Q&A with Jerry Siegel, PharmD, FASHP
Pharmacy Purchasing & Products: What are some strategies for minimizing IVIG waste?
Jerry Siegel: Even though IVIG shortages are not an issue at this moment, minimizing waste remains a priority given the high cost of this product. One strategy to help reduce waste is to only prepare the dose once the patient is cleared to receive it. Just because a patient comes in for an infusion, does not mean they will always be given it: How the patient feels as well as their temperature and renal status could impact their scheduled dose. Although preparing IVIG is time consuming, waiting until the patient is cleared to receive the dose will help ensure an expensive drug is not wasted.
Another strategy for reducing IVIG waste is to prepare the drug in batches. If patients receiving IVIG are scheduled at the same time, multiple doses can be prepared simultaneously. Rounding doses to the nearest vial size is yet another tactic to decrease waste.
PP&P: What are guidelines for dose rounding?
JS: All eight IVIG products in the US market (Flebogamma 5% DIF, Gamunex, Privigen, Carimune NF, Gammagard S/D, Gammagard Liquid, Octagam, and Gammaplex) come in a variety of dose vials ranging from 0.5 g to 20 g. Most facilities do not carry all available products or vial sizes, and at many facilities it is standard practice to round the patient’s dose to the closest vial size available. In adult settings, this is normally within 5 g, and in pediatric settings, it may be as low as 1 g to 2.5 g. When rounding, it is advisable to stay within 10% of the original defined order, whether you are rounding up or down. In addition, it is advisable to keep 5 g of the lowest dose size vials you carry in stock.
PP&P: Do you always dose on actual patient weight?
JS: There is much discussion as to what weight should be used when determining IVIG dosing. The assumption has been to dose based on the patient’s actual weight; however, if you study the pharmacokinetics of IVIG, as an immunoglobulin, it does not really distribute into fat, so the volume of distribution may in fact be higher in a patient at an ideal weight as opposed to a patient who is obese. Given this, once a patient’s weight is greater than 100 kg or their BMI is greater than 30, it is advisable to adjust their IVIG dose as follows to determine a more accurate dosing weight: first, take the difference between the patient’s actual weight and their ideal weight as defined by the Metropolitan Life tables and divide this in half; then, add this figure to their ideal weight. Based on this formula, if a patient weighed 120 kg and their ideal weight was 60 kg, 90 kg would be the dosing weight. This means that if the prescribed dose for the patient is 1 g of IVIG per kg, instead of 120 g, the patient would receive 90 g. Dosing based on this method significantly impacts both cost and waste.
PP&P: Can IVIG be given subcutaneously?
JS: In some countries—such as Denmark, Norway, and Sweden—administering subcutaneous, as opposed to intravenous, preparations of immunoglobulin is the common method of delivering this product. And, there are several reasons for taking this approach: When immunoglobulin is administered subcutaneously, there is less concern about aggregates causing adverse reactions because they will be filtered out by the tissue, and the same applies if the drug is given intramuscularly. In addition, the subcutaneous preparations currently available have concentrations of 16% (Vivaglobin) and 20% (Hizentra), which is significantly higher than intravenous products, which have a maximum concentration of 10%. Therefore, with a subcutaneous product the volume given will be less, which also decreases the possibility of adverse reactions. Lastly, when immunoglobulin is given subcutaneously, the peak IgG level is lower, but often is sustained for a longer period, making the area under the curve appear the same as an intravenous administration. With the lower peak, tolerability may be increased.
While there are benefits to using subcutaneous preparations, there is a significant downside to delivering intravenous preparations of immunoglobulin subcutaneously, as it will not have the absorption rate of an intravenous dose, thus requiring an increased dosage. This can result in a volume that is too high for the patient to tolerate. Since subcutaneous products are now commercially available, I would only recommend their use subcutaneously.
The reverse of this question is, can subcutaneous preparations of immunoglobulin be given intravenously, and the answer to that is no. Since these products have a higher concentration, even though they are quite purified, they are contraindicated from being given intravenously.
PP&P: Can two or more IVIG products be combined in the same container to make a final dose?
JS: This is a common question during times of shortages, but the answer remains—absolutely not. Combining products to make a final dose can cause an adverse reaction in patients due to destabilization of the product, even without a precipitation reaction. In fact, I believe it is best practice to keep a patient on the same product for life if it is well tolerated. Switching products requires significant caution in dosing, as the patient’s maximum tolerated dose may be very different with a new product, significantly increasing their risk for an adverse reaction. In addition, changes in concentration, stabilizers (sugars or amino acids), salt content, and pH need to be considered when switching from one product to another.
Should availability issues or formulary changes require a different product, the patient needs to then start their tolerance to IVIG all over again. If this step is skipped, as often happens when the product change is not clearly communicated to prescribers or the clinical staff, the risk of an adverse event increases. It also is important for the patient to be aware of what product they are on, even if their prescription is written generically, so they can advocate for themselves.
PP&P: Can all IVIG products be diluted?
JS: Although 5% concentrations of IVIG are available, sometimes 10% concentrations of IVIG are diluted, but this is generally not recommended. While some IVIG products on the market may tolerate some degree of dilution, others are rendered unstable when run through saline or otherwise diluted.
Early on, many 5% concentrations of IVIG were actually solubilized and in half the amount of fluid. For example, Gammagard was intended to be a 5% concentration, and when sterile water was added it became normal saline because of the sodium chloride already in the lyophilized powder. To decrease infusion time of this product, some facilities were using half the amount of sterile water to create a 10% solution. However, by doing so they were actually making a product that was almost 2% saline and had a milliosmolar load of 1250 mOsm/L—four times isotonicity. Adverse events associated with doing this have shown that improvising when mixing IVIG is generally not a good idea. I caution against not only diluting products, but also running them through lines that are not compatible with IVIG products.
PP&P: Is there a maximum dose of IVIG that can be given at one time or in one day?
JS: Originally, IVIG products were only intended for replacement therapy for primary immunodeficiency diseases, and oftentimes the doses were 150 mg/kg to 250 mg/kg. It was discovered that these amounts were not enough to raise the IgG level above 600 mg/dL. (The normal range is 620 mg/dL to1400 mg/dL.) Now, doses have increased to 400 mg/kg–500 mg/kg. Once IVIG started to be used for immunotherapy for diseases such as immune thrombocytopenic purpura (ITP) or chronic inflammatory demyelinating polyneuropathy (CIDP), then the doses went from 500 mg/kg to 1 g /kg, and, in some situations, such as Kawasaki disease, 2 g/kg.
When administering higher doses of IVIG it is important to consider any comorbid conditions the patient has that could be affected by a higher volume of fluid or protein load. Also, when using an IVIG product containing glucose, consider the patient’s tolerance for higher glucose loads. Patients with diabetes may require an adjustment in insulin when intravenous glucose is administered.
While there is not an absolute cut off for how much IVIG can be given at one time or in one day, some facilities consider 140 g a maximum daily dose, and this is a good ceiling to remain below, especially when adjusting doses for morbidly obese patients.
PP&P: Should IVIG be filtered?
JS: With early IVIG products there was a fear of IVIG aggregates causing an adverse reaction, and so quite often these products required or recommended filtration. Currently there is only one product on the market that requires a filter and it is provided with the product, although some other products recommend filtration. Because most of the products on the market are pure IVIG and aggregates are not present, a filter is generally unnecessary. If you do use a filter on an IVIG set prior to it going through an IVIG pump, it generally will make the pump harder to work. So, if you are going to use a filter, it needs to be after the tubing for the pump, as it is hard for a pump to pull across a filter. I would recommend following the manufacturer’s package insert for specific guidelines and recommendations on the use of filters for their products.
Jerry Siegel, PharmD, FASHP, is the former senior director for pharmaceutical services at The Ohio State University Medical Center, where he worked for over 35 years. He graduated from The Ohio State University College of Pharmacy with both his BS and PharmD. Jerry also served as assistant dean of medical center affairs at The Ohio State University College of Pharmacy. He remains clinical associate professor at the College of Pharmacy there. Prior to this, Jerry worked as a clinical microbiologist and as a clinical pharmacist in transplantation and hematology/oncology before focusing on administration. He has lectured extensively on immunology, infectious disease, and pharmacoeconomics, and is a fellow of the American Society of Health-System Pharmacists (FASHP).