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IGIV Therapy Overview and The ALPHA-TRAX TM Program

IGIV Therapy Overview and The ALPHA-TRAX TM Program. IGIV Therapy Outline. Evolution of IGIV Preparation of IGIV Viral Inactivation & Viral Partitioning Pharmacokinetics and Dosing of IGIV Safety of IGIV Therapy FDA-Approved Products ALPHA-TRAX TM Program Overview.

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IGIV Therapy Overview and The ALPHA-TRAX TM Program

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  1. IGIV Therapy OverviewandThe ALPHA-TRAXTM Program

  2. IGIV Therapy Outline • Evolution of IGIV • Preparation of IGIV • Viral Inactivation & Viral Partitioning • Pharmacokinetics and Dosing of IGIV • Safety of IGIV Therapy • FDA-Approved Products • ALPHA-TRAXTM Program Overview

  3. Human Immunoglobulins Ig Class Serum Level Function mg/mL (%) IgG 1200 (77) Major Ig in Humans IgA 200 (13) Protects Mucosa IgM 150 (9) Major Ig for 1° Immune Response IgD 2 (<1) Regulates B Cells IgE <1 (trace) Major Ig in Allergic Response

  4. Evolution of IGIV Products • Intramuscular Route (IMIG): 1940s • First Generation IGIV: 1960s Non-intact Fab Fragments from Cleavage; Non-immune Modulatory • Second Generation IGIV: 1981Intact IgG Isolated After Secondary Fractionation of Fraction II • Third Generation IGIV: 1991Intact IgG with Intentional Viral Inactivation Steps: (eg, Solvent/Detergent Treatment, Pasteurization)

  5. IGIV Manufacturing Processes • Primary cold ethanol fractionation • Secondary fractionation may include: • Chemical modification • Incubation at pH 4.0 with or without pepsin • PEG precipitation • Ion-exchange chromatography • Enzymatic cleavage • Solvent detergent treatment • Diafiltration and ultrafiltration

  6. Plasma 0°C Cryosupernatant Cryoprecipitate 8% EtOH pH 7.0 -3°C Supernatant I Fraction I 21% EtOH pH 6.8 -5°C Fraction II + III Supernatant II + III 20% EtOH pH 6.7 -5°C Supernatant II + III w Fraction II + III w 17% EtOH pH 5.2 -5°C Supernatant III Fraction III 25% EtOH pH 7.4 -5°C Supernatant II Fraction II IgG Cohn-Oncley Isolation of IgG

  7. Guidelines for IGIV Products • Pool size 1,000 - 60,000 donors • Donor screening • High % of native monomeric IgG • Normal IgG subclasses • Low IgA content

  8. Donor Screening Limitations

  9. IgG Content of IGIV Preparations AlphaBaxterBayerCenteonNovartis Donor Pool10000 8000 2000 1000 16000 (minimum) IgG (%) > 99 > 90 > 98 > 99 > 96 IgG All Low All Low All Subclasses IgG4 IgG4 IgA (mcg/mL)22 < 3.7 270 25 720

  10. Reducing Viral Load Two methods to decrease viral load in plasma products: • Viral inactivation • Viral partitioning or removal

  11. Reducing IGIV Viral Load Examples of viral inactivation methods: • Cold ethanol fractionation • Heating (pasteurization) • Solvent/detergent • Acidic environment (low pH)

  12. Reducing IGIV Viral Load • Methods of viral partitioningor removal: • Cold ethanol fractionation • Phase partitioning or PEG precipitation • Affinity chromatography • Ion exchange or gel exclusion chromatography • Filtration (membrane barrier)

  13. Solvent/Detergent (SD) Process Basis for FDA licensure of SD process: Viral inactivation of antihemophilic factor (AHF) • Demonstrated inactivation of marker viruses • Effects against lipid-enveloped viruses • No adverse effect of SD on AHF proteins

  14. Virucidal Action of SD Process Demonstrated virucidal action against: • VSV (vesicular stomatitis virus) • Sindbis virus • HIV (human immunodeficiency virus) • HBV (hepatitis B virus) • HCV (hepatitis C virus NANBHV)

  15. SD Process is Selective Proteins unaffected by SD treatment: • Antihemophilic Factor (AHF; Factor VIII) • Factor IX • Fibrin • Fibrinogen • IgG • IgM

  16. Indications for IGIV Therapy Summary of FDA-Approved Uses*: • Primary Immune Deficiencies (PID) • Idiopathic Thrombocytopenic Purpura (ITP) • Chronic Lymphocytic Leukemia (CLL) • Kawasaki Disease • Bone Marrow Transplantation (BMT) • Pediatric HIV Infection * Not all IGIV products are approved for all indications

  17. FDA-Approved Indications Alpha Baxter Bayer Centeon Novartis PIDY Y Y Y Y ITPY Y Y N Y CLLN Y N N N Kawasaki Y Y N N N BMTN N Y N N Ped HIV N N Y N N

  18. Pharmacokinetics of IGIV • Half-Life and Dosing for PID • Kinetics are complex and variable • IGIV Has a biphasic elimination Distribution ( phase) 3-5 days Elimination ( phase) 3-4 weeks • Dosage and administration (usual dose) 200 mg/kg once monthly • If clinical response is considered inadequate: 300-400 mg/kg once monthly or more frequently

  19. Safety of IGIV Therapy Recommended Infusion Rates from Package Inserts Product Initial Rate Maximum Rate (for 1st 30 min.) (as tolerated) Alpha TherapeuticVenoglobulin®-S (5% Solution) 0.01-0.02 mL/kg/min 0.08 mL/kg/min (10% Solution) 0.01-0.02 mL/kg/min 0.05 mL/kg/min BaxterGammagard®S/D 0.01 mL/kg/min 0.08-0.13 mL/kg/minBayer Gamimune®N 0.01 mL/kg/min 0.08 mL/kg/min Centeon Gammar®-P I.V. 0.01 mL/kg/min 0.03-0.06 mL/kg/min Novartis Sandoglobulin® 0.5-1.0 mL/min 1.5-2.5 mL/min

  20. Safety of IGIV Therapy Adverse Effects • Pallor, chills, and sweating • Nausea and vomiting • Low-grade fever • Back or muscle pains • Tachycardia and chest tightening • Blood pressure changes • Wheezing • Rash/hives • Tachypnea • General malaise • Aseptic meningitis syndrome • Acute renal failure (ARF)

  21. Safety of IGIV Therapy Adverse Effects of IGIV Dosage (Potential Viral Transmission) • Multiple reports of HCV transmission from IGIV without intentional viral inactivation steps • Specific product recalls • FDA now recommends validated viral inactivation or removal for IGIV manufacturing

  22. Safety of IGIV Therapy • Previous anaphylactic reaction to IGIV or IMIG • Allergies to formulation ingredients • Selective deficiency in IgA IGIVContraindications Patients with:

  23. Safety of IGIV Therapy Drug Interactions • Antibodies in IGIV may interfere with response to live attenuated viral vaccines: Measles vaccine Mumps vaccine Rubella vaccine • Immunizing physicians should be informed of recent IGIV therapy so that appropriate precautions may be taken.

  24. IGIV Product Comparison Added Viral Inactivation Form Product(s) Osmolarity (mOsm/L) Alpha Baxter Bayer Centeon Novartis IgA Content (µg/mL) Venoglobulin®-S 5% Sorbitol SD 5%:15 5%: 300 liquid PEG/Bentonite 10%:20-50 10%:330 Gammagard® S/D Dry SD <3.7 5%: 636 Polygram® S/D 10%: 1250 Gamimune®-N 10% glycine SD 270 5%: 305 liquid pH4.0 10%: 274 Gammar®-P I.V. Dry Pasteurization 25.0 339-354 Sandoglobulin® Dry Unknown 720 6%: 690 NaCl Panglobulin® 12%:1074 NaCl 6%:384 H2O 12%:768 H2O

  25. IGIV Product Shortage Reasons for IGIV Product Shortage • Increased usage • Better diagnosis and increased off-label use • GMP-related production shutdowns • Impact of CJD withdrawal

  26. IGIV Product Shortage Conservation Guidelines for IGIV • Develop IGIV-use criteria • Use alternative therapy when possible • Decrease waste (round down dosage) • Adjust dose and frequency to IgG level rather than by weight/time for replacement • Reserve supply for high-risk patients Seigel J. Intravenous immune globulin. Pharm Prac News. 1999;March: 21-23.

  27. IGIV Product InformationConclusion • Immunoglobulin use is important in several disease states • IGIV has several advantages over IGIM • Food for thought: How can we ensure that all IGIV products are used safely and effectively?

  28. ALPHA-TRAXTM Program Overview 300001 .01-.02 mL/kg/min for 1st 30 min 100002 700000

  29. ALPHA-TRAXTM Program Overview 300001 700000 100002 .01-.02 mL/kg/min for 1st 30 min Comments Warnings Information

  30. ALPHA-TRAXTM Program Overview • ALPHA-TRAX Program Features: • Tracks lot numbers back to patients • Calculates infusion rates • Displays key product messages and reminders • Privately organizes patient information and provides easy access to data

  31. ALPHA-TRAXTM Program Main Menu

  32. ALPHA-TRAXTM Program Inventory Entry

  33. ALPHA-TRAXTM Program Patient Infusion

  34. ALPHA-TRAXTM Program Patient Infusion (cont.)

  35. ALPHA-TRAXTM Program Patient Infusion (cont.)

  36. ALPHA-TRAXTM Program Reports

  37. ALPHA-TRAXTM Program Reports (cont.)

  38. ALPHA-TRAXTM Program Edit Patients

  39. ALPHA-TRAXTM Program Edit Inventory

  40. ALPHA-TRAXTM Program Conclusions • Tracks lot numbers back to patients in case of recall or other product action • Calculates infusion rates (for Venoglobulin-S products only) • Displays key product messages and reminders on how to use the products effectively • Organizes product and patient information in reports that can be printed out

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