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Immune Globulin Product and Route Differentiation

By Joe DiStefano, RPh

This is an updated blog article, originally published as IVIG Brands in December 2015. In addition to including some new and updated information, products administered subcutaneously are discussed.

With the announcement by the manufacturer of Carimune NF of its discontinuation as of the 3rd quarter of 2018, there will be eight different brands of intravenous immune globulin (IVIG) and five brands of traditional subcutaneous immune globulin (SCIG) commercially available in the United States. Three of the IVIG brands can also be administered subcutaneously. There is also one brand of facilitated SCIG (fSCIG), a two-drug product where hyaluronidase is administered first to temporarily expand the SC tissue space to accept large volumes of fluid, followed immediately by the Ig component. Brands are listed in Table 1. There are other IVIG and SCIG brands in development.

Table 1





Flebogamma DIF

5%, 10%

Gammagard SD LIGA

Powder (reconstitute to 5% or 10%)


5%, 10%


5%, 10%



IV, SC (traditional)

Gammagard Liquid






SC (traditional)





SC (facilitated)


10% (IG component; plus hyaluronidase)

The clinical efficacy of the various immune globulin (Ig) brands is thought to be comparable. While all currently available brands are manufactured using a cold ethanol fractionation process, each manufacturer has modifications to this process plus different, proprietary purification, viral inactivation/removal and formulation steps. There are also differences in pH, osmolality/osmolarity, stabilizers and other components. The primary component of Ig products is immune globulin G (IgG) but all brands also contain trace amounts of IgA and IgM. These differences, as well as route of administration, can affect a patient clinically and the overall tolerability of Ig.

All Ig products have a boxed warning for thrombosis. Although it is possible with SCIG/fSCIG, only IVIG products have the additional boxed warning of renal dysfunction and acute renal failure.

Some prescribers may write for a particular brand based on past experience and familiarity. Some payers have limited formularies and may require use of a specific brand. Some require failure (e.g., due to side effects) or contraindications to IVIG before authorizing SCIG.

Some Ig products are stable at controlled room temperature and some at refrigerated temperature only, while some refrigerated products also have extended controlled room temperature stability. Something as simple as storage temperature could be a consideration for patients with limited refrigerator space or access to a refrigerator while traveling.


The route of administration affects the pharmacokinetics of Ig and therefore some of the features. Administration of IVIG results in faster, higher serum Ig levels. Higher serum Ig peaks are associated with greater systemic adverse drug reactions (ADRs) and the need for relatively infrequent administration. Administration of SCIG/fSCIG results in more stable steady state Ig levels and is associated with less systemic ADRs. Considerations are summarized in Table 2.

Table 2




  • More systemic ADRs
  • Longer infusion time
  • Less frequent administration than SCIG, similar to fSCIG
  • Unless fluid restricted, volume for large doses not problematic
  • Nurse monitoring and administration required; possibly less flexibility with scheduling evening/weekend doses
  • Option for patients with inadequate SC tissue
  • Option for patients unable/unwilling to self-administer SCIG/fSCIG


  • Less frequent systemic ADRs
  • Common injection site reactions (which usually decrease over time)
  • Shorter infusion time
  • More frequent administration of SCIG compared to IVIG (and fSCIG)
  • Large volume doses may be problematic for SCIG (may not be problematic for fSCIG)
  • fSCIG requires 1 - 2 injection sites; SCIG usually requires more sites
  • Maximum flexibility of administration and independence once properly trained on self-administration
  • Option in patients at high risk of renal dysfunction, thrombosis or other serious ADRs
  • Option in patients with poor venous access
  • Option of SCIG in patients with low serum IgA and anti-IgA antibodies at risk of anaphylaxis (may be an option with fSCIG)

IVIG Brand Differentiation

Some Ig brands are available as a 5% and/or 10% solution. The volume of a 5% solution is double that for a 10% solution and may or may not be desirable. For example, a 40 gm dose requires 800 ml of a 5% solution but only 400 ml of a 10% solution. The extra volume could be beneficial in those patients who may not orally hydrate well and could help to minimize ADRs. Conversely, the extra volume could worsen underlying clinical conditions such as congestive heart failure, hypertension and renal dysfunction, or could take longer to infuse.

With the market withdrawal of Carimune NF, Gammagard S/D LIGA is the only brand in a lyophilized (powder) form. Because it is a powder, Gammagard S/D LIGA must be reconstituted before use. This will increase the visit time if the Nurse has to prepare it in the home before administration.

Sucrose has been implicated in the boxed warning for renal dysfunction and acute renal failure. With the market withdrawal of Carimune NF, there are no commercially available sucrose-containing brands on the market. However, renal effects are still possible with all brands and should be used with caution in those patients at renal risk, including those with diabetes mellitus, age >65, pre-existing renal insufficiency, volume depletion, sepsis, paraproteinemia and on concomitant nephrotoxic drugs.

Gammagard S/D LIGA contains glucose, which may be a consideration in diabetic patients. Octagam contains maltose and causes some glucose monitoring systems (machine or test strip) that use glucose dehydrogenase pyrroloquinoline quinone (GDH-PQQ) or glucose-dye-oxidoreductase methods for detecting glucose to give falsely elevated readings, which could lead to the administration of excessive insulin and hypoglycemia. It is prudent for the nurse or pharmacist to check for compatibility of these systems in patients receiving Octagam. Privigen is stabilized with the amino acid L-proline and is contraindicated in those with hyperprolinemia type I or II. Privigen contains a corn-derived component and may cause problems in those with a corn allergy.

Some patients with low serum IgA develop antibodies against IgA and are at greater risk of developing severe hypersensitivity or anaphylactic reactions. All IVIG brands contain some IgA and vary in the amount. Octagam 5% is at the high end and could contain up to 200 mcg/ml while some brands contain relatively low amounts of IgA (Gammaplex 5% and 10% and Privigen contain less than 25 mcg/ml). Gammagard S/D LIGA contains the least (1mcg/ml in a 5% solution) and is considered the brand of choice for those patients with IgA antibodies.

Sometimes IV hydration such as dextrose 5% or sodium chloride 0.9% (normal saline) is ordered in conjunction with IVIG. Some brands are not compatible and should not be diluted or administered concomitantly, or through the same IV tubing, without first being flushed with a compatible solution or changed.

Gamunex-C and Gammaked are made by the same manufacturer and are identical.

Gammaplex 5% (but not the 10% formulation) and Flebogamma 5% and 10% contain sorbitol, which could be metabolized to fructose and are contraindicated in the rare genetic disease Hereditary Fructose Intolerance. These products can be administered to patients with the more common condition fructose malabsorption.

SCIG Brand Differentiation

Traditional SCIG brands are available as either a 10% or 20% solution. The volume of a 10% solution is double that for a 20% solution, requiring double the volume for the same dose and possibly requiring more SC sites. Other than no recommendation for maximum volume per site for Gamunex-C and Gammaked, the package insert of each SCIG product contains different parameters for maximum volumes and rates per site. Cuvitru also recommends different parameters for the first two doses. Cuvitru and Gammagard Liquid have parameters based on two different patient weight classes; Gamunex-C and Gammaked have parameters based on three.

None of the SCIG products contains glucose or maltose so there are no concerns in diabetic patients. All SCIG products except Hizentra are stabilized with the amino acid glycine, and should be used with caution in glycine-sensitive patients. Hizentra is stabilized with the amino acid L-proline and polysorbate 80; the former is contraindicated in those with hyperprolinemia type I or II. Hizentra contains a corn-derived component and may cause problems in those with a corn allergy.

All SCIG products contain IgA, ranging between approximately 37 - 80 mcg/ml. Although SCIG labeling states they are contraindicated in patients with low serum IgA and anti-IgA antibodies, SCIG products have been reported to be safely tolerated in these patients.


Although HyQvia is the only brand of fSCIG with no comparable product, there are some considerations between fSCIG and the other products. While all other Ig products are FDA-indicated in children and adults, HyQvia is indicated in adults only. fSCIG administration steps are more complex; the ability of some patients to learn to self-administer may be problematic compared to traditional SCIG. First, hyaluronidase is administered SC push slowly using a syringe into one or two SC injection sites. Then, within 10 minutes, the Ig component (identical to Gammagard Liquid 10%) pooled into an empty medication container is administered through the same tubing into the same SC injection sites using an ambulatory infusion pump. An alternate to the pooled Ig is to administer Ig withdrawn into multiple syringes and then administer sequentially using a syringe pump.

Like some of the SCIG products, the HyQvia package insert contains different parameters for maximum volumes and rates per site, different parameters for the first two doses and parameters based on two different patient weight classes. An advantage of fSCIG is it combines some favorable aspect of both IVIG and SCIG: large, IV volume-size doses can be administered through one - two SC injection sites once per month with less systemic reactions seen with IVIG and similar SC site reactions seen with SCIG.

Many of the SC injection site considerations are similar for HyQvia and traditional SCIG, but the location of SC injection sites for HyQvia is limited to the upper abdomen and front of the upper thighs.

HyQvia is stabilized with the amino acid glycine and should be used with caution in glycine-sensitive patients. HyQvia contains an average IgA range of 37 mcg/ml. Like all other SCIG products, HyQvia is contraindicated in patients with low serum IgA and anti-IgA antibodies but there have not been any published reports indicating these patients safely tolerate HyQvia.

A component of HyQvia, human recombinant hyaluronidase (HY), warrants consideration. The potential exists for antibodies to develop against human recombinant HY and cross-react with endogenous HY, which is known to be expressed in the adult male testes, epididymis, and sperm. Also, animal studies show maternal antibodies to human recombinant HY are transferred to offspring in utero. The effects of HY antibodies on fertilization or embryos in humans is not known.

These are highlights of just some of the differences in Ig products and routes of administration. It is important to have thorough knowledge of the patient's clinical history and status, the many Ig products available and the differences that can have a significant impact on the patient.