

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  • How does the Gamunex® product profile compare to that of Gamimune® N, 10%?


    • Gamunex® starts with the best of Gamimune® N, 10% and adds:
      • improved purity (reduced IgA, IgM, albumin)
      • improved composition (more balanced subclass distribution)
      • better maintenance of IgG protein integrity

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  • What important safety information do I need to know?


    • Gamunex® is contraindicated in individuals with known anaphylactic or severe systemic response to immune globulin (human). Individuals with severe, selective IgA deficiencies (serum IgA <0.05 g/L), who have known antibody against IgA (anti-IgA antibody) should only receive Gamunex® with cautionary measures. Adverse effects similar to those previously reported with administration of intravenous and intramuscular immunoglobulin products may occur.
    • Immune globulin intravenous (human) (IGIV) products have been reported to be associated with renal dysfunction, acute renal failure, osmotic nephrosis, and death. While these reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IGIV products, those containing sucrose as a stabilizer accounted for a disproportionate share of the total number. Gamunex® does not contain sucrose. Glycine, a natural amino acid, is used as a stabilizer.
    • There have been reports of noncardiogenic pulmonary edema, rare reports of hemolytic anemia, and very rare reports of aseptic meningitis in patients administered with IGIV. Thrombotic events have been reported in association with IGIV. Patients at risk may include those with a history of atherosclerosis, multiple cardiovascular risk factors, advanced age, impaired cardiac output, and/or known or suspected hyperviscosity. As with all plasma-derived therapeutics, the potential to transmit infectious agents cannot be totally eliminated.

    Please see full Prescribing Information including boxed WARNING.

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Efficacy


  • How do the Gamunex® clinical evidence findings compare with those of Gamimune® N, 10%?


    • Based on an unprecedented, randomized, double- blind, comparative, therapeutic-equivalence clinical trial program versus Gamimune® N, 10%, Gamunex® presents exceptional clinical proof of an IGIV product's efficacy and tolerability.
    • Gamunex® is at least as efficacious as Gamimune® N, 10%.
    • Gamunex® demonstrated a consistent trend (in part, statistically significant) of enhanced efficacy in both primary humoral immunodeficiency (PI) and idiopathic thrombocytopenic purpura (ITP).1

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  • What are the U.S. approved indications for Gamunex®?


    • Gamunex® is indicated as replacement therapy for PI states in which severe impairment of antibody-forming capacity has been shown, such as congenital agammaglobulinemia, common variable immunodeficiency, X-linked immunodeficiency with hyper IgM, Wiskott-Aldrich syndrome, and severe combined immunodeficiencies.1
    • Gamunex® is indicated in ITP to rapidly raise platelet counts to prevent bleeding or to allow a patient with ITP to undergo surgery.1

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  • What clinical trials were performed with Gamunex®?


    • We conducted the first licensure-relevant randomized, double-blind, controlled, statistically powered, head-to-head therapeutic equivalence IGIV trials for PI and ITP. The trial program included 7 trials and more than 350 patients2:
      • 2 pharmacokinetic trials
      • 4 efficacy and tolerability trials
      • 1 rapid-infusion trial
    • The size and design of the studies have provided unprecedented proof of efficacy, safety, and tolerability. Gamimune® N, 10% was the comparator in many of these trials.2

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  • Why did we do PI and ITP studies?


    • We chose these 2 indications to best represent the models of anti-infective (model indication: PI) and immunomodulatory/autoimmune applications (model indication: ITP) of IGIV.

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  • Are all IGIVs equally efficacious in PI?


    • We have no reason to not believe that all IGIVs are effective. An open question remains, however: "How effective is each brand of IGIV?"
      • "Surprisingly, various IGIV products, which are manufactured differently, have not been thoroughly compared for efficiency and adverse events."3
      Roifman C, et al. Int. Immunopharmacol. 2003;1325-1333.

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  • Is there a rationale to doubt that not all IGIVs are equally efficacious?


    • Reason 1: After more than 2 decades of utilization, there has been no sound clinical data confirming that all IGIV products are the same.
    • Reason 2: A recent patient survey by the Immune Deficiency Foundation (IDF) uncovered a variety of perceptions about the efficacy of different IGIV products.

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  • What is different about the Gamunex® efficacy trial in PI?


    • Its size: Most previous licensure-relevant trials were in a magnitude of 20 to 40 patients-the pivotal Gamunex® trial included 172 patients.
    • Its design: It was the first licensure-relevant trial in PI that was randomized, double-blind, controlled, statistically powered, and included head-to-head comparisons of 2 different IGIV products.
    • Its endpoints: Previous licensure-relevant trials often focused on surrogate endpoints (eg, IgG level elevations). The primary endpoint in the Gamunex® trial was a clinical endpoint: proportion of patients with validated sinopulmonary infections.

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  • Why did we introduce "validated infection" as an endpoint?


    • Validated infections, a "hard" clinical endpoint, were confirmed by prospectively defined clinical, laboratory, and imaging criteria.
    • Validated infections are an established endpoint in antibiotic trials. The following is an example of how infections were validated in the Gamunex® trials:
      Symptoms lasted =5 consecutive days but <28 consecutive days, or the patient had documented fever (>38°C or >100.4°F) plus 2 of the following symptoms-nasal congestion, facial pressure, pain, tightness (toothache, frontal headache, pain behind the eyes), headache, bad breath, taste disturbances- plus seropurulent or mucopurulent nasal drainage and documentation by one of the following: CT scan (air fluid level, sinus opacification), lateral X-ray (waters, air fluid level, sinus opacification), or ultrasound of maxillary sinus in different angles (sinus opacification).3

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  • What about alternative clinical endpoints?


    • Surrogate endpoints…do not provide clinical evidence for a product's efficacy.
    • Clinically defined infections are easier to record, but could bias the validity of results since many symptoms and signs of infections are very unspecific and overlapping.

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  • What are the key findings in the PI study?


    • Gamunex® effectively prevented validated sinopulmonary infections in PI during a 9-month observation period3:
      • Gamimune® N, 10%, Immune Globulin Intravenous (Human), 10%, group: 23% suffered from infection
      • Gamunex® group: 12% suffered from infection (P=0.06)
    • Gamunex® significantly reduced the rate of validated sinopulmonary infections by one half, compared with Gamimune® N, 10%3:
      • Annual infection rate in Gamimune® N, 10% group: 0.43/yr
      • Annual infection rate in Gamunex® group: 0.18/yr (P=0.023)

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  • Are there data about Gamunex® efficacy in PI patients with underlying complications?


    • Patients with bronchiectasis who received Gamunex® showed a trend toward fewer infections compared with those who received Gamimune® N, 10% (7% vs 25%).

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  • What is different about the ITP efficacy study?


    • Its size, design, and scope: The ITP study (97 patients) was the first licensure-relevant study to include both adult and pediatric patients for both acute and chronic ITP in a randomized, double-blind, comparative, statistically powered manner.
      "The current investigation was the first prospective, randomized, controlled trial of IGIV to include both adults and children with ITP."4
      Bussel J, et al. Blood. December 2001;98:Part 1.

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  • What are the key findings in the ITP study?


    • Gamunex® was shown to be at least as effective as Gamimune® N, 10%, with a trend toward enhanced efficacy.
    • Gamunex® showed excellent platelet response (primary endpoint: increase in platelet counts from =20 to =50 x 109/L by the 7th day)1:
      • Gamimune® N, 10% group: 83%
      • Gamunex® group: 90%
      • Gamunex® was effective in maintaining the platelet response (secondary endpoint: maintenance rate =50 x 109/L for at least 7 days)1
        • Gamimune® N, 10% group: 60%
        • Gamunex® group: 74%

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  • Were there other clinical relevant findings in the ITP study?


    • Gamunex® patients experienced a trend toward fewer bleeding episodes than Gamimune N, 10%, patients (ecchymosis, petechiae).2
    • In the 3- to 6-month follow-up period, Gamunex® patients experienced fewer relapses necessitating treatment,2 eg:
      • significantly fewer emergency steroid treatments
      • fewer splenectomies in the Gamunex® group

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  • What conclusions can be drawn regarding Gamunex® clinical efficacy?


    • Gamunex®...
      1. brings unprecedented evidence for an IGIV's efficacy.1
      2. has demonstrated excellent clinical efficacy1 …setting a benchmark other IGIVs have to compare with.
    • Gamunex® is at least as effective as Gamimune® N, 10% (non-inferiority trial design).
    • A consistent trend in favor of Gamunex® challenges the perception that IGIVs produced by different processes are therapeutically equivalent.1

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Tolerability



Safety


  • Are Gamunex® and Gamimune® N, 10% equally safe with respect to viral safety?


    • Yes. An important precondition to gain FDA approval is to demonstrate conclusive evidence for a plasma-derived product's virus safety. Gamunex® has a multitude of preproduction and production safety steps.2

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  • Where does Talecris obtain the plasma used for production?


    • Talecris uses only U.S. plasmapheresed donors from FDA-licensed and IQPP (International Quality Plasma Program, an industry certification program with highest standards) collection facilities.2

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  • What tests are performed before plasma is processed at Talecris' manufacturing site in Clayton, North Carolina?


    • Extensive screening and testing of donors2
    • Inventory hold and look-back2
    • All plasma is tested for HIV-1 and HIV-2, HAV, HBV, and HCV. Talecris incorporates nucleic acid testing/polymerase chain reaction (NAT/PCR) testing for HIV, HBV, HCV, and Parvovirus B19.2

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  • What safety steps are implemented in the manufacturing process to eliminate potential viruses in the source plasma?


    • The Gamunex® manufacturing process incorporates 2 separate virus inactivation steps and 3 virus removal steps.
    • The Gamunex® Process, Talecris' new Caprylate/ Chromatography-based production process, also has been carefully evaluated for its prion removal capacity.2 The Gamunex manufacturing process incorporates 2 prion removal steps.

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  • Why did we substitute caprylate for solvent/detergent (S/D) in the new production process for Gamunex®?


    • The new advanced Gamunex® manufacturing process utilizes caprylate instead of S/D because caprylate provides multiple advantages: it efficiently purifies and is gentle on fragile IgG proteins, while remaining tough on viruses. The resulting product has better protein integrity and higher purity.2
    • Caprylate has the additional advantage of inactivating enveloped viruses much faster than S/D-under the production conditions of the Gamunex® process, caprylate inactivates test viruses almost instantaneously, adding to the overall margin of safety of Gamunex®.2

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  • What is caprylate?


    • Caprylic acid (octanoic acid) is a naturally occurring fatty acid.2
    • Besides gently precipitating nonimmunoglobulin proteins from human plasma, caprylate very effectively inactivates enveloped viruses such as HIV, HBV, and HCV.2
    • Caprylate has been used for more than 50 years as a stabilizer for albumin.2
    • At the administered concentration, caprylate is nontoxic to humans.
    • The caprylate used in the Gamunex® production process is completely removed prior to final product formulation.2

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  • How has the Gamunex® virus elimination program been tested?


    • We have introduced a new paradigm in safety evaluation to assess the virus reduction capacity of its Gamunex® process. It has 2 cornerstones2:
      • Robustness testing of all relevant safety steps (effectiveness validated outside normal production range)
      • Assessment of mechanistic independence of virus reduction steps

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  • Why is a robustness evaluation important?


    • Many of today's virus clearance evaluations were performed at set-points, basically assuming static and optimal processing conditions at a given time during the quite long and complex production of IGIV.2
    • We have conducted extensive robustness studies to evaluate the virus reduction capacity at worst-case conditions, critically reflecting that theoretical variations of a variety of process parameters (pH, temperatures, concentration of agents) can significantly depart from set-point conditions and thereby impact the virus inactivation/removal capacity.2
    • In robustness experiments, pathogen reduction of the Gamunex® process has been extensively tested at set-points, at upper/lower limits, and even beyond these established limits for relevant manufacturing parameters to ensure that variations in these parameters do not affect the amount of virus reduction. We stressed the process to ensure safety.2

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  • What is meant by "mechanistically independent" virus reduction steps?


    • A manufacturing process should include not only multiple virus reduction steps, but ideally these steps should have the capacity to eliminate viruses with different mechanisms of inactivation or removal. In calculating the effectiveness of the virus reduction steps, Talecris counted only the reduction value from steps that are truly additive.1
    • This concept addresses the challenge that viruses can differ significantly in their physicochemical resistance to certain reduction steps. This conservative approach avoids counting redundant virus reduction steps and addresses the threat from the widest range of viruses, including those yet unknown.2
    • To challenge the virus reduction capacity of the Gamunex® process, we used a study panel of 6 test viruses (3 enveloped and 3 nonenveloped), each with different physicochemical properties and resistance.2

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  • How does the new paradigm in safety evaluation translate into overall log-reduction number?


    • Whenever the virus reduction of individual steps was found to be based not on independent mechanisms of inactivation/removal, we did not consider the respective individual step(s) to be additive and did not include all of these steps in the overall calculation of the virus reduction capacity (log-reduction). We did not double-count redundant steps.2
    • This is a new approach to evaluate safety capacity; it leads to a more realistic assessment of the virus reduction capacity of a process and addresses the inflationary utilization of log-reduction numbers. While not counted, the aforementioned redundancies provide an additional margin of safety.2

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  • How safe is Gamunex® from prions?


    • The manufacturing process was investigated for its capacity to decrease the infectivity of an experimental agent of transmissible spongiform encephalopathy (TSE), considered as a model for the Creutzfeldt- Jakob disease (CJD) and vCJD agents. Several of the individual production steps in the Gamunex manufacturing process have been shown to decrease TSE infectivity of that experimental model agent. TSE reduction steps included cloth filtration and depth filtration. These studies provide reasonable assurance that low levels of CJD/vCJD agent infectivity, if present in the starting material, would be removed.

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  • Is there clinical evidence corroborating the pathogen safety of Gamunex®?


    • Yes. To gain FDA approval for Gamunex®, we performed the biggest and most rigorous licensure-relevant trial program ever for an IGIV. An important part of the protocols of 6 trials was to assess thoroughly, and obtain strong clinical confirmation for, pathogen safety in patients.1
    • In more than 350 patients tested, no evidence of viral transmission was documented.1
    • This provides the strongest body of clinical evidence ever for an IGIV product's virus safety at the time of launch.1

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  • What is Talecris doing about the potential for product tampering?


    • Responding to recent concerns about product tampering of liquid intravenous products, Gamunex® utilizes shrink-banding as an enhanced tamper-evident packaging innovation.2
    • The shrink-band is designed as a clear plastic wrap, imprinted with the company logo, covering the neck and lid of the bottle. The shrink-band comes with a pull-tab for easy removal. If tampering has occurred, the shrink-band will be broken or loosened, and the disruption will be obvious to the naked eye. If a disruption in packaging is identified, the product should not be opened or used.2

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Reliability


  • Will supply be an issue for Gamunex®?


    • Consistent and reliable supply of this lifesaving therapy is of utmost importance. Talecris has addressed this issue with a variety of measures and investments:
      • Talecris built a totally new, dedicated production facility for the manufacture of Gamunex®, a facility that meets or exceeds current Good Manufacturing Practices (cGMP) standards.
      • Talecris developed a new production process, caprylate/chromatography-based Gamunex® Process, that is easier to manage and minimizes the complexity and related trade-offs of current industry standards in IGIV production.
      • All production equipment in the new facility is dedicated to Gamunex® production.
      • Two separate production lines for Gamunex® ensure a consistent supply.
      • The facility is fully automated to reduce the potential for operator error and to maintain batch-to-batch consistency.

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  • What effect does the Gamunex® production process have on clinical issues?


    • The process is the product!
    • Each of today's IGIV purification processes consists of a combination of quite diverse steps, distinguishing one brand from another and offering a multitude of opportunities to introduce differences that can impact:
      • biological activity of the fragile IgGs, a critical precondition for a product's clinical efficacy
      • product features and composition, which determine differences in tolerability, convenience, or safety profile

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  • How does the production method for Gamunex® differ from that for other IGIVs?


    • Other IGIVs are manufactured based on decades-old technology retrofitted over time by adding steps to meet changing standards.
    • With a foundation of 2 decades of manufacturing experience, we developed a new caprylate/chromatography-based process "from scratch". This fundamentally different approach was developed to combine and integrate multiple functions into single (fewer) steps, rather than adding steps, to make the process:
      • shorter
      • gentler
      • more consistent
      • more efficient
      • easier to control
      • all critical preconditions to creating a true advance in the manufacture of IGIV.

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Convenience


  • What concentration is Gamunex®?
    • Gamunex® is available as a 10%, ready-to-use, liquid.1

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  • Which vial sizes are available and how can they be distinguished?


    • To minimize potential waste, we offer the widest range of package sizes for individual dosing. Gamunex® packages are color-coded and supplied in the following sizes1:

      NDC Number    13533-0645-12
      Size    10 mL
      Grams Protein    1.0
      Pkg Color Code    green
        
      NDC Number    13533-0645-15
      Size    25 mL
      Grams Protein    2.5
      Pkg Color Code    purple
        
      NDC Number    13533-0645-20
      Size    50 mL
      Grams Protein    5.0
      Pkg Color Code    red
        
      NDC Number    13533-0645-71
      Size    100 mL
      Grams Protein    10.0
      Pkg Color Code    yellow
        
      NDC Number    13533-0645-24
      Size    200 mL
      Grams Protein    20.0
      Pkg Color Code    grey
        

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  • Are Gamunex® components latex-free?


    • No. Caution should be exercised in patients hypersensitive or allergic to latex. As a precaution, latex-sensitive healthcare providers should use proper gloves when handling the product stopper.2

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  • Is an inline filter required for Gamunex® administration?


    • An inline filter is not required for infusions of Gamunex®.1

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  • What are the storage conditions for Gamunex®?


    • Gamunex® offers a long shelf life. Product may be stored for 36 months at 2°C to 8°C (36°F–46°F), and product may be stored at temperatures not to exceed 25°C (77°F) for up to 6 months anytime during the 36-month shelf life, after which the product must be immediately used or discarded. Do not freeze. Do not use after expiration date.1

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  • What is the recommended infusion rate of Gamunex®?


    • It is recommended that Gamunex® should initially be infused at a rate of 0.01 mL/kg/min (1 mg/kg/min) for the first 30 minutes. If welltolerated, the rate may be gradually increased to a maximum of 0.08 mL/kg/min (8 mg/kg/min). If side effects occur, the rate may be reduced, or the infusion interrupted until symptoms subside. The infusion may then be resumed at a rate that is comfortable for the patient.1

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  • How does the overall infusion time of Gamunex® compare to other brands?


    • Gamunex® compares very favorably through its combination of a high maximum infusion rate (0.08 mL/kg/min) and high concentration (10% formulation).1
      • If well-tolerated, the overall infusion time, in any patient, of any brand, is defined by its concentration and maximum labeled infusion rate.
      • Patients tolerate IGIV differently. As a general recommendation, the infusion rate of any IGIV should be adapted to the individual patient.
    • The Gamunex® convenience advantage does not come at the cost of excess osmolality or high sodium concentration, as seen in some lyophilizates when dissolved with less diluent to make a more highly concentrated product.8

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  • Can Gamunex® be diluted to a concentration lower than 10%?


    • Gamunex® may be diluted with 5% dextrose in water (D5W). No other drug interactions or compatibilities have been evaluated.1
    • Gamunex® is not compatible with saline.1

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  • What other IV solutions are compatible with Gamunex®?


    • Gamunex® is compatible with 5% dextrose in water (D5W).1
    • Gamunex® is not compatible with saline.1
    • No other drug interactions or compatibilities have been evaluated.1

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  • Can Gamunex® be pooled into sterile glass or plastic containers?


    • Multiple vials of Gamunex® may be pooled into either sterile glass or plastic containers suitable for IV administration. Any residual fluid other than D5W contained in an evacuated container must be removed prior to adding Gamunex®. This is especially important if even a small amount of saline solution is present in the container, as a precipitate may form.1

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Trust


  • What is our experience with IGIV?


    • We have been an innovator in IGIV therapy for more than 20 years. We introduced the first liquid IGIV, Gamimune®, Immune Globulin Intravenous (Human), to the United States in 1981 and has continuously improved on it since then. In 1992, we launched worldwide the first ready-to-use 10% formulation IGIV. Gamunex® is the next-generation IGIV, based on a revolutionary new manufacturing concept.

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  • Will Gamunex® be reimbursed by third-party payers?


    • Talecris expects that Gamunex® will be reimbursed by most payers.
    • Talecris is working with third-party payers such as Medicare, Medicaid, Federal Supply Schedule (FSS), insurance carriers, and others, to minimize possible reimbursement issues.
    • Please consult with your specific group to determine the current status of reimbursement for Gamunex®.

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  • What support services does Talecris provide for Gamunex®?


    • Talecris Customer Service: 1-800-243-4153 (8:00 AM - 5:00 PM Eastern Standard Time)
    • Talecris Clinical Communications: 1-800-520-2807 (8:30 AM - 5:00 PM Eastern Standard Time)
    • Talecris Reimbursement Helpline: 1-877-TBR EIMB (827-3462) (8:30 AM - 5:30 PM Eastern Standard Time)
    • www.gamunex.com

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†Gamimune N 10%, Immune Globulin Intravenous (Human)


Please contact us for more information or with any specific questions you may have.

Please see full Prescribing Information including boxed WARNING.

References

  1. Gamunex® full Prescribing Information.
  2. Data on file, Talecris Biotherapeutics.
  3. Roifman CM, Schroeder H, Berger M, et al. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency. A randomized double-blind trial. Int Immunopharmacol. 2003;3:1325-1333.
  4. Bussel JB, Eldor A, Kelton JG, et al. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life. Thromb Haemost. 2004;91:771-778.
  5. "Life. Guard It." Baxter promotional brochure. January 2003. 023571.
  6. Nydegger UE, Sturzenegger M. Adverse effects of intravenous immunoglobulin therapy. Drug Saf. 1999;21:171-185.
  7. Ballow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc. 2002;42:449-459.
  8. Siegel J. Intravenous Immune Globulins: Therapeutic, Pharmaceutical, & Cost Considerations. Pharmacy Practice News. April 2001:11-13.
  9. Lebing W, Remington KM, Schreiner C, Paul HI. Properties of a new intravenous immunoglobulin (IGIV-C, 10%) produced by virus inactivation caprylate and column chromatography. Vox Sang. 2003;84:193-201.
  10. Remington JP, ed. Remington's Pharmaceuticals Sciences. 17th ed. Easton, Pa: Mack Publishing Company; 1985.