All IG Products Are Not the Same!

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Ever since the availability of more than 2 intravenous immunoglobulin (IVIG) biologics, the question has been, are they the same or different? In 2023, 14 IV and 4 subcutaneous products are available, as well as 1 facilitated subcutaneous product, and the question remains: Are all immunoglobulin (Ig) products the same? Are they all generic equivalents or biosimilars? And yet the most important question is, who cares?

The perspective makes a significant difference from a payor’s standpoint, that if they are all the same, and thus interchangeable, then the lowest price might dictate selection. From a prescriber’s perspective, if they are all the same, then generic prescribing means that all patients are the same and comorbidities do not need to be considered. From a patient’s perspective, if they are all the same, then tolerability and efficacy should be the same. If the products are not the same and switching products is based solely on cost savings, then ethical consideration ought to be taken into account if the risk and harm to the patient are increased due to a change in drug selection.

Background

Let’s start with some fundamental premises that define all Ig products: Are they generic drugs or biosimilars, and why should it matter for a health plan’s medical director? The generic name for IVIG formulations is immune globulin (human) (IgG), but that does not mean all products are generic.

According to the American Academy of Allergy, Asthma & Immunology, IVIG is not a generic drug and IVIG products are not interchangeable.¹ A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. By law, the active ingredient in a generic drug must be the same as the original drug, but generics may include different inactive ingredients such as preservatives or fillers.

By contrast, a biosimilar is a biologic medical product that is almost an identical copy of a reference product that is manufactured by a different company. Biosimilars are officially approved versions of original “innovator” products and can be manufactured when the original product’s patent expires.

As biologic medicines, biosimilars are inherently different from generics due to their molecular size and structure, complexity, and cost of their development.

Of note, Ig is a blood product prepared from plasma of between 1,000 and 30,000 donors per batch. Commercial Ig preparations contain a “species repertoire” of antibody specificities, resulting in neutralization of a wide range of antigens, including pathogens and superantigens; however, there is significant batch-to-batch variation in the concentration of a particular antibody.

Each batch of Ig varies within each manufacturer because of variations of batch sizes and the release specifications have a broad range. The manufacturing processes from each producer differ for Ig products, resulting in products that vary pharmaceutically even though they may have similar clinical effectiveness.

Pharmaceutical Differences

Stabilizers

The first IVIG product in the United States was Gamimune, which was stabilized with glycine, an amino acid. This product was in liquid form with a pH of 4.2. The low pH helped prevent the product from forming aggregates, and glycine proved to be an effective stabilizer. Gammagard (Takeda) was the second Ig product that was stabilized with glucose, but the product was lyophilized and required reconstitution. The resulting reconstitution with sterile water resulted in a solution of normal saline at 5% and neutral pH, but the glucose had to be accounted for in patients with diabetes.¹ The third product, Sandoglobulin, resolved this issue by using sucrose as the stabilizing agent and fractionating at a pH of 4.2. The lyophilized product could be reconstituted with sterile water, normal saline, or dextrose 5% in water at concentrations of 3%, 6%, 9%, or 12%.² Each of these diluents and concentrations resulted in very different osmolarities. The differences of these 3 products enlightened our understanding of the variations of IVIG products and the impact on patients’ comorbidities.

Sucrose-containing products are no longer on the market, partly due to the propensity for renal insufficiency and failure in patients with predisposing renal risk because sucrose products, even at 6% concentration in normal saline, are hyperosmotic. Glucose-containing products remain challenging to use in diabetic patients. Other carbohydrate-stabilized products such as maltose are challenging as well because of corn allergies and cross-reactivity with certain glucometers.³ Sorbitol-stabilized products have a potential risk in patients with hereditary fructose intolerance because sorbitol is metabolized to fructose.⁴ For amino acid–stabilized products other than glycine, proline is used in one product, Privigen (immune globulin intravenous [human], 10% liquid, CSL Behring) because of its ability to extend stability at room temperature, but is a risk for patients who are hyperprolinemic (Table 1).⁴

When looking at stabilizers alone, it is easy to see why Ig products cannot be interchangeable and can have deleterious effects on patients with various comorbidities.

Sodium Content and Ig Concentration

One of the first lyophilized products contained enough sodium chloride that when a 5% solution of IVIG was reconstituted with sterile water, it would result in a solution of normal saline. This seemed reasonable until pharmacists were asked to concentrate the product to a 10% solution to restrict volume in patients who could not tolerate the fluid. By adding half the volume to reconstitute the IVIG, the 10% solution resulted in a very hyperosmolar solution that led to numerous adverse reactions including renal insufficiency and thrombosis (Table 2).⁵

To make products that were iso-osmolar, manufacturers removed sodium and lowered the pH of the solutions. This also enabled them to increase concentrations from 5% to 10% to decrease volume.

It can be very confusing to look at a particular brand of IVIG and not understand that the 5% concentration may have a higher osmolarity than the same 10% brand. Because the rate of administration is based on weight, the osmolar and sodium load can cause hypernatremia or even pseudohyponatremia.⁶ Most adverse reactions can be controlled by slowing the rate of administration.

Clinical Differences

FDA Indication

There are 7 FDA-approved indications for IVIG in the United States; however, no product has more than 4 indications. All of the products have primary immune deficiency indications, except one: Octagam 10% (immune globulin intravenous [human], Pfizer).⁸ Conducting placebo-controlled trials in orphan diseases is very challenging and expensive with IVIG, as well as potentially unethical in some of these rare diseases. Compendium coverage for a number of these diseases has been recognized for decades. Although it is not illegal for a prescriber to authorize a medication off-label, the liability to administer may be left to the facility and staff in the case of any adverse events associated with such dispensing. In addition to this issue, the manufacturer cannot promote or provide information outside the approved indication for the product they represent.

IgA and IgG Subtypes

All currently marketed IVIG products in the United States have varying amounts of IgA, which is difficult to remove entirely because it is similar in size to the IgG3 subtype. One older IVIG product attempted to market a product with “NO IgA,” but it also had no IgG3. Ideally for replacement therapy, a balance of the 4 subtypes of IgG is maintained. Although the exact mechanism of each of these subtypes is not well understood, subtypes IgG1 and IgG3 are thought to work together, and IgG3 targets respiratory organisms with a half-life of only 7 days compared with the normal 28 to 35 days of the other 3 subtypes (Table 3). The amount of IgA in a particular batch of IVIG is relatively unimportant in most patients unless they have anti-IgA antibodies. They could have IgG or IgE antibodies, and if they are IgE type, then the amount of IgA is irrelevant because it will trigger a reaction up to and including anaphylaxis. All IVIG products carry a warning about the risk for anaphylaxis in patients with antibodies even though it is rare.⁹

Only 1 product is highly selected for very low IgA titers and should be used in these patients with caution. Also, the release specification per batch may not reflect the average per batch, which may be significantly lower.

Key Factors to Consider When Switching IVIG Products

If it is deemed necessary to switch an Ig product for any reason, the following process may be helpful to ensure a smooth transition:

• If going from a 5% to 10% product or vice versa, calculate the grams per kilogram and the resultant milligrams per kilograms per minute for infusion correctly to allow for the change in percentage.
• If going from a subcutaneous product to IV, consider the change in dose due to the change in bioavailability. The same applies when going from IV to subcutaneous.
• For IV products, remember that some products such as Gamunex-C (Grifols) and Gammaked (Kedrion) are identical except for the name and distributor.
• If moving from an amino acid base to a carbohydrate base, assess comorbidities that may affect tolerability.
• Try to keep osmolar loads similar to the original product.
• Evaluate renal and thrombotic risks for rate assessment.
• Review tolerability and premedication requirements of previous product.
• Establish new a maximum rate tolerability by using a 3-stage escalation titration.
• Do not assume that if all pharmaceutical factors are identical that the antibody content is identical.

Plasma Source

Normally, plasma is collected through plasmapheresis at FDA-registered sites. IVIG used for US patients must be collected from US plasma sources, even if it is fractionated outside the United States. The goal is to mimic regional antibodies as best as possible.

One notable exception is the source of plasma for Asceniv (immune globulin intravenous, human – slra 10% liquid, ADMA Biologics), which is manufactured from blending normal source plasma with plasma from donors who possess high antibody titers against respiratory syncytial virus (RSV). Asceniv is considered a polyvalent IVIG product because it is manufactured with plasma obtained from more than 1,000 donors and titers against diphtheria toxin, measles and polio as required by the FDA’s Center for Biologics Evaluation and Research. The true difference is in the standardization of the plasma pool of Asceniv for RSV titers and 8 other virus antibodies compared with Bivigam (immune globulin intravenous [human], 10% liquid, ADMA Biologics) and other commercial sources of polyclonal Ig products.^11-13

Ethical Implications of Interchanging IVIG Products

Most health systems stock one Ig product with an alternative second product for patients with high-risk comorbidities. The formulary of accepted medications may list Ig products as human immune globulin, but the pharmacy and therapeutics committee has selected the brand product based on contract pricing and several other factors, including product availability, vial size, storage, 340B pricing, and/or physician preference. Specialty and home care pharmacies may carry several products based again on product availability, price, and patient need. Quite often the payors and pharmacy benefit managers will select only certain brands that they will cover. Patients often develop tolerability to certain brands and rates of infusion. Changes in brands and rates of infusion can increase adverse reactions.

Switching products is sometimes necessary when a patient exhibits issues with tolerability, such as fever, chills, rash, malaise, and hyper- or hypotension. Often slowing the rate of infusion will mitigate the adverse reaction, but at times, premedications such as acetaminophen, diphenhydramine, or even corticosteroids are necessary.¹⁴ More severe reactions such as aseptic meningitis and hemolytic anemia may not be relieved by either rate adjustments or premedications.

Switching Ig products for a patient who is clinically stable for the sake of cost savings alone raises the ethical concern of introducing harm to the patient. Among the several tenets of the common ethics are the principles of non-maleficence and beneficence.¹⁴ Non-maleficence, or sometimes regarded as non-malfeasance, dictates that providers have an obligation to not cause harm toward their patients. This professional duty is so ingrained in our healthcare system that it harks back to a rudimentary element of the Hippocratic Oath: “First, do not harm.” The second principle, that of promoting the welfare and benefit of the patient, carries far more weight than what may intuitively appear as the flip side of avoiding harm: Beneficence requires the active and deliberate duty of a clinician to advocate for and affect their well-being.

The biomedical principles of non-maleficence and beneficence play a central role in the decision to interchange an Ig product for a well-controlled patient, or conversely to avoid switching to an appropriate Ig product when that patient continues to experience recurrent infection. Failure to adhere to these ethical hallmarks exposes the patient to harm and undermines the clinician’s ability to foster well-being and health outcomes.¹⁵

Conclusion

It may take a considerable time to find the right IVIG product and individual rate of infusion to optimize tolerability. When a patient changes site of care and the brand of IVIG product is not available, all effort should be taken to find the product that most closely resembles the product the patient is currently receiving, even though it will not be an exact match. In the case when a health-system, specialty pharmacy or home care pharmacy changes products with only cost in mind and not the product matching the tolerability of that individual patient, the patient’s rights and the clinician’s duty related to unnecessary additional adverse reactions need to be considered. Every patient’s biological and physiologic system is unique. This distinction is critical to ensuring that he or she receives the most appropriate IVIG treatment that optimizes clinical outcomes.

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Dr. Siegel reported financial relationships with ADMA, Bavarian Nordic, Kedrion and Takeda.

References

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This article is from the February 2024 print issue.