Intravenous immunoglobulins (IVIG) are fractionated blood products made from pooled plasma of 5000–10,000 donors per batch. Although originally intended to treat primary immune deficiencies, their usefulness has been demonstrated in the treatment of a variety of disorders, including secondary immune deficiencies, autoimmune diseases and inflammatory disorders. Furthermore, their use has expanded to treatment of haematologic, neurologic, dermatologic, oncologic and obstetric diseases.1–3
Many IVIG brands are commercially available.4 All products are mostly IgG (>96%, according to the European Pharmacopeia) but can contain trace amounts of IgM and IgA. The remainder of the products are made up of stabilising agents.
IVIGs differ in their approved indications, available concentrations, formulations (lyophilised powder or liquid), stabilisers, immunoglobulin A content, pH, sodium concentration and osmolality. All of these factors need to be carefully considered when choosing a product for a particular patient.5
For pharmacists, it is essential to understand how these products differ and how these differences may affect the clinical outcome for the patient. This report will focus on indications, pharmaceutical considerations, administration and adverse effects of intravenous and subcutaneous immunoglobulins (SCIG).
There are two main clinical uses, either as replacements in antibody deficiency or as immune modulators in inflammatory and autoimmune diseases.1–4,6
IVIGs are indicated as replacement therapy for primary immunodeficiencies (agammaglobulinaemia) and secondary immunodeficiencies (hypogammaglobulinaemia caused by chemotherapy or monoclonal antibody therapy, as well as immunosuppressive therapies).
In addition to antibody replacement, immunoglobulins also have anti-inflammatory and/or immunomodulatory effects.
An overview of licensed indications is shown in Box 1. For specifications per product, see the individual Summary of Products Characteristics (SPC).4
Pharmaceutical aspects potentially affecting tolerability
All IVIGs are not equivalent. There are differences in the following aspects:3,4,7–9
IVIGs are supplied as liquids or lyophilised powders. Liquid formulations have no reconstitution requirements, while powders must be reconstituted.
The volume load might be a critical factor in some patient populations (very young children, elderly). Higher concentrations (for example 10–12%) require less volume for a given dose and smaller volumes require shorter infusion times.
Powder formulations may be associated with a higher incidence of adverse events. Some liquid formulations need to be stored in refrigeration; others are stored at room temperature (according to specifications provided by the manufacturer).
Stabilisers are added to immunoglobulin products to stabilise the IgG molecules and prevent them from aggregating.
Stabilisers used in IVIGs include different sugars (glucose, sucrose, mannitol, maltose) and/or amino acids. They are added in various amounts and may pose a risk for some patients.
Use of glucose-stabilised IVIG products may influence diabetic control and insulin requirements in diabetic patients (risk for hyperglycaemia). Patients with diabetes should be careful with glucose-containing products.
Sucrose intravenously administered in IVIGs has no impact on blood glucose levels. Sucrose is enzymatically hydrolysed in the stomach or within the duodenum via sucrose into its component sugars.
However, up to 90% of reported IVIG-associated renal events are linked to use of sucrose-containing formulations. Exposure of the renal tubules to sucrose results in greater injury than exposure to glucose or maltose as the body is unable to cleave the disaccharide when given intravenously.
In patients with predisposed renal dysfunction, sucrose-containing products may be avoided, while maltose may produce hypersensitivity reactions in patients with allergy to corn.
Adverse effects due to amino acid stabilisers, such as glycine or proline, have not been reported. However, proline-containing products should not be given to patients with hyperprolinaemia.
The sodium content may vary from 0–1.8% between different formulations. It is important to know the amount and concentration of sodium being infused. This is especially of concern in patients with hypertension or renal dysfunction (on low-salt diets). Increased concentrations are associated with a higher thrombotic incidence and other adverse reactions.
Lyophilised products that have already sodium chloride are of particular concern. Doubling the concentration of lyophilised products may double the sodium concentration as well as the sugar concentration. Liquid IVIGs normally do not contain sodium chloride.
Both osmolarity and osmolality are related to the sugar and sodium content. Osmolality of the final IVIG solutions can range between 192 and 1074mOsm/kg, with physiologic osmolality ranging between 280 and 296mOsm/kg. Osmolality of lyophilised products may vary according to the diluent used for reconstitution. A liquid product has a fixed osmolality based on its composition.
Lyophilised products may cause hyperosmotic IVIG solutions, especially when reconstituted at higher concentrations. These solutions have a possible association with thrombotic events such as stroke and myocardial infarct. Patients at risk are those with peripheral poor access and patients with for example, renal dysfunction, who cannot tolerate large osmotic loads.
To minimise adverse events, the osmolality of IVIG products that are close to the physiologic osmolality are recommended.
There are small amounts of IgA in all IVIG products. No threshold has been established for IgA concentrations associated with anaphylactic risk. If a patient has a true selective IgA deficiency, this can pose the patient at risk for anaphylaxis. However, this is a very rare condition. Patients with low (or undetectable levels) of IgA may be able to tolerate all immunoglobulin without problems but it is advisable to monitor them carefully.
Alternatively, IgA deficient patients could receive subcutaneously administered immunoglobulins, as serious systemic reactions are rare with this route of administration, and induction of tolerance to IgA in treated individuals has been reported.
The optimal pH range for IgG to remain unaggregated without need for stabilisers is 4.0–4.5. Low pH is associated with risk for phlebitis, although unbuffered solutions will normalise on infusion and are generally well tolerated.
Various components present in an IVIG formulation can affect patients differently. To ensure that an appropriate product is selected and to avoid adverse drug events, the medical history and patient risk factors, such as contraindications, age and comorbidities must be carefully outweighed.
Dosing and administration
IVIG dosing regimens depend upon whether they are administered for prevention of infections in immune deficient patients or to suppress an inflammatory or autoimmune process. Dosing regimens range from 400–800mg/kg (replacement therapy in primary immunodeficiency) to 2000mg/kg (Kawasaki disease, chronic inflammatory demyelinating polyneuropathy).4,5,7
Routes of administration
Immunoglobulins may be administered by different routes. Most products are administered via the intravenous, subcutaneous, or intramuscular routes. Subcutaneous (SCIG) and intramuscular (IMIG) immunoglobulins are generally more concentrated than IVIG preparations and should not be given intravenously.
For immunoglobulins administered intravenously, the bioavailability is by definition 100%. As a criterion of adequacy of treatment in patients with hypogammaglobulinaemia receiving IVIG, serum trough levels of IgG are often used. However, this is not established to be relevant in patients with autoimmune disorders, where the endpoint is clinical improvement.
Subcutaneous administration of IgG is associated with a decrease in bioavailability to approximately two-thirds that of intravenously administered IgG, probably due to catabolism and/or binding in the tissues.1,2,4
Rate of administration
Each product has a recommended rate of infusion that should be followed (~SPC). As IVIGs are biologics and an immune reaction of the body is possible, an initial rate that allows observation and monitoring during 15–30 minutes should be used. If the product is tolerated, the rate can be increased as defined and a subsequent increase can be instituted to determine the maximum tolerated rate.
Patients receiving IVIGs should be monitored for short-term tolerance (blood pressure, heart rate, temperature, and monitoring of other adverse events) at repeated intervals following the infusion of the new product.
Adverse events (AE)
IVIGs should preferably be administered in a hospital facility (the first infusions should be especially administered with medical supervision) or in the home setting, usually by an experienced infusion nurse.1,2,7,10
These reactions occur during or within six hours of IVIG infusion and account for approximately 60% of adverse IVIG reactions. They include:
- Rate related reactions – especially seen in patients receiving their first IVIG infusion or when changing to a different IVIG product.
- Phlogistic reactions, concurrent infections – phlogistic reactions may accompany the use of IVIGs, especially in patients with an acute infection.
- Reactions resembling anaphylaxis – these are usually rate-related and often occur midway through an IVIG infusion. Symptoms include urticaria, flushing, tachycardia, wheezing, or dyspnea; pain in the chest or lower back; nausea and/or vomiting. They are usually managed by temporarily interrupting the infusion and/or treating specific symptoms.
- Management of symptoms – in many cases simply stopping the infusion until symptoms subside spontaneously and/or have been treated and restarting the infusion at a lower rate are sufficient.
- Pain (back/chest pain, headache etc.) may be treated with paracetamol or aspirin (in adults) or non-steroidal anti-inflammatory drugs. More severe pain may require opioids.
- Flushing, pruritus, or urticaria may be treated with intravenous and/or oral antihistamines. If not sufficient, glucocorticoids may be added.
- Nausea/vomiting can be treated with antiemetics, while for muscle spasms diazepam may alleviate symptoms.
- Other transfusion reactions occurring are transfusion-related acute lung injury (TRALI), which is a transfusion reaction characterised by the sudden onset of respiratory insufficiency during or shortly after transfusion of a blood product.
- Anaphylaxis during IVIG administration is extremely rare. When it occurs, it may be life-threatening and is defined as a medical emergency and should be rapidly treated with epinephrine and other therapies.
These reactions may occur during the infusion or a few days afterwards and account for approximately 40% of adverse reactions related to IVIG administration.
Most important are thromboembolic events (boxed warning about the risk) or complications affecting the central nervous system (headache), kidney (boxed warning about the risk of acute renal failure, osmotic nephorsis etc.).
Mild headaches during IVIG infusions can be prevented and/or treated with paracetamol or aspirin (adults only) or other non-steroidal anti-inflammatory drugs. Administration of IVIG at a slower rate may also help preventing recurrent headaches.
Aseptic meningitis is a post-infusion reaction. Patients with this disorder will exhibit severe headache with nuchal rigidity, but lumbar puncture will not show evidence of infection. Patient education is imperative. The benefit of the IVIG therapy needs to be out-weighted to the risk in such patients, and use of isotonic products with a lower dose and rate of administration is warranted.
Haemolysis associated with IVIG administration occurs rarely and the exact mechanism and risk factors are not very clear. Haematuria may cause darkening of urine within few hours of IVIG administration and can be a first sign of haemolysis.
As adverse reactions of IVIG can be serious, it is very important to document all infusions carefully, preferably in an electronic patient data management system. Documented items should include:
- Actual health status, any changes in this status in the period between infusion
- Premedications (if applicable)
- Name, dose and batch number of product
- Symptoms and severity of the reaction
- Infusion rate and infusion time
- Moment of appearance of the reactions
- Management of the response and outcome (with correlation to time)
The majority of patients tolerate IVIGs with a minimum of adverse events when premedication is used and a correct infusion rate schedule is followed. It is important that, once a patient has found a product that is well tolerated, it is advisable not to change products unless there is a compelling reason to do so.
IVIGs cannot be considered as generic products and administration of alternative products is only justified with the physician’s approval. When switching to an alternative product, it is prudent to use slow infusion rates and monitor the patient closely.
- Pharmaceutical aspects can potentially affect the tolerability of an intravenous immunoglobulin (IVIG).
- IVIGs cannot be considered as generic products.
- The majority of patients tolerate IVIGs with a minimum of adverse events.
- Once a patient has found a product that is well-tolerated, it is advisable not to change products unless there is a compelling reason to do so.
- Silvergleid AJ, Berger M. General principles in the use of immune globulin. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Last accessed October 2015.
- Silvergleid AJ, Stiehm E. Intravenous immune globulin: Adverse effects. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. Last accessed October 2015.
- Abolhassani H et al. Different brands of intravenous immunoglobulin for primary immunodeficiencies: how to choose the best option for the patient? Expert Rev Clin Immunol 2015;11(11):1229–43.
- Summary of product characteristics. Available at: www.medicines.org.uk. Last accessed March 2016.
- Siegel J. The product: all intravenous immunoglobulins are not equivalent. Pharmacotherapy 2005;25(11Pt2):78S–84S.
- Jolles S, Sewell WA, Misbah SA. Clinical uses of intravenous immunoglobulin. Clin Exp Immunol 2005;142(1):1–11.
- Siegel J. IVIG medication safety: a stepwise guide to product selection and use. Available at: http://www.pharmacypracticenews.com/download/IVIG_safety_ppn1210_WM.pdf. Last accessed March 2016.
- Ochs H, Siegel J. Stabilizers used in intravenous immunoglobulin products: a comparative review. Available at: http://pharmacypracticenews.com/download/SR1019_Stabl_IVIG_WM.pdf. Last accessed March 2016.
- Bolli R et al. L-Proline reduces IgG dimer content and enhances the stability of intravenous immunoglobulin (IVIG) solutions. Biologicals 2015;38:150–7.
- Ballow M. Safety of IGIV therapy and infusion-related adverse events. Immunol Res 2007;38(1–3):122–32.