Q&A with Jerry Siegel,
Jerry Siegel: Initially, intravenous immunoglobulin (IVIG) was used to replace the use of intramuscular immunoglobulin G (IgG) for the treatment of patients with primary immune deficiency (PID). Due to the limited volume and physical pain associated with the injections, doses of IgG were low and relatively ineffective in preventing infection in patients with PID. The first IVIG products to be introduced enabled much higher doses of IgG to be administered at a single time with a single infusion. The original doses of IgG were smaller (125-250 mg/kg) compared to today where average IVIG doses are in the range of 400-500 mg/kg for replacement therapy.
Another known cause of immune system deficiency was chronic lymphocytic leukemia (CLL) and routine infusions of IVIG were found to decrease the risk of infection in these patients. Furthermore, a somewhat serendipitous discovery was made when patients with PID that also had idiopathic (immune) thrombocytopenic purpura (ITP) were found to experience significant improvement of their thrombocytopenia following IVIG therapy. This discovery, despite not understanding the mechanism of action, led to clinical trials and ultimately an approved indication for ITP. An additional inflammatory process, Kawasaki syndrome, was found to be successfully treated in children using IVIG.
The discovery of IVIG as an immune modulating agent has led to research in many areas but it also has been particularly successful in treating autoimmune neurological disorders. For example, chronic inflammatory demyelinating polyneuropathy can be modified and controlled with the routine administration of IVIG. Many other autoimmune neurological diseases, such as Guillain-Barré syndrome, myasthenia gravis, and a dozen other syndromes, have shown positive response to IVIG therapy. However, the prevention and treatment of infections has generated mixed results.
Regarding interchangeability, while there have not been direct-comparison clinical trials between IVIG products to date, it is generally agreed that all IVIG products are clinically comparable. The exact pharmaceutical qualities of the various products are what differentiate them, as patient tolerability can vary widely from product to product. Thus far, IVIG has been primarily used to treat orphan diseases and the total use of IVIG remains relatively small. Going forward, however, evidence of effective treatment using IVIG for disorders such as Alzheimer’s disease—with over 5.4 million patients in the US alone—could alter the landscape of IVIG supply tremendously.
PP&P: What are the different forms of IVIG products available on the market?
Siegel: There are currently nine IVIG products being produced by six different manufacturers in the US market. There are three products that are produced in 5% concentrations, one of which is lyophilized—Gammagard from Baxter. Another lyophilized product, Carimune NF from CSL Behring, can be made as a 3% or 6% concentration, which, in the past, has commonly been concentrated to 9% or 12%, but with a very high osmolality. The remaining products are all in liquid form and come in 10% concentrations.
PP&P: What are the newest products that have been introduced?
Siegel: One of the newer products is Gammaplex 5% from Bio Products Laboratory (BPL). Compared to other 5% products, Gammaplex has three steps to partition for inactivate viruses. Using solvent detergent and nanofiltration, as well as low pH incubation, makes this product unique from the other available products. At this point, it is only FDA approved for treating PID, but new products tend to have limited use in other off-label indications until more experience is gained. Gammaplex 5% is stabilized with both glycine and sorbitol (see Table 1).
Click here to view a larger version of this Table
Another relatively recent product on the market is Flebogamma 10% from Grifols. This product is actually quite similar to the Flebogamma 5% with the exception of the concentration. Given its concentration, it should be considered comparable to other 10% liquid products. It is labeled as dual inactivated nanofiltered (DIF) because it is nanofiltered twice through progressively smaller filters—35 nm then 20 nm. Flebogamma 10% is stabilized with 5% sorbitol (see Table 2).
PP&P: Can you share some tips on improving IVIG tolerability?
Siegel: The key to improving tolerability is to understand the maximum tolerated rate of infusion per individual patient. For example, while some patients may be able to receive IVIG at rates greater than 250 ml/hr and feel fine or only slight discomfort, other patients may develop significant fever, chills, and headache at just 75 ml/hr. This clearly demonstrates a great variability among patients and their comorbid conditions. Therefore, it is important to ascertain the patient’s past medical history before starting IVIG therapy. Examples abound of conditional IVIG tolerance based on medical history. Patients with risk of renal insufficiency—as outlined in any given product’s black box warning—should initially be administered IVIG at the lowest possible rate and that patient should be carefully monitored for tolerance issues. Patients with a hypercoagulable state or past history of myocardial infarction (MI), deep vein thrombosis (DVT), or cerebrovascular accident (CVA) may be more sensitive to the infusion of products with higher osmolality. Slow infusion rates are necessary for all of these types of patients.
For all patients beginning a new IVIG therapy, a three-phase rate escalation plan is advised. If the patient demonstrates signs of infusion-related reactions, such as fever, chills, or headache, the rate of infusion should be reduced. As well, and in order to prevent a repeat of such a situation in the event of a transfer in care, the patient’s maximum tolerated rate should be recorded and not exceeded in subsequent infusions.
PP&P: What are the current approved therapeutic uses for IVIG?
Siegel: Collectively, there are only five currently approved indications for IVIG for all nine products available in the US:
- Primary immune deficiencies
- Autoimmune (idiopathic) thrombocytopenic purpura (ITP)
- Kawasaki syndrome
- Chronic lymphocytic leukemia
- Chronic inflammatory demyelinating polyneuropathy (CIDP)
PP&P: Looking ahead, what areas are receiving the most research for possible IVIG therapy impact?
Siegel: The areas currently receiving the most therapeutic research are Alzheimer’s disease, autism, and Clostridium difficile (C. diff) infection. To date, there are several completed studies on IVIG use in treating Alzheimer’s disease and more Phase 3 trials are open. So far, the studies have been hopeful, as there appears to be some prospect of not only slowing the progression of the disease but possibly improving the condition as well.
Research into the effect of IVIG on autism is very limited and has demonstrated equivocal results. As for C. diff infections, IVIG therapy research has also been limited, as it has been reported for patients with refractory disease. However, it has shown promise in limited studies and case reports.
While IVIG could be studied for effectiveness against any autoimmune disorder, to date, limited studies have not been quite so promising in most of these areas. However, this may be due to not knowing the appropriate therapeutic dosage regimen and the appropriate time to initiate therapy.
PP&P: How can pharmacists work with physicians to refine the scope of therapeutic use of IVIG?
Siegel: Pharmacists need to work with physicians to determine the appropriate medication use evaluation (MUE) criteria for IVIG use at their institution and create a policy for approval of off-label indications. In times of IVIG shortages, pharmacists have had to develop these criteria to ensure that patients with evidence-based indications were not denied therapy in preference to those with alternative therapies. The next IVIG shortage may be just around the corner, so ongoing pharmacovigilance of these products is essential to protect patients and ensure each facility is prepared to the best of its ability.
PP&P: What patient education should pharmacy provide on IVIG?
Siegel: The most important piece of information that a pharmacist can impart to a patient taking IVIG is the brand name of the product being given. Likewise, the nurse in charge of administering IVIG needs to keep specific information on the infusion rate escalation and the maximum tolerated rate, and this information also should be shared with the patient. Finally, the patient should be educated as to the most common side effects of IVIG administration, including fever, chills, and headache, as well as what pre-medications are commonly administered to patients that experience these side effects.
Almost two-thirds of patients receiving IVIG do not require pre-medications and administrating them to all IVIG patients may in fact mask more serious side effects. In an effort to predetermine potential side effects, the patient should be screened for risk factors and the administration rate and/or product selection should be determined based on comorbidities. For example, patients with hemolysis risk factors should be educated to watch for blood or brown discoloration in the urine. Keep in mind that headaches are the most common side effects of IVIG administration and are more common in patients with migraine histories. Aseptic meningitis also can be associated with IVIG administration but is uncommon and usually occurs two to five days after IVIG administration. Ultimately, the patient should understand the reasons behind IVIG administration and be instructed to report any unusual post-infusion adverse reactions immediately.
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 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.
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