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Clinical Considerations in Managing the IVIG Shortage

Michael Wagner, PharmD, BCCCP
Ryan Hakimi, DO, MS, FNCS, NVS


Intravenous immunoglobulin (IVIG), first approved for use in the 1980s, is an essential treatment used in a wide variety of clinical specialties including neurology, hematology, immunology, nephrology, rheumatology, and dermatology. In 2017, the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma, and Immunology reviewed the U.S. Food and Drug Administration’s (FDA) approved uses of IVIG, as well as IVIG’s off-label uses. There are currently 10 IVIG products on the market, with eight indications currently approved by the FDA.
 
The use of IVIG in daily clinical practice often includes indications without FDA approval, including Guillain-Barré syndrome, acute exacerbation of myasthenia gravis, and relapsing-remitting multiple sclerosis.
 
Market supply of IVIG has been a recurrent issue for decades, with significant shortages occurring in the late 1990s and mid-2000s. These shortages are attributed to the expanding use of IVIG in clinical conditions outside of FDA-approved indications and the complicated two-year manufacturing process, which requires pooled IgG from the plasma of at least 1000 donors per batch.
 
IVIG is produced by centrifuging plasma, which results in the separation of albumin, IVIG, and factor VIII concentrate, among other derivatives. Historically, there have been very few albumin-based products; thus, market demands made production of albumin very profitable for manufacturers. Therefore, there was an ample supply of IVIG as a by-product of albumin production.
 
The current IVIG shortage stems from manufacturer consolidation, decreased plasma donations, and decreased IVIG production secondary to the market excess of albumin products. As this shortage intensifies, hospital pharmacy and therapeutics committees will be tasked with strategizing to ensure judicious use of the current IVIG supply.
 
IVIG Dosing Strategies
The most common strategies implemented by hospital systems to decrease IVIG use have been centered on cost-saving initiatives. Therefore, many medication use evaluations are aimed at reducing cost and usage of IVIG by focusing on dose optimization and reduction of waste.
 
Dose Rounding to Nearest Vial Size
A common pharmacy practice (not specific to IVIG) involves rounding drug doses to the nearest vial size. Extrapolating from the position statement of the Hematology/Oncology Pharmacy Association (HOPA), rounding biologic agents within 10% of the ordered dose is appropriate in routine clinical practice. HOPA also recommends that each hospital system establish its own dose rounding policy to reduce waste and excess healthcare costs. A common rounding technique for IVIG includes rounding to the nearest 5 grams, an automated process performed by many electronic medical record systems. For many of the IVIG products on the market, 5 grams represents the smallest commercially available vial.
 
Requiring IVIG Orders to Be Input Daily or Through Specified Order Sets
By only allowing one-time orders for IVIG, the clinician must reorder the IVIG doses daily, which ensures that all prepared doses are administered to patients and not discarded. Routinely, in both inpatient and outpatient practice, consecutive (eg, daily, weekly) orders have resulted in prepared doses of IVIG not being administered to the patient for a variety of reasons, such as lack of intravenous access, other planned procedures, fluctuating renal function, and hemodynamic instability. Alternatively, some systems have used an IVIG order set aimed at streamlining the order entry process.
 
Dosing Based on Ideal Body Weight or Adjusted Body Weight
Currently, there is no consensus in the literature on the weight that should be used for dosing IVIG. As the severity of the IVIG shortage increases, adopting a standard dosing weight based on ideal body weight (IBW) or adjusted body weight (ABW) may have drastic conservational results for a hospital system. When considering the pharmacokinetic parameters of IVIG, it is important to remember that IVIG has a small volume of distribution, predominantly accumulating in the plasma with minimal distribution in adipose tissue.
 
Many academic medical centers across the United States have implemented standard dosing using IBW or ABW. However, the clinical literature supporting this practice is limited. Most available literature is retrospective in nature and is based on small numbers of patients. Chart reviews in primary immunodeficiency, variable immunodeficiency, chronic inflammatory demyelinating polyneuropathy, and hematologic malignancies have been completed, with varying results. Importantly, although the available evidence demonstrates significant variability of the IVIG pharmacokinetics in the obese population, it has not been shown to clinically impacted outcomes. Finally, due to the low volume of distribution in adipose tissue, obese patients who are dosed at ABW may be put at additional risk for adverse reactions due to excess plasma concentration.
 
IVIG Restriction by Indication
Implementing restrictions for IVIG based on indications is highly hospital specific based on patient population and is undoubtedly a challenging endeavor. The American Academy of Allergy, Asthma, and Immunology has published a review of available literature for IVIG, categorizing indications into four categories: definitely beneficial, probably beneficial, may provide benefit, and unlikely to be beneficial. Combining this literature with clinical experience provides a framework for hospital multidisciplinary committees to make necessary decisions regarding IVIG stewardship. This approach was implemented at the Brigham and Women’s Hospital, which demonstrated a successful example of how an institution-specific prescribing guideline can ensure the appropriate use and dosing of IVIG.