IVIG Therapy: Mechanisms, Formulations, and Key Considerations for Safe and Effective Use

Intravenous immunoglobulin (IVIG) is a plasma-derived therapy composed mainly of immunoglobulin G (IgG), prepared from pooled human plasma donations. It is used primarily to treat patients with humoral immunodeficiency, where the body cannot produce adequate antibodies to fight infections, and in various autoimmune disorders where the immune system attacks the body’s own tissues. Examples of autoimmune indications include immune thrombocytopenia, autoimmune hemolytic anemia, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, lupus, and idiopathic arthritis.¹

Image Credit: © Niser - stock.adobe.com

IVIG’s Origin and Mechanism of Action

IVIG therapy originated in 1952 as intramuscular immune serum globulin (ISG) used to treat antibody deficiencies. However, dosing was limited due to painful administration and small volumes. By the 1970s and 1980s, research advances led to the development of IVIG for intravenous use, allowing larger and more effective doses. Commercial IVIG became available in the US in 1980, and it has since become a mainstay in treating primary immunodeficiency (PI). Subcutaneous immunoglobulin (SCIG), though explored since the 1970s, was not FDA-approved until 2006.²

IVIG exerts its effects through several immunomodulatory mechanisms. It can block Fc receptors (FcRs) on immune cells, such as macrophages and natural killer cells, thereby preventing pathogenic antibody interactions that lead to phagocytosis or antibody-dependent cellular cytotoxicity. This effect occurs even in the absence of the inhibitory FcγRIIB receptor.³ Additionally, IVIG contains anti-idiotypic antibodies that neutralize pathogenic autoantibodies, helping prevent tissue damage. It also inhibits the complement cascade by binding complement proteins, reducing formation of membrane attack complexes and minimizing inflammation.⁴ Further, IVIG modulates cytokine production—downregulating pro-inflammatory mediators like IL-2, IL-6, and TNF-α—and affects immune cell activity by suppressing autoreactive B cells and dendritic cells and promoting regulatory T cells.³,⁴

Brands of IVIG

In the US, there are 10 IVIG brands: Bivigam (ADMA Biologics), Carimune (CSL Behring), Flebogamma (Instituto Grifolis), Gammagard S/D (Takeda), Gammagard Liquid (Takeda), Gammaked (Grifols Therapeutics), Gammaplex (Bio Products Laboratory), Gamunex (Grifols Therapeutics), Octagam (OctaPharma), and Privigen (CSL Behring).⁵ All brands primarily contain IgG, with trace IgA and IgM. While none has proven superior in efficacy, they differ in formulation, sugar content, IgA levels, and fluid compatibility—factors that may influence tolerability and clinical outcomes. Carimune and Gammagard S/D are powdered and require reconstitution, making them more time-consuming. The rest are liquid formulations, ready for infusion.

IVIG is available in 5% and 10% concentrations. A 10% solution has half the volume of a 5% solution for the same IgG dose, reducing infusion time and fluid burden—beneficial for patients with heart failure, renal impairment, or hypertension. Conversely, 5% may be better for patients needing hydration.⁵ Carimune contains sucrose and poses a higher risk of renal dysfunction, especially in older adults, diabetics, or those on nephrotoxic drugs. Gammagard S/D contains glucose, and Octagam contains maltose, which may interfere with glucose monitoring and lead to inappropriate insulin administration. Privigen and Bivigam contain corn derivatives and should be avoided in patients with corn allergies.⁵

IgA content varies across brands. Gammagard S/D has the lowest IgA (1 mcg/mL in 5%), making it ideal for patients with anti-IgA antibodies or IgA deficiency. In contrast, Carimune has high IgA levels (720 mcg/mL in 6%) and should be avoided in such patients.⁵ Some IVIGs are incompatible with common IV fluids like D5W or normal saline unless flushed or administered using separate tubing. Gamunex and Gammaked are identical products from the same manufacturer.⁵ Brand selection should be based on individual patient factors, including renal function, comorbidities, allergies, hydration status, and administration logistics.

Possible Adverse Effects and the Role of Clinicians

IVIG is generally well-tolerated, but approximately 25% of patients may experience adverse effects (AEs), especially with high doses or infrequent administration. The most common AE is headache. Others include fever, chills, flushing, fatigue, muscle or joint pain, nausea, vomiting, and rash. These effects often occur with the first dose or after switching brands. Delayed effects, such as persistent headaches, rashes, and cytopenias (eg, anemia), can appear days after infusion.⁶ Rare but serious reactions include allergic or anaphylactic responses and severe drops in blood counts.

To minimize risks, clinicians may conduct blood tests before and after treatment, ensure patients are adequately hydrated, slow the infusion rate, divide large doses over multiple days, and consider premedication with acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids.⁶ Most patients do not require pretreatment medications. Since IVIG is derived from donated blood, there is a theoretical risk of transmitting infections. However, stringent screening, viral testing, and purification methods significantly reduce this risk. No cases of HIV transmission via IVIG have been reported. Still, since novel pathogens cannot be entirely ruled out, IVIG use is reserved for clearly indicated situations, and specific product lots are carefully documented.⁶

IVIG is administered intravenously, usually in a hospital or infusion clinic, and sessions can take up to 4 hours. The frequency and duration depend on the underlying condition and the physician’s judgment. Using the same brand for each infusion can reduce the risk of side effects. Regardless of brand or administration method, the therapeutic effect of immunoglobulin is temporary, lasting about 1 to 4 weeks.⁶ Since antibodies degrade over time, patients with primary immunodeficiency require ongoing, lifelong replacement therapy to maintain protective IgG levels and prevent infections.²

IVIG remains a cornerstone treatment for both immunodeficiencies and autoimmune conditions due to its broad immunomodulatory capabilities. Understanding its mechanisms, formulations, side effect profile, and patient-specific considerations is essential for optimizing outcomes and minimizing risks.

REFERENCES

1. UpToDate. Intravenous immune globulin (IVIG): Beyond the basics. https://www.uptodate.com/contents/intravenous-immune-globulin-ivig-beyond-the-basics. Accessed May 9, 2025.

2. Immune Deficiency Foundation. Immunoglobulin Replacement Therapy. Updated 2024. https://primaryimmune.org/understanding-primary-immunodeficiency/treatment/immunoglobulin-replacement-therapy. Accessed May 9, 2025.

3. Anthony RM, Wermeling F, Karlsson MC, Ravetch JV. Inhibition of FcγR-mediated phagocytosis by intravenous immunoglobulin requires sialylated IgG. Blood. 2014;124(25):3709–3716. doi:10.1182/blood-2014-05-574327

4. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. Neurology. 2002;59(12 Suppl 6):S13–S21. doi:10.1212/WNL.59.12_suppl_6.S13

5. International Pemphigus & Pemphigoid Foundation. IVIG Brands. https://www.pemphigus.org/wp-content/uploads/IVIG-Brands.pdf. Accessed May 9, 2025.

6. Lee ML, Butani L. Intravenous immune globulin (IVIG): Beyond the Basics. UpToDate. https://www.uptodate.com/contents/intravenous-immune-globulin-ivig-beyond-the-basics. Accessed May 9, 2025.