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Frequently Asked Questions

What data are available to direct dosing of intravenous immunoglobulin G based on total versus ideal or adjusted body weight?

Introduction

Intravenous immunoglobulin (IVIG) is a serum antibody preparation of human immunoglobulin G (IgG) manufactured from pooled human plasma.1 IVIG is Food and Drug Administration (FDA)-approved for the treatment of various primary immunodeficiency syndromes and is also utilized in numerous off-label immune-related conditions.2 Although the dosing of IVIG varies by indication, the administered dose is usually weight-based. Despite the frequent use of weight-based dosing, little data exist to clarify a safe and efficacious dosing weight for IVIG in overweight or obese patients. 3 This lack of data is relevant to pharmacy departments, as unwarranted supratherapeutic dosing may compromise supplies of this costly resource. This article aims to review clinical and pharmacokinetic data, guideline recommendations, practice patterns, and practical considerations relevant to weight-based dosing of IVIG.

Literature Review

Body weight is one of the determinants of appropriate IVIG dosing, along with trough serum levels of immunoglobulin G (IgG) and clinical response. 1 Therefore, it is important to consider pharmacokinetic parameters when dosing IVIG. The low volume of distribution (Vd) of IVIG indicates that it minimally distributes into fat.3,4 Therefore, an overweight or obese patient may not necessarily experience subtherapeutic outcomes when IVIG is dosed based on ideal body weight (IBW) or adjusted body weight (ABW). Despite the potential for dosing weight to influence safety and efficacy of IVIG treatment, few investigations have evaluated this factor. The ideal trial evaluating clinical efficacy and safety of different weight-based dosing regimens of IVIG has not been performed. However, some data demonstrate that body weight and body mass index (BMI) do not influence the IVIG dose required to produce a target trough IgG level.4

Khan and colleagues evaluated immunoglobulin therapy in 107 patients with common variable immunodeficiency to evaluate the correlation between IVIG dose and trough levels of IgG when adjusted for patient weight or BMI.4 All patients were on a clinician-determined IVIG replacement dose that was stable for at least 6 months. Patients had mean ± standard deviation (SD) weight of 70.8 ± 14.6 kg and received a mean ± SD annual dose of 383 ± 118 mg/kg every 3 weeks. The analysis found that trough IgG levels were not correlated with the dose of IVIG when adjusted for patient weight (R2=0.06, p=0.1) or BMI (R2=0.04, p=0.1), indicating that dosing based on IBW or ABW may still yield appropriate trough levels of IgG in patients who receive IVIG.

Guidelines and Expert Opinion

Currently, guidelines in the United States for labeled and unlabeled uses of IVIG do not provide recommendations on the most appropriate weight to use when calculating IVIG doses.5-9 However, international guidelines and institutional protocols provide guidance in this area.10-16

Guidelines from the United Kingdom on the use of IVIG recommended dosing of IVIG based on ABW in 2007.11 While these 2007 guidelines supported adjusted doses, this recommendation was removed from the 2008 second edition and the 2011 update, citing the limited evidence to support a firm recommendation.12-13 However, 2008 and 2011 guidelines still provide the formula for dosing based on ABW, stating there is evidence to support this approach. Also, guidelines published in Australia and various Canadian provinces recommend adjustment of IVIG dosing based on ABW.14-16

Citing the pharmacokinetic properties of IVIG presented earlier, Siegel at Ohio State University Medical Center recommends patients with a BMI of 30 kg/m 2 or higher or who weigh greater than 120% of IBW should be dosed based on ABW.10 The ABW is calculated by adding IBW and 40% of the difference between actual and IBW. Similarly, the Hospital Corporation of America (HCA) created a policy requiring all IVIG doses to be based on IBW (except in neonates), rather than total body weight.17

Practical Considerations

Besides choosing the most appropriate dosing weight, additional steps in dosing IVIG include rounding the dose to be administered in order to avoid product waste.10 For example, doses can be rounded to the nearest whole vial size to avoid discarding product from partially used vials. This practice is included in the HCA IVIG policy.17

A recent comprehensive study of global markets found that the use of IVIG is rapidly growing.18 From 1984 to 2008, the use of IVIG increased by 12% per year, with the United States and Canada being the leading consumers. Furthermore, usage can reasonably be expected to increase based on the rise in obesity, the potential expansion of labeled indications, and continuing widespread use in off-label indications.18-20 Despite the likely rise in demand, the manufacture of IVIG is dependent on supply of human plasma and whole blood; thus, supplies are ultimately limited.1 Institutions have published results of attempts to address such limited supplies.21,22 A pilot study in Australia reported a 3-year cost savings of at least $781,830 and reduced consumption of IVIG by 2.4% to 4.2% after instituting a protocol for dosing IVIG on ABW.21 As such, dosing considerations for IVIG may become increasingly relevant to maximize product stewardship and cost-effectiveness.

Conclusion

There is a paucity of data evaluating the effect of weight-based dosing of IVIG on clinical outcomes, and no data clearly indicate whether actual, ideal, or adjusted body weight is optimal. However, pharmacokinetic studies suggest that dosing based on ABW may be appropriate and this practice is advocated by various international guidelines and required by some institutional policies. As consumption of IVIG continues to increase despite limited supply, stewardship measures including dosing based on ABW or IBW may promote product conservation and cost-effective drug use.

References

1. Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. 2005;62(16 Suppl 3):S5-S11.

2. Micromedex Healthcare Series [database online]. Greenwood Village, CO: Thomson Reuters (Healthcare), Inc; 2013. http://www.thomsonhc.com/hcs/librarian. Accessed October 19, 2013.

3. Koleba T, Ensom MH. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy. 2006;26(6):813-27.

4. Khan S, Grimbacher B, Boecking C, et al. Serum trough IgG level and annual intravenous immunoglobulin dose are not related to body size in patients on regular replacement therapy. Drug Metabolism Letters. 2011;5(2):132-6.

5. Orange JS, Hossny EM, Weiler CR. 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(4 Suppl):S525-53.

6. Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immuno. 2005;94(5 Suppl 1):S1-63.

7. Neunert C, Lim W, Crowther M. The American Society of Hematology 2011 evidence based practice guideline for immune thrombocytopenia. Blood. 2011 21;117(16):4190-4207.

8. Newburger JW, Takahashi M, Gerber MA. Diagnosis, treatment and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in Young, American Heart Association. Pediatrics. 2004;114(6):1708-1733.

9. Patwas HS, Chaudhry V, Katzberg H, Rae-Grant AD, So YT. Evidence-based guideline: intravenous immunoglobulin in the treatment of neuromuscular disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology. 2012 ;78(13):1009-1015.

10. Siegel J. Immunoglobulins and obesity. Pharmacy Practice News. http://www.pharmacypracticenews.com/ViewArticle.aspx?d=IVIG+FAQs&d_id=401&i=January+2010&i_id=597&a_id=14546 . Accessed September 30, 2013.

11. Wimperis J, Lunn M, Jones A, et al. Clinical guidelines for immunoglobulin use: second edition update. National Health Services website. http://www.ivig.nhs.uk/clinicinfo.html. Updated July 2011. Updated January 2010. Accessed September 30, 2013.

12. Provan D, Nokes TJC, Agrawal S, Winer JB, Wood P. Clinical guidelines for the use of intravenous immunoglobulin. National Health Services website. http://www.ivig.nhs.uk/clinicinfo.html. Updated 2007. Accessed September 30, 2013.

13. Provan D, Nokes TJC, Agrawal S, Winer JB, Wood P. Clinical guidelines for immunoglobulin use. National Health Services website. http://www.ivig.nhs.uk/clinicinfo.html. Updated May 2008. Accessed September 30, 2013.

14. Criteria for clinical use of intravenous immunoglobulin in Australia. National Blood Authority Australia website. http://www.blood.gov.au/ivig-criteria. Updated July 2012. Accessed September 30, 2013.

15. Utilization of intravenous immunoglobulin. Newfoundland Labrador Department of Health and Community Resources website. http://www.health.gov.nl.ca/health/index.html. Accessed September 30, 2013.

16. Intravenous immunoglobulin. British Columbia Provincial Blood Coordinating Office website. http://www.pbco.ca/index.php?option=com_content&task=category&id=18&Itemid=59 . Updated August 2012. Accessed September 30, 2013.

17. IVIG HCA Pharmacy Protocol. ASHP website. http://www.ashp.org/s_ashp/docs/files/DShort_IVIGHCAPharmacyProtocol.doc . Updated 1995. Accessed October 19, 2013.

18. Research and markets: immunoglobulins market to 2019. Wall Street Journal website. http://online.wsj.com/article/PR-CO-20130520-904965.html. Updated May 20, 2013. Accessed October 19, 2013.

19. Loeffler DA. Intravenous immunoglobulin and Alzheimer’s disease: what now. J Neuroinflammation. 2013;10(1):70.

20. Leong H, Stachnik J, Bonk ME, Matuszewski KA. Unlabeled uses of intravenous immune globulin. Am J Health Syst Pharm. 2008;65(19):1815-1824.

21. Aston L, McNae A, Taylor J. The effect of ideal body weight adjusted dosing on the use of intravenous immunoglobulin in Western Australia. Australian Red Cross Blood Service website. http://www.transfusion.com.au. Accessed September 30, 2013.

22. Chow S, Salmasi G, Callum JL, Lin Y. Trimming the fat with an IVIG approval process. Transfus Apher Sci. 2012;46(3):349-52.

Prepared by: Aparna Reddy, PharmD

PGY-2 Drug Information Specialty

University of Illinois at Chicago

October 2013