Intravenous immune globulin

Transcription

1 Unlabeled uses of intravenous immune globulin Hoyee Leong, Joan Stachnik, Mary Ellen Bonk, and Karl A. Matuszewski Intravenous immune globulin (IVIG) has been used for the treatment of immunodeficiency disorders for more than 50 years. Advances in the purification and fractionation processes have allowed for an increasingly higher concentration of immunoglobulin G (IgG) in these products, the major immunoglobulin found in human blood. 1 The pharmacokinetics and varying product compositions of IVIG have been extensively detailed elsewhere. 2,3 As of October 2007, a total of seven IVIG products are marketed in the United States: Carimune NF (CSL Behring, King of Prussia, PA), Flebogamma (Grifols, Los Angeles, CA), Gammagard Liquid (Baxter, Deerfield, IL), Gammagard S/D (Baxter), Gamunex (Bayer, Leverkusen, Germany), Octagam (Octapharma, Lachen, Switzerland), and Privigen (CSL Behring). 4 IVIG mechanisms of action are complex and include antiinfective, immunoregulatory, and antiinflammatory properties. In primary and secondary immunodeficiency diseases, IVIG restores normal humoral Supplementary material is available with the full text of this article at Purpose. The unlabeled uses of intravenous immune globulin (IVIG) were reviewed. Summary. A literature review was conducted to identify studies examining the unlabeled uses of IVIG. A review of 138 clinical trial abstracts identified 10 trials examining 2 labeled uses (635 patients) and 128 trials examining 61 different off-label uses (6781 patients). The most common off-label indications included multiple sclerosis, graft-versus-host disease in transplant patients, prevention of antiphospholipid syndrome in miscarriage, Guillain-Barré syndrome, and progression of human immunodeficiency virus after delivery. The studies appeared to support many of the acceptable off-label uses cited by various guideline groups. A total of 276 case reports were identified, with 268 reports representing 156 different off-label uses (362 patients). Seven meta-analyses were identified, evaluating recurrent miscarriage, in vitro fertilization failure, infection in preterm infants, multiple sclerosis, immune thrombocytopenic purpura, and immune function by increasing antibody levels and possibly enhancing other immune functions, such as removing immunosuppressive complexes. 5,6 Several mechanisms have been proposed for the immunomodulatory action of IVIG in autoimmune disorders. Short-term actions pemphigoid. With the exception of recurrent miscarriage and infection in preterm infants, the off-label use of IVIG for these indications was associated with positive outcomes. An examination of IVIG guidelines by specialty society, payer, and other review organizations revealed that the biomedical evidence supporting off-label uses is being interpreted in different ways. Health care institutions are strongly urged to approve and closely monitor specific uses of IVIG to reserve dwindling supplies for the best-evidence uses. Clinicians should be aware of the limits of knowledge in many off-label uses and exercise restraint in prescribing for unproven indications. Conclusion. A literature review identified more than 150 unlabeled uses of IVIG. The evidence for these uses is being interpreted in different ways by various reviewing organizations. Index terms: Drugs; Globulin immune; Serums Am J Health-Syst Pharm. 2008; 65: include neutralization of circulating autoantibodies or superantigens, blockade of Fc receptor-mediated events, and modulation of cytokines. Long-term IVIG therapy may promote down regulation of antibody production and regulate the production of helper or suppressor T-cell Hoyee Leong, Ph.D., is Senior Research Specialist, Drug Information and Technology Assessment Groups, University HealthSystem Consortium (UHC), Oak Brook, IL. Joan Stac h n i k, Pharm.D., is Assistant Professor, University of Illinois Medical Center at Chicago, Chicago, IL. Mary Ellen Bonk, Pharm.D., is Manager, Drug Information Group; and Karl A. Mat u s z ews k i, M.S., Pharm.D., is Senior Director, Clinical Knowledge Service, UHC. Address correspondence to Dr. Matuszewski at University Health- System Consortium, Suite 700, 2001 Spring Road, Oak Brook, IL (matuszewski@uhc.edu). Sue Carey is acknowledged for her assistance with manuscript preparation. Copyright 2008, American Society of Health-System Pharmacists, Inc. All rights reserved /08/ $ DOI /ajhp Am J Health-Syst Pharm Vol 65 Oct 1,

2 cytokines. 7 The antiinflammatory actions of IVIG may occur through several possible mechanisms, including the reduction of complementmediated damage, neutralization of microbial toxins, and activation of leukocytes. 6 Labeling approved by the Food and Drug Administration (FDA) for a prescription product like IVIG allows for the manufacturer to market the product for specific indications. In practice, however, clinicians can use IVIG for any indication for which they perceive a patient benefit. FDA does not restrict or interfere with the clinical practice of approved products and made the following statement in a 1998 guidance document to institutional review boards and clinical investigators 8 : Good medical practice and the best interests of the patient require that physicians use legally available drugs, biologics and devices according to their best knowledge and judgment. If physicians use a product for an indication not in the approved labeling, they have the responsibility to be well informed about the product, to base its use on firm scientific rationale and on sound medical evidence, and to maintain records of the product s use and effects. Use of a marketed product in this manner when the intent is the practice of medicine does not require the submission of an Investigational New Drug application (IND), Investigational Device Exemption (IDE) or review by an Institutional Review Board (IRB). Economic issues and product availability have converged to make the continuing use of IVIG therapy challenging for health providers. Reductions in reimbursement by Medicare (causing shifts in the site of care from physician offices to hospitals), consolidation in manufacturers (leading to decreased production), and overall increases in the number of patients prescribed IVIG (many prescribed for unlabeled indications) have led to dramatic increases in pharmacy budgets with concomitant difficulties in acquiring the needed amount of product to treat all potential patients. 9,10 Status of IVIG The marketing of IVIG products is approved by FDA for indications that may be categorized into replacement therapy, the treatment of autoimmune diseases, or passive immunotherapy. Labeled indications for IVIG preparations currently marketed in the United States are listed in Table 1 and include idiopathic thrombocytopenic purpura, primary immunodeficiency, chronic lymphocytic leukemia, and Kawasaki disease. 11 The various uses of IVIG for unlabeled indications, however, far exceed uses for the labeled indications. These indications include the treatment of a host of immunologic, presumed immunologic, and idiopathic diseases involving nearly all organ systems. Over 150 unlabeled uses have been identified, including the most studied indications (e.g., multiple sclerosis, prevention of antiphospholipid syndrome in miscarriage, Guillain- Barré syndrome) (etable 1, available at The majority of unlabeled indications of IVIG are derived mainly from anecdotal reports or inadequately controlled studies. 12 The likelihood of manufacturers pursuing the required clinical trials to gain new labeling is remote due to the high costs of conducting such trials, with no probable extra profits or competitive marketing advantages. A University HealthSystem Consortium (UHC) electronic survey of pharmacy directors (n = 37) in January 2007 revealed that, on average, the majority of IVIG use (61%) was for outpatients. 13 Outpatient use of IVIG has increased in the past two years in 75% of respondents institutions, remained the same in 19%, and decreased in 6%. Reasons given for the changes in outpatient use were related to an increase in patient volume (82%), changes in delivery site (hospitals treating patients previously seen in physician offices) (46%), previous inpatient treatment moving to outpatient clinics (25%), declining reimbursement by payers Table 1. Labeled s for Intravenous Immune Globulin Preparations Product Carimune NF (CSL Behring) Flebogamma (Grifols) Gammagard Liquid (Baxter) Gammagard S/D (Baxter) Gamunex (Bayer) Octagam (Octapharma) Privigen (CSL Behring) Primary Immunodeficiency Idiopathic Thrombocytopenic Purpura Chronic Lymphocytic Leukemia Kawasaki Disease 1816 Am J Health-Syst Pharm Vol 65 Oct 1, 2008

3 (18%), dumping of patients to hospitals (18%), new indications (14%), cherry picking of patients (11%), and a declining margin for specialty pharmacies (4%). Administration The dose and interval of IVIG administration are variable because of interpatient differences in the rate of IVIG catabolism. 14 Serum IgG concentrations can be used as a surrogate endpoint (with a goal of >500 to 600 mg/dl); however, treatment efficacy is best determined by the rate of recurrent infections and complications. IVIG dosages for the treatment of primary immunodeficiency disorders range from 0.2 to 0.8 g per kilogram of body weight, given every four weeks. Although IVIG products are generally well tolerated, specific properties may need to be considered for certain patient populations and may contribute to an increase in adverse events. Patients should be evaluated for potential risk factors, including renal dysfunction, cardiac impairment, diabetes mellitus, and the presence of antiimmunoglobulin A antibodies before therapy is initiated. Properties such as immunoglobulin A concentration, sugar and sodium content, osmolality, and ph may affect product selection. 6 Recommendations In September 1994, UHC convened a multidisciplinary expert panel to consider the appropriate use of IVIG. This group of 10 clinical experts reviewed graded published biomedical trial evidence prepared by UHC staff. Using an evidencebased, consensus-driven process, the expert panel determined that of the 54 unlabeled indications identified, 3 were considered acceptable for clinical use, 38 were not recommended, and 13 were not recommended for routine use but might be considered under limited circumstances. These recommendations were released to UHC member institutions in April 1995 and subsequently published in a peer-reviewed journal. 15 In the fall of 1998, UHC updated its review of the biomedical literature, reconvened the expert panel, and released new recommendations for IVIG use. 12 The expert panel determined that of 71 off-label indications reported, 3 were recommended, 51 were not recommended due to a lack of published efficacy evidence, and 17 were not recommended for routine use but might be considered under limited circumstances. Since the March 1999 release of the UHC IVIG use guidelines to UHC members, two additional consensus statements have been published. The first was published in 2003 by the Autoimmune Mucocutaneous Blistering Diseases Consensus Development Group 16 ; the second statement, issued by the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology, followed in The first consensus statement, developed by an international group of 35 clinicians (mostly dermatologists) was funded by a grant from Bayer Corporation and focused on five mucocutaneous diseases. The use of IVIG was supported in the treatment of pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, mucous membrane pemphigoid, and epidermolysis bullosa acquisita, but the authors emphasized the need for larger multicenter trials. The American Academy of Allergy, Asthma, and Immunology sponsored an IVIG expert panel that reviewed graded evidence from the biomedical literature through November 2005 in five major categories of unlabeled uses. This group comprised 16 clinical experts from a variety of medical specialties and was funded by a grant from Octapharma USA Inc. In reviewing primary and secondary immune deficiencies, the committee concluded that 2 uses were definitely beneficial, 3 were probably beneficial, 1 might provide benefit, and 2 were unlikely to be beneficial. For various autoimmune diseases, the committee concluded that 2 uses were definitely beneficial, 2 were probably beneficial, 10 might provide benefit, and 2 were unlikely to be beneficial. For neuroimmunologic disorders, 3 uses were found to be definitely beneficial, 4 were probably beneficial, 12 might provide benefit, and 5 were unlikely to be beneficial. For infection-related diseases, 2 uses were deemed definitely beneficial, 5 were probably beneficial, 4 might provide benefit, and 3 were unlikely to be beneficial. For a final miscellaneous category of uses, the committee classified 1 use as probably beneficial and 7 as unlikely to be beneficial; the committee concluded that 10 uses might provide benefit. In summary, of the 80 unlabeled uses considered by the members of the primary immunodeficiency committee, 9 were definitely beneficial, 15 were probably beneficial, 37 might provide benefit, and 19 were unlikely to be beneficial. Only 19 (24%) of reviewed unlabeled uses were considered unlikely to be beneficial. Other organizations have also published coverage guidelines for IVIG. Medical policies from payer organizations vary considerably. While Aetna s 2006 medical policy cited 28 unlabeled uses of IVIG as medically necessary and 87 as experimental or investigational, 18 Blue Cross of California s policy allows for 17 unlabeled indications for IVIG without addressing other unapproved uses. 19 The Medical Letter on Drugs and Therapeutics published a summary review of IVIG uses in December 2006, advising that 14 of the 19 unlabeled indications reviewed are reasonable therapeutic options. 20 A comparative review of the guidelines provided by these six organizations (appendix) revealed the existence of 153 unlabeled uses of IVIG, 43 (28%) of which were reviewed by at least three organizations. s were ranked by these organiza- Am J Health-Syst Pharm Vol 65 Oct 1,

4 tions as not recommended (scored as 0), potentially beneficial (1), and acceptable (2). Only 34 indications (22%) were scored an average of 1.5 or higher by the various groups, suggesting that at least one organization found the use to be beneficial. Only 11 indications (7%) averaged 1.5 or higher by ratings from at least three organizations. Drug-use evaluations Three drug-use evaluation studies were conducted to compare various uses of IVIG with established guidelines or protocols. Studies conducted in the United States included one single-center study by Darabi et al. 21 and a multicenter study conducted by Chen et al. 22 Another multicenter study evaluated the use of IVIG in four hospitals in Canada. 23 After reviewing IVIG use in 251 patients from 12 U.S. academic health centers, Chen et al. concluded, using 1995 UHC guidelines, that 107 patients (43%) received IVIG for labeled indications, 130 (52%) for unlabeled indications, and 14 (5%) for undefined treatment. Examination of the unlabeled subset revealed that the indications of 95 patients (73%) met guidelines and 35 (27%) did not. Darabi et al. 21 retrospectively reviewed IVIG use for calendar year 2004 at Massachusetts General Hospital and found that it was given to 194 patients for the following indications: chronic neuropathy (n = 56), secondary hypogammaglobulinemia (n = 34), idiopathic thrombocytopenia (n = 20), primary hypogammaglobulinemia (n = 18), renal transplantation (n = 12), myasthenia gravis (n = 9), Guillain-Barré syndrome (n = 8), common variable immunodeficiency (n = 8), necrotizing fascitis (n = 6), autoimmune hemolytic anemia (n = 6), Kawasaki disease (n = 5), and various other uses (n = 12). A total of 104 patients (54%) received IVIG for unlabeled indications, consistent with the findings of Chen et al. 22 Darabi and colleagues 21 stated that the majority of unlabeled IVIG use was consistent with the hospital s guidelines, though these guidelines were not defined in the article. Finally, Pendergrast et al. 23 reported the results of IVIG use at four Toronto hospitals from 1995 through In 429 patients, IVIG use was distributed among the following types of conditions: neurologic (26%), hematologic (24%), bone marrow transplants (15%), infectious disease (13%), dermatological (6%), rheumatology (3%), and other or unknown (13%). The authors stated that most (75%) of the IVIG use in this retrospective study would be considered reasonable, though no specific guidelines were offered. A review of the study s published data revealed that 156 of 375 patients received IVIG for indications consistent with those on FDA-approved labeling, similar to the findings of the two above-mentioned IVIG-use studies. Unlabeled uses Clinical studies in the biomedical literature on unlabeled uses of IVIG preparations were identified by searching the PUBMED (MEDLINE+) database using the key terms immune globulin and intravenous (administration and dosage) or immune globulin and intravenous (therapeutic use). The search was limited to articles in English, clinical trials, meta-analyses, randomized controlled trials, and case reports published between January 1, 1998, and January 1, This time period was chosen to examine the extent of new clinical publications regarding IVIG since the last UHC IVIG technology assessment was published in Several review articles on the use of IVIG were also identified A total of 138 IVIG clinical trial citations were identified, with 10 trials dedicated to examining two labeled uses (total of 635 patients) and 128 trials (etable 1, available at examining 61 different unlabeled uses (total of 6781 patients). While a properly designed and powered randomized clinical trial is considered the strongest form of clinical evidence, only a limited amount of information can be discerned from reviewing abstracts, as was done for this review. A list of retrieved citations is provided in eappendix A (available at The retrieved clinical studies appeared to support many of the acceptable unlabeled uses cited by various guideline groups. The top unlabeled indications reported in clinical trials, ranked by number of patients, included multiple sclerosis, graft-versus-host disease in transplant recipients, prevention of antiphospholipid syndrome in miscarriage, Guillain-Barré syndrome, and human immunodeficiency syndrome progression after delivery (etable 1). An average score for each indication was calculated by dividing the sum of recommendation scores by the number of rating organizations (appendix). A total of 17 (28%) of 61 unlabeled uses scored an average rating of 1.0 (i.e., conditional acceptance). However, more than 50% of the supportive clinical trials included study populations of fewer than 36 patients. A total of 276 case reports were identified, with 8 reports concerning labeled use (12 total patients) and 268 reports (etable 2, available at representing 156 different unlabeled uses (362 total patients). Patient outcomes as discerned from published abstracts were rated as positive for 267 patients (74%), partial for 8 patients, and nonresponsive for 27 patients. Absence of an outcome in etable 2 indicates a lack of discernible outcomes from reviewing the respective abstract or lack of an abstract altogether. Of the 156 different unlabeled uses mentioned in case reports, 94 (60%) were not covered by any organizational guidelines reviewed for this article. Unlabeled uses examined 1818 Am J Health-Syst Pharm Vol 65 Oct 1, 2008

5 in case studies consisting of more than 10 patients included peripheral neuropathy, toxic epidermal necrolysis, myasthenia gravis, and Stevens- Johnson syndrome (etable 2). Meta-analyses were also reviewed, including seven published reports (Table 2) The reports reviewed randomized controlled trials evaluating the use of IVIG for indications including recurrent miscarriage, in vitro fertilization failure, infection in preterm infants, multiple sclerosis, immune thrombocytopenic purpura, and pemphigoid. With the exception of recurrent miscarriage and infection in preterm infants, the unlabeled use of IVIG for these indications resulted in positive outcomes. Economic and reimbursement issues Coverage and payment for IVIG therapy vary by payer organizations. Few payers differentiate between labeled and unlabeled uses in the outpatient environment where most therapy is delivered. 18,19 Drug cost payment is reported to be decreasing, while product acquisition costs are increasing. 35,36 On an inpatient basis, diagnosis-related group-based hospital reimbursement for Medicare and Medicaid recipients typically does not provide additional payments for use of expensive drug therapy. A standard course of IVIG for an adult costs approximately $2,700 per infusion. The need for multiple courses of treatment (e.g., monthly) for many immunodeficiency disorders, often at higher-than-labeled doses, can quickly increase annual IVIG costs per patient to $50,000 or more. 5 Discussion The biomedical literature detailing IVIG use continues to expand, with 138 new clinical trials, 276 case reports, and 7 meta-analyses between January 1998 and December 2006 investigating 156 unlabeled uses. This trend is likely to continue, as many clinical disciplines are involved in potential uses of IVIG (e.g., neurology, hematology, dermatology, infectious diseases, rheumatology). An examination of recent IVIG guidelines by specialty society, payer, and other review organizations revealed that the biomedical evidence is being interpreted in different ways regarding the acceptability of many unlabeled uses. A large degree of inconsistency exists concerning how unlabeled uses are evaluated and scored. Health care institutions are strongly urged to convene a local clinical committee (e.g., pharmacy and therapeutics) to review and approve specific uses of IVIG. These approved uses should be closely monitored to reserve dwindling supplies of IVIG products for the best-evidence uses. Coverage and reimbursement policies from hospitals major payers need to be evaluated to ensure adequate cost recovery. Clinicians should be aware of the limits of knowledge in many unlabeled uses and exercise restraint in prescribing for unproven indications. Institutional control mechanisms may need to be implemented, such as specialty consultations and restricted prescribing authority. Conclusion A literature review identified more than 150 unlabeled uses of IVIG. The evidence for these uses is being interpreted in different ways by various reviewing organizations. References 1. Ballow M. Intravenous immunoglobulins: clinical experience and viral safety. J Am Pharm Assoc. 2002; 42: Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006; 26: Siegel J. The product: all intravenous immunoglobulins are not equivalent. Pharmacotherapy. 2005; 25(11, pt 2):78S-84S. 4. Drug facts and comparisons. Immune globulin intravenous (IGIV). online.factsandcomparisons.com/ MonoDispaspx?book=DFC&monoID= fandc-hcp11075&searched=igiv (accessed 2007 Oct 16). 5. Pirofsky B, Kinzey DM. Intravenous immune globulins: a review of their uses in selected immunodeficiency and autoimmune diseases. Drugs. 1992; 43:6-14. Table 2. Meta-analyses of Unlabeled Uses of Intravenous Immune Globulin n In vitro fertilization failure Immune thrombocytopenic purpura, chronic Miscarriage, recurrent Miscarriage, recurrent Multiple sclerosis 33 Prophylaxis or treatment of infection, preterm infants 34 Pemphigoid, bullous a RCTs = randomized controlled trials No. RCTs Reviewed a Overall Results Positive outcomes based on live-birth rates Likelihood of platelet count of >20,000 at 48 hr greater with corticosteroids Negative outcomes based on birth rate Inconclusive Positive outcomes, dose not established, not first-line therapy Heterogeneous outcomes in prophylaxis, no effect on mortality in treatment studies 70% of patients with clinical benefit Am J Health-Syst Pharm Vol 65 Oct 1,

6 6. Ballow M. Clinical and investigational considerations for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(suppl 3):S Emmi L, Chiarini F. The role of intravenous immunoglobulin therapy in autoimmune and inflammatory disorders. Neurol Sci. 2002; 23(suppl 1):S Food and Drug Administration. Offlabel and investigational use of marketed drugs, biologics, and medical devices. (accessed 2008 Jul 24). 9. Public Hospital Pharmacy Coalition. Access to IVIG by safety net hospitals participating in the 340B drug discount program. DShort_IVIGAccesssafetynethospSept06. pdf (accessed 2008 Jul 2). 10. Tag HM. Reimbursement status and trends in IGIV therapy. journal.com/formulary/data/ articlestandard/formulary/502006/ / article.pdf (accessed 2007 Jan 23). 11. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health-Syst Pharm. 2005; 62(suppl 3):S Ratko TA. Technology assessment: intravenous immunoglobulin preparations. Oak Brook, IL: University HealthSystem Consortium; 1999 Mar. 13. Data on file; Oak Brook, IL: University HealthSystem Consortium. 14. Thürmann P, Harder S. Criteria for the appropriate drug utilisation of immunoglobulin. Pharmacoeconomics. 1996; 9: Ratko T, Burnett D, Foulke G et al. Recommendations for off-label use of intravenously administered immunoglobulin preparations. JAMA. 1995; 273: Ahmed AR, Dahl MV. Consensus statement on the use of intravenous immunoglobulin therapy in the treatment of autoimmune mucocutaneous blistering diseases. Arch Dermatol. 2003; 139: Orange JS, Hossny EM, Weiler CR et al. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology. J Allergy Clin Immunol. 2006; 117(suppl 4):S [Erratum, J Allergy Clin Immunol. 2006; 117:1483.] 18. Aetna Clinical Policy Bulletin. Intravenous immunoglobulins (IVIG). www. aetna.com/cpb/data/cpba0206.html (accessed 2006 Nov 22). 19. Blue Cross of California Clinical UM Guideline. Intravenous immunoglobulins (IVIG). bluecrossca.com/policies/guidelines/ DRUG/ivig.html (accessed 2006 Nov 22). 20. Intravenous immunoglobulin (IVIG). Med Lett Drugs Ther. 2006; 48: Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion. 2006; 46: Chen C, Danekas LH, Ratko TA et al. A multicenter drug use surveillance of intravenous immunoglobulin utilization in US academic health centers. Ann Pharmacother. 2000; 34: Pendergrast JM, Sher GD, Callum JL. Changes in intravenous immunoglobulin prescribing patterns during a period of severe product shortages, Vox Sanguinis. 2005; 89: Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile. Pharmacol Ther. 2004; 102: Harvey RD. The patient: emerging clinical applications of intravenous immunoglobulin. Pharmacotherapy. 2005; 25(11, pt 2):85S-93S. 26. Kumar A, Teuber SS, Gershwin ME. Intravenous immunoglobulin: striving for appropriate use. Int Arch Allergy Immunol. 2006; 140: Sokos DR, Berger M, Lazarus HM. Intravenous immunoglobulin: appropriate indications and uses in hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2002; 8: Clark DA, Coulam CB, Stricker RB. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilization and embryo transfer (IVF). J Assist Reprod Genet. 2006; 23: Beck CE, Nathan PC, Parkin PC et al. Corticosteroids versus intravenous immune globulin for the treatment of acute immune thrombocytopenic purpura in children: a systematic review and meta-analysis of randomized controlled trials. J Pediatr. 2005; 147: Daya S, Gunby J, Clark DA. Intravenous immunoglobulin therapy for recurrent spontaneous abortion: a meta-analysis. Am J Reprod Immunol. 1998; 39: Daya S, Gunby J, Porter F et al. Critical analysis of intravenous immunoglobulin therapy for recurrent miscarriage. Hum Reprod Update. 1999; 5: Sorensen PS, Fazekas F, Lee M. Intravenous immunoglobulin G for the treatment of relapsing-remitting multiple sclerosis: a meta-analysis. Eur J Neurol. 2002; 9: Lacy JB, Ohlsson A. Administration of intravenous immunoglobulins for prophylaxis or treatment of infection in preterm infants: meta-analyses. Arch Dis Child Fetal Neonatal Ed. 1995; 72:F Engineer L, Ahmed AR. Role of intravenous immunoglobulin in the treatment of bullous pemphigoid: analysis of current data. J Am Acad Dermatol. 2001; 44: American Society of Health-System Pharmacists. Changes in IVIG marketplace challenge pharmacists. CID=167&DID=2024&id=13177 (accessed 2008 Jul 24). 36. BNet Business Network. Eye on IVIG: a series of unfortunate supply chain events: how demand, production and reimbursement has impacted availability of a lifesaving product. findarticles.com/p/articles/mi_mdbpc/ is_3_31/ai_n (accessed 2008 Jul 24) Am J Health-Syst Pharm Vol 65 Oct 1, 2008

7 Appendix Summary of intravenous immune globulin (IVIG) indications in various guidelines Guideline Conclusion about a Ref 12 b c 19 c 20 Mean Score Labeled Allogeneic bone marrow transplant NI 1 NI NI NI Chronic lymphocytic leukemia NI 1 NI Idiopathic thrombocytopenic purpura NI 2 NI Kawasaki disease NI 2 NI Pediatric HIV (to decrease bacterial infections) NI 1 NI Primary immunodeficiencies NI 2 NI Unlabeled Acquired hemophilia 0 1 NI 0 NI NI 0.3 Acquired von Willebrand s disease 0 NI NI 0 NI NI 0.0 Adrenoleukodystrophy 0 0 NI 0 NI NI 0.0 Alzheimer s disease NI NI NI 0 NI NI 0.0 Amyotrophic lateral sclerosis 0 0 NI 0 NI NI 0.0 Anemia, aplastic 0 NI NI 0 NI NI 0.0 Anemia, hemolytic autoimmune, refractory 1 1 NI 2 NI NI 1.3 Anemia, hemolytic neonatal 1 NI NI 2 NI NI 1.5 Angioedema NI NI NI 0 NI NI 0.0 Antiphospholipid syndrome in pregnancy NI 0 NI 0 NI NI 0.0 Asthma, severe and chronic chest symptoms 0 1 NI 0 NI NI 0.3 Asthma, noncorticosteroid-dependent 0 0 NI 0 NI NI 0.0 Autistic disorder NI 0 NI 0 NI NI 0.0 Autoimmune blistering skin diseases and manifestations of systemic disease NI NI 1.8 Autoimmune inner ear disease NI NI NI 0 NI NI 0.0 Bacterial infections in lymphoproliferative disease NI 1 NI NI NI NI 1.0 Behçet s syndrome 0 NI NI 0 NI NI 0.0 Cardiomyopathy, acute, dilated 0 0 NI 0 NI NI 0.0 Cerebral infarctions with antiphospholipid antibodies NI 1 NI NI NI NI 1.0 Chronic fatigue syndrome 0 0 NI 0 NI NI 0.0 Chronic inflammatory demyelinating polyneuropathy 2 2 NI NI Churg-Strauss syndrome, allergic granulomatosis NI NI NI 2 NI NI 2.0 Clostridium difficile colitis/pseudomembranous colitis NI 1 NI 0 NI Congenital heart block 0 NI NI 0 NI NI 0.0 Convulsive syndromes NI NI NI 0 NI NI 0.0 Cystic fibrosis 0 NI NI 0 NI NI 0.0 Dermatitis, atopic NI 0 NI 0 NI NI 0.0 Dermatomyositis, polymyositis 1 1 NI Dermatosis, autoimmune blistering 0 NI 2 0 NI NI 0.7 Diabetes mellitus 0 1 NI 0 NI NI 0.3 Diamond-Blackfan anemia 0 NI NI 0 NI NI 0.0 Dysautonomia, acute idiopathic 0 1 NI 0 NI NI 0.3 Eczema NI NI NI 0 NI NI 0.0 Encephalitis, demyelinative brain stem NI 1 NI 0 NI NI 0.5 Encephalomyelitis, acute disseminated 0 1 NI 0 NI NI 0.3 Encephalopathy NI NI NI 0 NI NI 0.0 Endotoxemia 0 NI NI 0 NI NI 0.0 Enteritis, Campylobacter species-induced NI 1 NI NI NI NI 1.0 Enteroviral meningoencephalitis NI 1 NI NI NI NI 1.0 Epidermolysis bullosa acquisita NI NI 2 NI NI NI 2.0 Epilepsy, pediatric intractable 1 1 NI 0 NI NI 0.7 Fetomaternal alloimmune thrombocytopenia NI 1 NI NI NI Goodpasture s syndrome NI NI NI 0 NI NI 0.0 Grave s ophthalmology NI 2 NI NI NI Continued on next page Am J Health-Syst Pharm Vol 65 Oct 1,

8 Appendix (continued) Guideline Conclusion about a Ref 12 b 17 Guillain-Barré syndrome 2 2 NI Hemolytic jaundice, neonatal autoimmune NI 1 NI NI NI NI 1.0 Hemolytic transfusion reaction 0 NI NI 0 NI NI 0.0 Hemolytic-uremic syndrome NI NI NI 0 NI NI 0.0 Hemophagocytic syndrome 0 NI NI 0 NI NI 0.0 Hyperimmunoglobulinemia E syndrome NI NI NI 2 2 NI 2.0 IgA deficiency, isolated NI 0 NI NI NI NI 0.0 IgG subclass deficiency with severe infection NI NI NI 2 NI NI 2.0 IgG4 deficiency, isolated NI 0 NI NI NI NI 0.0 IgM antimyelin-associated glycoprotein paraprotein-associated peripheral neuropathy NI 1 NI NI NI NI 1.0 Immunosuppression, secondary to major surgery and disease NI NI NI 2 NI NI 2.0 Inclusion body myositis 0 0 NI 0 NI Infection prophylaxis, high-risk neonates 1 1 NI 0 2 NI 1.0 Infection prophylaxis, solid organ transplant 1 NI NI NI NI NI 1.0 Infection treatment, adults in surgery/trauma/burns 0 NI NI NI NI NI 0.0 Infection treatment, high-risk neonates 0 NI NI NI NI NI 0.0 Infection treatment, HIV infection (adults) 0 0 NI NI NI NI 0.0 Infection treatment, surgery/trauma 0 NI NI NI NI NI 0.0 Lambert-Eaton myasthenic syndrome 1 1 NI Leukemia, acute lymphoblastic 0 NI NI 0 NI NI 0.0 Liver disease, autoimmune NI 1 NI NI NI NI 1.0 Lower motor neuron syndrome 0 NI NI 0 NI NI 0.0 Lumbosacral or brachial plexitis NI 1 NI 0 NI NI 0.5 Malignancy, nonhematologic NI NI NI 0 NI NI 0.0 Miscarriage, recurrent 0 0 NI 0 NI NI 0.0 Multifocal motor neuropathy 1 2 NI Multiple myeloma 1 NI NI 2 NI NI 1.5 Multiple sclerosis, monoclonal gammopathy 1 1 NI NI NI Multiple sclerosis, relapsing-remitting NI NI NI 2 NI Myalgia, myositis NI NI NI 0 NI NI 0.0 Myasthenia gravis 1 1 NI Myelopathy, HTLV-1 associated 0 1 NI 0 NI NI 0.3 Myelopathy, transverse NI NI NI 0 NI NI 0.0 Myocarditis, acute, viral NI 1 NI 0 NI NI 0.5 Necrotizing enterocolitis NI NI NI 0 NI NI 0.0 Neonatal lupus syndromes NI NI NI 0 NI NI 0.0 Nephritic syndrome 0 NI NI 0 NI NI 0.0 Nephropathy, membranous 0 NI NI 0 NI NI 0.0 Nephrotic syndrome 0 NI NI 0 NI NI 0.0 Neuromyelitis optica (Devic s disease) NI NI NI 0 NI NI 0.0 Neuromyotonia (Isaac s syndrome) NI NI NI 0 NI NI 0.0 Neurosarcoidosis NI NI NI 0 NI NI 0.0 Neuropathy, demyelinating associated with monoclonal IgM NI 0 NI NI NI NI 0.0 Neuropathy, sensory NI NI NI 0 NI NI 0.0 Neutropenia, immune mediated 1 1 NI 0 2 NI 1.0 Ophthalmopathy, euthyroid 0 NI NI 0 NI NI 0.0 Opsoclonus-myoclonus 0 1 NI 2 NI NI 1.0 Optic neuritis, acute NI NI NI 0 NI NI 0.0 Oral use 0 NI NI 0 NI NI 0.0 Otitis media, recurrent 0 NI NI 0 NI NI 0.0 Paraneoplastic cerebellar degeneration 0 0 NI 0 NI NI 0.0 Paraneoplastic opsoclonus-myoclonus-ataxia associated with neuroblastoma NI NI NI 2 NI NI c 19 c 20 Mean Score Continued on next page 1822 Am J Health-Syst Pharm Vol 65 Oct 1, 2008

9 Appendix (continued) Guideline Conclusion about a Ref 12 b 17 Paraproteinemic neuropathy 0 1 NI 0 NI NI 0.3 Parkinson s disease NI NI NI 0 NI NI 0.0 Parvovirus infection (general) 0 NI NI 2 2 NI 1.3 Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections NI 1 NI 0 NI NI 0.5 Pemphigoid, bullous NI NI 2 NI NI NI 2.0 Pemphigoid, mucous membrane, cicatricial NI NI 2 NI NI NI 2.0 Pemphigus NI NI Pemphigus foliaceus NI NI 2 NI NI NI 2.0 Pemphigus vulgaris NI NI 2 NI NI NI 2.0 POEMS syndrome 0 0 NI 0 NI NI 0.0 Polyarteritis nodosa NI NI NI 0 NI NI 0.0 Polyneuritis cranialis NI NI NI 0 NI NI 0.0 Postinfectious cerebella ataxia NI 1 NI NI NI NI 1.0 Posttransfusion purpura NI 1 NI 2 NI Primary immune defect with normogammaglobulinemia and impaired specific antibody production NI 1 NI 2 NI NI 1.5 Progressive lumbosacral plexopathy 0 NI NI 0 NI NI 0.0 Pseudomembranous colitis/clostridium difficile colitis NI 1 NI NI NI Pure red cell aplasia 1 NI NI 0 NI NI 0.5 Radiculoneuritis, Lyme 0 NI NI 0 NI NI 0.0 Rasmussen s syndrome 0 1 NI 0 NI NI 0.3 Reiter s syndrome 0 NI NI 0 NI NI 0.0 Renal failure, acute 0 NI NI 0 NI NI 0.0 Rheumatic fever, acute NI 0 NI NI NI NI 0.0 Rheumatoid arthritis 0 1 NI 0 NI NI 0.3 Rotaviral enterocolitis NI 1 NI NI NI NI 1.0 RSV lower-respiratory-tract infection NI 1 NI NI NI NI 1.0 Scleroderma NI NI NI 0 NI NI 0.0 Sepsis, neonatal NI 1 NI NI NI NI 1.0 Sepsis, postoperative NI 1 NI NI NI NI 1.0 Sinusitis, chronic NI NI NI 0 NI NI 0.0 Stiff-person (Moersch-Woltmann) syndrome NI 1 NI Sydenham s chorea NI NI NI 0 NI NI 0.0 Systemic lupus erythematosus 1 1 NI 2 NI Systemic vasculitides 1 1 NI 0 NI NI 0.7 Thrombocytopenia, HIV associated NI NI NI 2 NI NI 2.0 Thrombocytopenia, neonatal alloimmune/autoimmune 1 NI NI 2 2 NI 1.7 Thrombocytopenia, nonimmune 0 NI NI 0 NI NI 0.0 Thrombocytopenia, posttransfusion purpura 2 NI NI NI NI NI 2.0 Thrombocytopenia, refractory to platelet transfusion 1 NI NI 0 NI NI 0.5 Thrombocytopenia, TTP/HUS 0 NI NI 0 NI NI 0.0 Tic disorders NI NI NI 0 NI NI 0.0 Toxic epidermal necrolysis, Stevens-Johnson syndrome NI 1 NI 0 NI Toxic necrotizing fascitis due to group A streptococcal bacteria NI NI NI 2 NI NI 2.0 Toxic shock syndrome, streptococcal or staphylococcal 0 1 NI 2 2 NI 1.3 Transplant, bone marrow, GVHD and infection prevention NI 1 NI NI NI NI 1.0 Transplant, bone marrow, prevention of chronic GVHD NI 0 NI NI NI NI 0.0 Transplant, bone marrow/stem cell, prevention of severe infections with marked hypogammagolinemia NI NI NI 2 NI NI 2.0 Transplant, renal, live donor with ABO incompatibility or positive cross-match NI NI NI 2 NI NI 2.0 Transplant, renal, prevention of acute humoral rejection NI 1 NI NI 2 NI c 19 c 20 Mean Score Continued on next page Am J Health-Syst Pharm Vol 65 Oct 1,

10 Appendix (continued) Guideline Conclusion about a Ref 12 b 17 Transplant, renal, treatment of acute humoral rejection NI 1 NI NI NI Transplant, solid organ, CMV infection NI 2 NI NI 2 NI 2.0 Urticaria, chronic NI 1 NI 0 NI NI 0.5 Urticaria, delayed pressure NI 1 NI NI NI NI 1.0 Uveitis 0 1 NI 0 NI NI 0.3 Vasculitis associated with other connective tissue disorders NI NI NI 0 NI NI 0.0 Vogt-Koyanagi-Harada syndrome 0 NI NI 0 NI NI 0.0 Wegener s granulomatosis NI NI NI 0 NI NI c 19 c 20 Mean Score a Score of 0 = IVIG not recommended, 1 = IVIG may be beneficial, and 2 = acceptable use of IVIG. NI = not included, IgA = immunoglobulin A, IgG = immunoglobulin G, IgM = immunoglobulin M, HTLV = human T-cell lymphotropic virus, RSV = respiratory syncytial virus, TTP/HUS = thrombotic thrombocytopenia purpura/hemolytic-uremic syndrome, GVHD = graft-versus-host disease, CMV = cytomegalovirus. b IVIG may be considered for treatment under certain circumstances; refer to full UHC guidelines for additional information. c Many conditions must meet specific criteria; refer to full policy for additional information Am J Health-Syst Pharm Vol 65 Oct 1, 2008

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