Risks associated with the use of intravenous immunoglobulin 1

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Abstract

Although US immune globulin intravenous (human) (IGIV) products have been regarded as safe, it is important to recognize that many of the controlled clinical studies of IGIVs have been of modest size and have limited power to define the incidence of only the most common adverse events (AEs). A significant number of “postmarketing” serious AEs affecting renal, cardiovascular, CNS, integumentary, and hematologic organ systems have been reported. Variables potentially affecting the risk and intensity of adverse events associated with administration of IGIV include patient age, underlying condition, history of migraine, cardiovascular or renal disease, dose, concentration, rate of infusion, specific brand/formulation/excipients, and lot(s) of the particular IGIV product being administered. Each manufacturer’s IGIV preparation is a unique product carrying its own specific evidence-based indications and safety profile. In view of the seriousness of potential adverse effects of IGIV products, and current lack of data surrounding their frequency, clinicians are advised to limit their prescription of these products for conditions for which efficacy is supported by adequate and well-controlled clinical trials. Prescribers should pay close attention to patient selection; consider the potential risk/benefit ratio vis-a-vis alternate therapies; and familiarize themselves with the identification, management, and proposed strategies to minimize the risks of IGIV.

Section snippets

Conceptual framework for the classification of adverse events associated wth IGIV

Various classification schemes have been proposed for categorizing adverse events attributable to IGIV products. These criteria include whether the AEs may be reasonably ascribed to (1) contaminating proteins, IgG aggregates, viruses and other adventitious agents, immunoglobulins other than IgG, trace chemical substances used in IGIV purification and excipients versus (2) native monomeric IgG, the “active principle.” This review will instead focus on a classification scheme rooted in the

Incidence of reported adverse events associated with IGIV

Clinical trials performed to evaluate the safety and efficacy of investigational IGIV products have heretofore not been standardized with respect to the definitions, collection, and reporting of AE safety data. Most trials have been of limited size, and few trials that were performed to support licensure of marketed products have included a placebo or active control group. The lack of controls increases the difficulty of unambiguously ascribing causality, not to mention the frequency, for the

Review of specific adverse events associated with IGIV administration

Whether an AE develops in association with infusion of IGIV may depend on a number of factors including, but not necessarily limited to, the specific disease being treated, the presence or absence of other underlying medical conditions, the particular formulation and/or lot(s) of the IGIV used, the age of the patient, the dose, concentration, and/or infusion rate of the IGIV used, and the use/lack of use of concomitant medications, including prophylactic pre-medications designed to prevent or

Summary and conclusion

IGIV products have been associated with a variety of adverse effects ranging from mild to life threatening. IGIV-associated acute renal dysfunction/osmotic nephropathy, although assumed to be rare, has been widely reported in the literature and to FDA’s medWatch postmarketing surveillance system and has been associated with a number of deaths. The incidence of such reactions has never been systematically studied and is therefore unknown. Aseptic meningitis caused by IGIV can result in

Acknowledgements

The authors wish to acknowledge the support and input of the following individuals currently/formerly from the Center for Biologics Evaluation and Research (CBER), FDA: Ann Gaines, PhD; Miles Braun, MD, PhD; Jay S. Epstein, MD; Mark Weinstein, PhD; Basil Golding, MD; John Finlayson, PhD; Mei-Ying Yu, PhD; and Toby Silverman, MD.

References (54)

  • N. Cailleux et al.

    Une cause rare d’hemorragie intra-alveolaire: l’accident transfusionnel avec leucoagglutination par anticorps antigranuleux (syndrome Trali)

    Rev Med Interne

    (1998)
  • M.W. Yu et al.

    Hepatitis C transmission associated with intravenous immunoglobulins

    Lancet

    (1995)
  • M.W. Yu et al.

    Safety of intravenous immunoglobulin with regard to hepatitis C virus

    Clin Ther

    (1996)
  • C. Duhem et al.

    Side effects of intravenous immune globulins

    Clin Exp Immunol

    (1994)
  • C. Schiavotto et al.

    Adverse reactions after high-dose intravenous immunoglobulinIncidence in 83 patients treated for idiopathic thrombocytopenic purpura (ITP) and review of the literature

    Haematologica

    (1993)
  • D.A. Kessler

    Introducing medWatchA new approach to reporting medication and device adverse effects and product problems

    JAMA

    (1993)
  • S. Rosenthal et al.

    The reporting sensitivities of two passive surveillance systems for vaccine adverse events

    Am J Public Health

    (1995)
  • D.B. Winward et al.

    Acute renal failure after administration of intravenous immunoglobulinReview of the literature and case report

    Pharmacotherapy

    (1995)
  • M.A. Perazella et al.

    Acute renal failure and intravenous immune globulinSucrose nephropathy in disguise?

    Am J Ther

    (1998)
  • B.W. Tan Hajinazarian et al.

    Acute renal failure resulting from intravenous immunoglobulin therapy

    Arch Neurol

    (1993)
  • J.S. Epstein et al.

    Important Drug Warning Immune Globulin Intravenous. FDA Medical Bulletin

    (2003)
  • A. Gaines et al.

    Hospital Infections Program, National Center for Infectious Diseases, an EIS Officer, CDC

    MMWR

    (1999)
  • R.K. Wali et al.

    Recent developments in toxic nephropathy

    Curr Opin Nephrol Hypertens

    (2002)
  • R.H. Rigdon et al.

    Renal lesions following the intravenous injection of hypertonic solutions of sucroseA clinical and experimental study

    Arch Intern Med

    (1942)
  • W.D. Anderson et al.

    Renal lesions following administration hypertonic solutions of sucrose

    JAMA

    (1940)
  • M.C. Dalakas

    High-dose intravenous immunoglobulin and serum viscosityRisk of precipitating thromboembolic events

    Neurology

    (1994)
  • A.S. Wolberg et al.

    Coagulation factor XI is a contaminant in intravenous immunoglobulin preparations

    Am J Hematol

    (2000)

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    This review article reflects the opinions of the authors and not necessarily those of the U.S. Food and Drug Administration.

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