Refer to domain search and domain methodology section.

1.            INTRODUCTION AND PRODUCT DESCRIPTION

Intravenous immunoglobulins (IVIG), human normal immunoglobulin for intravascular administration (ATC code J06BA02), is a medicinal product derived from human plasma of at least thousands of healthy voluntary donors, prepared industrially, containing polyclonal antibodies to produce passive immunity and other protective effects. Human normal immunoglobulin is a highly purified protein extracted from human plasma. It contains mainly immunoglobulin G (IgG), with a broad spectrum of antibodies against infectious agents. IVIG has been used as a medicine since the 1980s and has a wide range of activity against organisms that can cause infection. In 1982, IVIG use in the US was approximately 40,000 g, and in 2006 consumption was estimated to reach 36 million grams annually {Duff, 2006}{1}. IgG works by restoring abnormally low IgG levels to their normal range in the blood.

Human normal immunoglobulin contains mainly IgG with a broad spectrum of antibodies against infectious agents. Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donors, usually thousands of blood donors. It has a distribution of IG subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.

Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments. The median IgG half-life after administration varies around 30 to 40 days approximately. This half-life may vary from patient to patient and clinical condition, in particular in primary immunodeficiency.

The rate of metabolism does not appear to increase with chronic administration. However, detailed pharmacokinetic studies are not available in patients with autoimmune diseases given repeated high dosages of IVIG.

Intravenous preparations of immune globulin (IVIG) first became available in the 1979 {The Consensus Working Group, 1997; Laupland KB, 2002}{2,3}, although these contained impurities that caused severe anaphylactoid reactions and protein aggregates that cause thromboembolies. Subsequent refinements allowed for safe administration of higher doses intravenously that more closely approximated physiologic levels.

Immune globulin may be administered by different routes: Intravenously (immune globulin, intravenous [human] "IVIG" or "IGIV"); subcutaneously (SCIG or IGSC) or intramuscularly (IGIM). Multiple products are available, which vary in concentration of IgG, additives and stabilizers, and IgA content. Most products are labeled for a specific route of administration. Subcutaneous and intramuscular products are generally more concentrated than intravenous preparations and should not be given intravenously.   

1.1 IVIG production and composition

Production of IVIG begins with pooled human plasma from several thousand screened volunteer donors. Cold alcohol fractionation is used to isolate the immunoglobulin-containing fraction. This is followed by further purification techniques, including additional precipitation steps to remove non-IgG proteins and ion exchange chromatography. Most IgG preparations also undergo several specific treatments to inactivate or removal potentially present blood-borne pathogens. These include low pH treatment, fatty acid treatment, solvent-detergent treatment, heat-treatment (pasteurization) and/or nanofiltration.

The World Health Organization has published minimum standards for manufacturing IVIG preparations {WHO 2008}{4}.

IVIG should be extracted from a pool of at least thousands of healthy screened donors.

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

It should contain as little IgA as possible.

The IgG molecules should be modified biochemically as little as possible and possess opsonizing and complement-fixing activities.

It should be free from preservatives or stabilizers that might accumulate in vivo.

There are slight differences in the manufacturing procedures utilized by the different producers, and different stabilizers are used in the excipients. However, the final preparations are highly purified (>90 percent) polyvalent IgG. Products differ in storage requirements and shelf life. Stabilizers may include sugars, such as sucrose, glucose, or maltose. Some IVIG products contain amino acids such as glycine or proline. The sodium content of different products also varies.

The resulting products are generally believed to be equally effective for treatment of the autoimmune and immunodeficiency disorders. However, they differ from each other in ways that may be important in a particular patient.

Product presentation varies in concentration of human normal immunoglobulins. The product is packaged in different volume vials (glass) as solution for infusion. The content is high purity IgG. The distribution of IgG subclasses also is variable. The solution is clear or slightly opalescent and colourless or pale yellow.

1.2 Main therapeutic indications

(From Core Summary of Product Characteristics. Clinical Particulars)

Replacement therapy in adults, and children and adolescents (0-18 years) in:

- Primary immunodeficiency syndromes with impaired antibody production.

- Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.

- Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.

- Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).

- Congenital AIDS with recurrent bacterial infections.

Immunomodulation in adults, and children and adolescents (0-18 years) in:

- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.

- Guillain Barré syndrome.

- Kawasaki disease.

- Product specific auto-immune indications (e.g. multifocal motor neuropathy (MMN), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), myasthenia gravis exacerbations) and other product specific indications – see Guideline on the Clinical Investigation of Human Normal Immunoglobulin for Intravenous Administration (IVIg) EMA/CHMP/BPWP/94033/2007 rev. 2.

There has been a rapid expansion in the use of intravenous immunoglobulin (IVIG) for an ever growing number of conditions and often used more extensively than the authorized indications (“off-label use”). IVIG use has had a major impact in neurology, haematology, immunology, rheumatology and dermatology. (See B002)

1.3 Dosing

The dose and dose regimen is dependent on the indication. (See TEC-1 Figure 1)

Replacement therapy in primary immunodeficiency syndromes:

The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/l. The recommended starting dose is 0.4-0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four weeks. Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.

Subcutaneous preparations are widely used in immunodeficiency because the gradual and steady introduction of immune globulin into the patient's circulation appears to have advantages. In addition, subcutaneous immune globulin (SCIG) is frequently self-administered at home, which could be more convenient for some patients.

Infusion rates for intravenous immunoglobulin:

Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.

Initial intravenous infusion rates are low, and if well tolerated, the rate of administration may be increased, as specified in the products’ Summary of Product Characteristics (SPC). For certain products, the SPC indicates that if the higher rate is tolerated, the rate may be further increased in primary immunodeficiency (PID) patients to the maximum infusion rate. Higher infusion rates may lead to improved convenience for patients and may reduce nursing time and the need for hospital resources. Patients at high risk for tromboembolic events should not receive rapid infusion of IVIG. Infusion rates for each of the licensed immunoglobulins are provided in the table below. Immunoglobulin should be administered according to the manufacturers’ recommendations. The table below gives the infusion rates, and the infusion time at maximum infusion rate of 1 g/kg dose in a 70 kg person {Department of Health, 2011}{5}.(See TEC-1 Figure 2). 

Patients with particular clinical conditions are at risk for certain adverse events. Adverse events can be reduced by downgrading the dose, the rate and the volume of the infusion. IVIG is well tolerated by the majority of patients, but it is important to note that, just as each patient may require a different immunoglobulin product, each may also require an individualized infusion regimen in order to achieve the desired therapeutic response. Once a successful regimen has been developed, it should be carefully followed with every infusion. This includes not only the rate of the infusion and necessary premedications, but the specific product, as well.

1.4 Adverse effects

Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infectious agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.

The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and for the non-enveloped viruses HAV and parvovirus B19.

It is strongly recommended that every time that IVIG preparation is administered to a patient, the name and batch number of the product are recorded in order to maintain a link between the patient and the batch of the product.

Serious reactions are uncommon. Adverse reactions occur more often when a patient is either receiving IVIG for the first time, or switching from one preparation to another or when there has been a long interval since the previous infusion.

It is important to maintain patients consistently on one IVIG product to reduce the risk of adverse events.

Certain patient groups are at higher risk for serious complications, such as those receiving high dose IVIG, patients with dehydration, the elderly, and those with preexisting renal or cardiovascular disorders, previous IVIG treatment complications, history of migraine, diabetes, concomitant use of nephrotoxic drugs, sepsis and fluid volume depletion.

Many reactions are dose rate-related. Common adverse reactions include fever, chills, malaise, headache, dizziness, nausea vomiting, allergic reactions, arthralgia, influenza-like illness, chest discomfort, chest tightness, chest pain, asthenia, malaise, peripheral oedema, infusion site pain, infusion site swelling, infusion site reaction, rigors, pruritus, rash, urticaria, back pain, myalgia, muscle spasms, muscular weakness. These reactions usually respond to temporary discontinuation of the infusion. If reactions are anticipated, a patient can be premedicated with antihistamines and intravenous hydrocortisone.

Patients with active infections may experience fever, rigors, and "flu-like" symptoms during infusion of IVIG, which is believed to result from lysis of bacteria and release of cytokines. When possible, infections should be treated with antibiotics before administration of IVIG.

Hematologic and thrombotic complications include hemolysis, anaemia, lymphadenopathy, neutropenia, and thrombotic and thromboembolic events such as myocardial infarction, stroke, pulmonary embolism and deep vein thrombosis {Micromedex Drugdex Database, 2014; Loeffler DA, 2013}{6,7}.

2.            IVIG IN NEUROLOGICAL DISEASES

Intravenous immunoglobulin (IVIG) has been successfully used to treat a number of immune-mediated diseases of the central and peripheral nervous system.

Although underlying mechanisms of action of IVIG have not been fully explained, it is known that IVIG can interfere with the immune system at several levels. The effect of IVIG in one of particular diseases may not be attributed to only one of its mechanisms of action, because the pathophysiology of these diseases is complex.

The efficacy of IVIG has been proven in Guillain-Barre´ syndrome (level A), chronic inflammatory demyelinating polyradiculoneuropathy (level A), multifocal mononeuropathy (level A), acute exacerbations of myasthenia gravis (MG) and short-term treatment of severe MG (level A recommendation), and some paraneoplastic neuropathies (level B). IVIG is recommended asa second-line treatment in combination with prednisone in dermatomyositis (level B) and treatment option in polymyositis (level C). IVIG should be considered as a second or third-line therapy in relapsing–remitting multiple sclerosis, if conventional immunomodulatory therapies are not tolerated (level B), and in relapses during pregnancy or post-partum period (good clinical practice point). IVIG seems to have a favourable effect also in paraneoplastic neurological diseases (level A), stiff-person syndrome (level A), some acute-demyelinating diseases and childhood refractory epilepsy (good practice point) {EFNS, 2008}{8}.

2.2          IVIG AND ALZHEIMER’S DISEASE

IVIG products are thought to contain the full range of antibodies present in the human repertoire. IVIG’s mechanisms of action in different disorders are generally poorly understood. It contains several antibodies that have the potential to reduce AD-type pathology, but whether these antibodies can actually do so is unclear {Loeffler DA, 2013}{7}.

IVIG products contain antibodies to Aβ oligomers and fibrils and perhaps also to monomeric Aβ. These drugs differ in their levels of anti-Aβ antibodies. IVIG has been shown in vitro to disaggregate preformed Aβ fibrils, promote Aβ phagocytic removal, protect against Aβ neurotoxicity, and prevent formation of Aβ soluble oligomers {Dodel R, 2010} {9}.

IVIG’s antibodies recognize multiple sites on conformational Aβ epitopes, and its main binding to Aβ is reportedly to Aβ25-40. This differs from the monoclonal anti-Aβ antibodies that have been used in clinical trials, Bapineuzumab and Solanezumab, which recognize only one epitope in linear Aβ and bind to Aβ1-5 and Aβ13-28, respectively. A recent review {Moreth J, 2013}{10} suggested that using the IVIG polyclonal antibody approach in an effort to deplete the spectrum of aggregated Aβ species might be more promising than using monoclonal antibodies targeting a single Aβ species.

Other proposed mechanisms of action are anti-inflammatory effects, possible anti-tau effects, alteration of Aβ passage in and out of the brain and other non-antibody-mediated effects.

IVIG contains other non-antibody proteins in addition to sLRP, which could influence its actions in AD in ways that are not clear. Interferon-γ, an inflammatory cytokine that also has some anti-inflammatory actions, is present in IVIG. Soluble human leukocyte antigen (HLA) class I and II molecules are present in some IVIG products, as are their “physiological ligands,” CD4 and CD8. Soluble CD4 in IVIG might interfere with HLA class II molecules on antigen-presenting cells, competing with HLA-class II-restricted T cells and possibly causing immunosuppression. Transforming growth factor (TGF)-β1 and TGF-β2 are also present in IVIG. TGF-β1 is increased in AD brain, where it is associated with plaques, but it also may promote Aβ clearance, so its significance in AD is unclear.

Intravenous immunoglobulin (IVIG) products are being investigated as potential agents for treatment or prevention of Alzheimer´s Disease (AD). Polyclonal naturally occurring autoantibodies against amyloid β are found in serum of healthy persons and are reduced in AD patients. The IVIG product Octagam (Octapharma) was shown by Dodel et al. in 2002 to contain antibodies against amyloid β (Aβ), suggesting that IVIG might be useful for treatment of AD. These antibodies might interfere with metabolism of Aβ and be reduced in patient with AD {Dodel R, 2002}{11}. This provided the rationale for IVIG pilot studies in AD patients. Three small clinical trials have tested the efficacy of intravenous immunoglobulin for mild-to-moderate Alzheimer’s disease. In an initial uncontrolled trial, five patients received 1-2 g/kg intravenous immunoglobulin every 4 weeks for 6 months. The concentration of total Aβ decreased in CSF and increased in blood compared with baseline. The patients had no cognitive deterioration {Dodel R, 2004}{12}. These results were independently reproduced in an uncontrolled trial {Relkin NR, 2009}{13} with eight patients (given 0.4–2. 0 g/kg per month for 6 months). Finally, a placebo-controlled (saline) multiple dose study {Weksler M, 2010}{14} of 24 patients (given 0.2 g/kg or 0.4 g/kg once every 2 weeks or 0.4 g/kg or 0.8 g/kg per month for 6 months) has been done. Patients who were treated with intravenous immunoglobulin 0.4 g/kg every 2 weeks had the best outcome, with no decline in cognitive and functional measures. The results of these studies were encouraging leading to phase II AD trials with these products {Dodel R, 2013}{15}. Additional phase III AD trial with another IVIG product is in progress. Now it is unclear whether any IVIG products will offer a breakthrough for treatment of AD. Differences have been reported between IVIG products for the concentrations of some of their antibodies and their biological activities. These may be due to differences in manufacturing practices and/or the antigenic exposure of the plasma donors. With regard to AD, differences between IVIG preparations have been found for anti-Aβ and anti-tau antibodies. Determination of whether IVIG products differ in their ability to slow AD’s progression will require comparative studies, as have been done for other diseases (Kawasaki disease and primary immune deficiency){Loeffler DA, 2013}{7}.

Refer to domain search and domain methodology section.

1.         The Interventions on Alzheimer´s Disease

At present there is no cure for AD. The current mainstays of drug treatment are pharmaceuticals intended to address the cognitive symptoms of AD, in combination with supportive medical and behavioral intervention {Upadhyaya P, 2010} {16}.

HTA and coverage bodies value trials of a new therapy given in combination with already-employed therapies that target different physiological processes than the new drug. Disease-modifying therapies should be assessed in combination with symptomatic therapies such as cholinesterase inhibitors or NMDA receptor antagonists. Add-on studies are one strategy to accomplish this assessment. Other strategies include limited placebo period studies, randomized withdrawal, factorial designs, and three-arm trials. The specific goals of the trial should determine the relative timing of the combination of drugs, but will typically involve adding the investigational drug to a stable dose of a commonly prescribed drug with regulatory approval {Green Park Collaborative (GPC), 2013}{17}.

Symptomatic treatment of dementia with cholinesterase-inhibitors is considered as standard of care, particularly in mild to moderate Alzheimer’s disease. Therefore in the future new treatments for dementia may be evaluated more and more by using add-on-designs, particularly in long term studies the “pure” use of placebo control for demonstration of efficacy may be difficult to justify.

Two major classes of drugs are currently available to treat the symptoms of AD:

Marketed Drugs

Acetylcholinesterase inhibitors (AChEIs): These include donepezil, rivastigmine, and galantamine. An older AChEI, tacrine, is rarely used due to concerns about liver toxicity. AChEIs boost the amount of acetylcholine, an important neurotransmitter in the areas of the brain that control learning and memory. These drugs have been approved for use in patients with mild-to-moderate AD on the basis of short-term (i.e., 6 months or less) improvements in memory and cognition in clinical trials. There are no data suggesting that use of AChEIs modifies or delays disease progression.

N-methyl-D-aspartate (NMDA) receptor antagonists: A single NMDA receptor antagonist, memantine, is currently approved for the treatment of symptoms of moderate-to-severe AD. Memantine binds to NMDA receptors that are associated with excessive stimulation and eventual death of neurons. Findings from clinical trials suggest small positive effects of memantine on cognition, activities of daily living, and behavior. Memantine is not thought to affect disease trajectory or progression.

Disease-Modifying Therapy

In addition to the symptomatic treatments currently marketed, a host of potentially disease-modifying therapies have been studied, and numerous others are in development. These include treatments that modulate inflammation and oxidative damage, as well as treatments that interfere with Aβ deposition such as anti-amyloid aggregation agents, drugs to reduce Aβ production, drugs to promote Aβ clearance as active vaccination or passive immunization with monoclonal anti-amyloid antibodies, and other potential therapeutic approaches { Moreth J, 2013; Salomone S, 2011; Nygaard HB, 2013}{10,18,19}.

Non drugs interventions

There is much interest in the use of cognitive therapies in AD. Preliminary studies seem to suggest a beneficial effect of cognitive stimulation, also known as Reality Orientation. Although promising, cognitive stimulation and exercise have limited evidence to support their use in persons with mild to moderate dementia or mild cognitive impairment.

Treatment of behavioural and psychological symptoms. 

Management of BPSD begins with careful search for trigger and/or exacerbating factors including environmental cues, physical problems (infections, constipation), medication and depression or psychosis. As studies of BPSD indicate a high placebo response, safe non-pharmacological management (education, exercise, aromatherapy, sensory  stimulation, personalized music) should be tried wherever possible in the first instance as symptoms may naturally resolve within a short time {Hort J, 2010; NICE, 2014; Lin JS, 2013}{20,21,22}.

2. The Interventions on Mild Cognitive Impairment

At present time there is no effective drug to treat or delay the progression from mild cognitive impairment (MCI) to dementia. There are no evidence-based interventions for MCI. Cognitive enhancers are agents that are often used to treat dementia, but did not improve cognition or function among patients with mild cognitive impairment and were associated with a greater risk of gastrointestinal harms. {Tricco AC, 2013; Russ TC,  2012; Birks J, 2006; Cooper C 2013 }{23,24,25,26}.

Refer to domain search and domain methodology section.

There has been a rapid expansion in the use of intravenous immunoglobulin (IVIG) for an ever growing number of conditions. IVIG has had a major impact in neurology, haematology, immunology, rheumatology and dermatology.

In the last ten years many reviews and evidence based clinical guidelines on the use and indications of IVIG have been published {Micromedex Drugdex Database, 2014; Patwa HS, 2012; Anderson D, 2007}{6,27,28}. In the European context some guidelines have been produced by medical societies {EFNS 2008}{8} or they have been supported and adopted as a reference for best practice guideline to be implemented. The UK Clinical Guidelines for Immunoglobulin Use were first implemented in 2008. The Guidelines were developed utilising an evidence review and extensive consultations with clinicians and other stakeholders. This update fulfils the commitment made in the Second Edition to undertake a biennial review from 2009. The 2011 update limited its focus on defining selection criteria for appropriate use; efficacy outcomes to assess treatment success; and reassignment of existing indications /inclusion of new indications. We show her as a reference the summary of conditions for which IVIG use is considered appropriate {Department of Health, 2011}{5}.(See TEC-2 Figure 1)

SUMMARY OF GREY INDICATIONS

Grey indications are those diseases for which the evidence is weak, in many cases because the disease is rare. Approval from both the local Immunoglobulin Assessment Panels and the Primary Care Trust is required for immunoglobulin treatment. In cases of ‘unlisted’ diseases, those not listed in the guidelines are to be considered as Grey. {5}. (See TEC-2 Figure 2)

Individual manufacturers are exploring the feasibility of developing IVIG therapy for Alzheimer’s disease including Mild Cognitive Impairment but, at time of writing, no manufacturers applied for market authorisation to EMA {Appendix CUR-3}. No data are available regarding the monitoring of off-label or compassionate use of IVIG for Alzheimer’s disease including Mild Cognitive Impairment {Appendix CUR-3}.

IVIG is presently very widely used for the treatment of a variety of immunologic disorders. IVIG is being used as a treatment in many different conditions, including mainly primary and secondary antibody deficiency states, haematology (acquired red cell aplasia, alloimmune thrombocytopenia, autoimmune haemolytic anaemia, haemolytic disease of the newborn, immune thrombocytopenic purpura), neurology (Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculneuropathy, inflammatory myopathy, Myastenia gravis, multifocal motor neuropaty) and other conditions (Kawasaki disease, transplantation, toxic epidermal necrolysis, staphylococcal or streptococcal toxic shock syndrome, autoimmune congenital heart block, autoimmune uveitis). See {TEC2}.

For more than thirty years, IVIG has been used for the treatment of post-exposure to infectious diseases, immune disorders and the management of patients with neurological conditions. IVIG treatment is used routinely for some immune-mediated neurological disorders such as Guillain-Barre syndrome, and recently IVIG has been investigated for the treatment of neurodegenerative disorders.

IVIG has not been approved for prevention or treatment of AD and mild cognitive impairment.

IVIG treatment of AD patients was first reported in a pilot study in 2004 {20}. Five patients with mild to moderate AD – Mini Mental State Examination (MMSE) mean score 19.4 – received Octagam (Octapharma; dose = 0.4 g/kg) on 3 successive days, every 4 weeks for 6 months. MMSE scores improved slightly in four of the AD patients and were unchanged in the fifth one, while their Alzheimer's Disease Assessment Scale-Cognitive sub-scale (ADAS-cog) scores decreased, suggesting increased cognitive functioning, in four patients and did not change in the fifth one. In 2009 results were published from a pilot study in which eight AD patients (mean MMSE score 23.5) were administered Gammagard S/D (Baxter Healthcare). After 6 months of treatment the mean MMSE score increased to 26.0, reflecting increased scores for six patients and no change in scores for two patients. After a 3-month washout period, the mean MMSE score returned to baseline (23.9). Following an additional 9 months of treatment, MMSE scores were essentially unchanged (mean 24.0).

Before publishing these results, in 2006 Baxter began a double-blind Phase II AD trial with Gammagard. Improved outcomes were noted in the Gammagard-treated subjects compared to those initially treated with placebo at 3, 6, and 9 months.

The results of a double-blind, placebo-controlled, 24- week phase II AD trial with Octagam were published in January 2013 {20}. Octagam had no apparent effects on cognitive or functional scores in the AD patients. No increase was found for plasma Aβ1-40; this had been reported in the pilot studies and suggested that IVIG products might increase efflux of Aβ from the brain. The only positive finding reported in this study, less reduction in glucose metabolism in some brain regions in the Octagam-treated individuals, was of uncertain significance. In conclusion, this trial showed favourable safety and tolerability of intravenous immunoglobulin and the absence of severe autoimmune reactions. Longer studies of larger populations are needed to assess effects on cognition and function in patients with Alzheimer’s disease.

In May 2013, the results of a placebo-controlled phase III AD trial with Gammagard were announced. Three hundred ninety patients had been treated every 2 weeks for 18 months with 200 mg/kg Gammagard, 400 mg/kg Gammagard, or placebo. No significant differences were found for the rate of cognitive decline between the Gammagard-treated group and placebo group.

Two AD-related IVIG trials are still in progress. Flebogamma (Grifols Biologicals) is being evaluated, together with albumin, in an AD phase III trial, and NewGam (Octapharma) is being investigated by Sutter Health in a phase II trial to determine its effects in patients with amnestic mild cognitive impairment (MCI) and its influence on the risk for these patients to develop AD. A possible reason for the failures in the most recent IVIG trials is that by the time AD’s clinical features become evident, its pathology, including extensive neuronal loss, is already well established. The trial with MCI patients should provide an indication of whether earlier IVIG treatment may be beneficial.

Newer research and developing human trials are becoming established for the use of intravenous immunoglobulins (IVIG) for the treatment and prevention of Alzheimer’s disease.

The IVIG trials reported to date in AD patients have produced conflicting findings. Because the most recent trials produced negative results, enthusiasm for IVIG as a treatment for AD has been reduced. Polyvalent antibody therapy for AD, as typified by IVIG, should have advantages over administration of individual monoclonal antibodies. To identify which antibodies should be included in an AD-specific IVIG preparation, more must be known about the range of anti-AD antibodies in IVIG and their effects on AD pathology in animal models. 

Refer to domain search and domain methodology section.

IVIG is usually administered in an infusion center or health care facility, indicated by specialized medical staff and supervised by health professionals. IVIG can be given in the hospital, doctor’s office, or patients’ home. In any setting, nurses administer 90% of the transfusions {White-Reid K, 2008}{29}. They should complete an accredited blood transfusion education program and be assessed upon their competency. Accredited nurses are responsible for checking blood and blood products, administering IVIG, monitoring patients during transfusion, and carrying out the appropriate actions should an adverse effect occur, ensuring adequate documentation in the medical notes, and reporting of transfusion reactions or other incidences related to the transfusion. (See TEC13. B0013). IVIG may be infused in the home setting, usually by an experienced infusion nurse. In some situations, this practice has been found to be more cost effective and result in improved quality of life measures. The first few infusions should be administered with medical supervision, regardless of the longer-term plan.

Many institutions require signed consent before any blood product is administered, and they document in the records of all of the patients that potential risks have been explained and that the patient/parent has received this information, has been given the opportunity to ask questions, and has given consent to receiving IGIV before initiating therapy.

The risk of transmission of viruses and prions from IVIG treatment is felt to be extremely low. Nevertheless, patients should be tested for exposure to known blood borne pathogens before starting IVIG therapy. Serologic tests for exposure to or infection with common pathogens such as Epstein-Barr virus, CMV and Hepatitis B will become positive in recipients of immune globulin therapy because of the passively transferred antibody. Therefore, if it is important to know if a patient has been infected with one of these organisms, antigen tests, such as PCR, should be done before IgG is administered.

It is recommended to perform testing for HIV and hepatitis A, B, and C, and measure complete blood count, hepatic transaminases and renal function before initiating immune globulin therapy by any route. In hematologic disease, Coombs’ testing should be done prior to IVIG therapy. This may identify preexisting infection or Coombs’ positivity before the immune globulin was administered and not transmitted iatrogenically. (See TEC10, B0010).

Solution products and reconstituted solutions of lyophilized products that have been stored in refrigerators should be allowed to reach room temperature before administration, to minimize adverse events. However, immune globulin solutions should not be microwaved or otherwise heated because the immunoglobulin protein could become denatured. Reconstituted lyophilized products should be inspected before administration to assure that the product has been completely dissolved and that the solution is uniform, although vigorous mixing causing excessive foaming should be avoided. All products should be inspected for the presence of particulates and evidence of tampering before pooling or administration to the patient.

(See TEC13, B0013)

Refer to domain search and domain methodology section.

IVIG is usually administered in hospitals, in an infusion center or health care facility, including hospital–based outpatient clinics (immunology, hematology, oncology) and ambulatory infusion centers {Duff 2006}{1}. Patients may benefit from receiving infusion treatment in outpatient settings if these settings maintain a consisting nursing staff and a physician is available during the infusion to monitor patient vital signs, in case of emergencies. For some patients, IVIG may be also infused in the home setting, usually by an experienced infusion nurse. In some situations, this practice has been found to be more cost effective and could result in improved quality of life measures. To determine whether the patient is a homecare candidate, the physician must be comfortable with the patient´s reaction to the IVIG infusion. The first few infusions should be administered with medical supervision, in a controlled setting, regardless of the longer-term plan, after which the physician assesses the overall risk. Patients also need to feel confident about starting their treatment options and should be educated about which location, if alternatives are available, would best serve to their interests (See also TEC7, B007- TEC14, B014).

In the European context this products are usually administered in public or private hospitals or hospital-based outpatient clinics, for a limited number of approved indications, under clinical protocols to ensure the appropriate management and use of IVIG.

Refer to domain search and domain methodology section.

IVIG products authorized by EMEA

{ European Medicines Agency}{30}

Flebogamma DIF presentations:

Flebogamma DIF*: 50 mg/ml; solution for infusion; intravenous use; vial (glass); content: 10, 50, 100, 200, 400 ml

Flebogamma DIF*: 100 mg/ml; solution for infusion; intravenous use; vial (glass); content: 50, 100, 200 ml

Privigen presentations:

Privigen*: 100mg/ml; solution for infusion; intravenous use; vial (glass); content: 25, 50, 100, 200 ml

Kiovig presentations:

Kioviog*: 100mg/ml; solution for infusion; intravenous use; vial (glass); content: 10, 25, 50, 100, 200, 300 ml

Other IVIG products authorized by national regulatory agencies in the European Union

BAXTER:

-Gammagard* S/D: 2,5g/50ml; 5g/96ml; 10g/192ml;

-Gammagard liquid*: 10 gr/100ml

BIOTEST PHARMA:

-Intratect*: 1g/20ml; 2,5g/50ml; 5g/100ml; 10g/200ml

-Intratect* 100gr/l solution for infusion

-Pentaglobin* 50mg/ml (10, 50, 100 ml)

BIO PRODUCTS LABORATORY:

-Gammaplex*: 5gr/100ml

-Vigam*:  5gr/100ml solution for infusion

CSL BEHRING:

-Sandoglobulin* 1 g/33ml; 3g/100ml; 6g/200ml;12g/200ml

GRIFOLS:

-Flebogamma  IV 5%* (10, 50, 100, 200 ml)

-Gamunex*: 100 mg/ml (10, 50, 100, 200 ml)

KEDRION:

-Igvena*: 50gr/l (20, 50, 100,200 ml)

-Keiven*: 50 g/l (20, 50, 100,200 ml)

-Venita*l: 50gr/l (20, 50, 100,200 ml)

OCTAPHARMA:

-Octagam*: 50mg/ml (50, 100 y 200ml); 100mg/ml (20, 50, 100 y 200ml)

-Gamten*: 100mg/ml (20, 50, 100, 200 ml)

IVIG products authorized by FDA

{ Micromedex Drugdex Database, 2014; FDA, 2014}{6, 31}

Baxter Healthcare Corporation:

Gammagard Liquid* 

Gammagard S/D* 

Bio Products Laboratory:

Gammaplex* 

Biotest Pharmaceuticals Corporation:

BIVIGam* 

CSL Behring AG:

Carimune NF* 

PrIVIGen* 

Grifols Therapeutics, Inc:

Gamunex-C* 

Gammaked*. (Distributed by Kedrion Biopharma)

Flebogamma DIF*  5% & 10%

Octapharma Pharmazeutika Produktionsges.m.b.H:

Octagam* 

Refer to domain search and domain methodology section.

The material investment needed for the use of IVIG is mainly {NZ Clinical Immunology Group, 2013; ACT Health, 2013; Octapharma 2007; Octapharma 2014; Baxter 2011}{ 32,33,34,35,36}:

- For the proper storage of IVIG products according to the product SPC (storage and handling part) which may require for some - including all IVIG supplied as liquids, refrigerated storage between 2°C and 8°C, whereas others, could be stored at room temperature. In some instance, when refrigeration is required, eg. in the case of the product is diluted, the preparation should be used as soon as practicable, in order to reduce microbiological hazard,but if storage is necessary, it should be stored at 2°C to 8°C for not more than eg. 24 hours(depends on stability studies).  Accredited blood refrigerators are needed and a close temperature monitoring shall be performed in order to guarantee a correct temperature range for this storage. IVIG that requires refrigeration and that are stored at a temperature below 2°C should not be used because of the likelihood of the product damage. Solutions must be kept away from freezing.

 - For the use of IVIG, an infusion pump (see TEC9) may be needed and standardized emergency equipment should be readily available during the infusion.

- For traceability of IVIG use: establishment and maintenance by the hospital or the institution of a system, ideally a computer program in order to ensure both patient and product traceability. The system shall allow linking each patient to the product received and vice versa.

- For potential (recurrence of) shortage of IVIG: discussion of a risk management plan to identify, characterize, prevent and minimize the risks of shortage. This plan may include, in some premises / hospitals back-up investments.

(Please also refer to TEC12, B0012).

Refer to domain search and domain methodology section.

IVIG infusions are usually given every 3 to 4 weeks and usually require three to four hours for infusion to the patient. Therefore, comfort measures during the infusion are needed, especially if side effects occur (medical bed or chair, blankets or pillows).

The infusion of IVIG are usually administered at hospital or in a health care facility at least during the first infusions with one brand, when it should be performed under strict medical supervision, with a medical doctor accessible at all times during IVIG transfusion and with resuscitation equipment available, in an area where the patient can be easily observed and monitored {ACT Health, 201; Younger MEM, 2012}{33,37}.

Under some specific conditions and in case of no occurrence of adverse reaction, subsequent IVIG infusion could be performed in the “home setting” if supervised by an experienced nurse.

Refer to domain search and domain methodology section.

The equipment and supplies needed for the intravenous use of immunoglobulins are {NZ Clinical Immunology Group, 2013; ACT Health, 2013; Younger MEM, 2012}{32,33,37}:

-Needles, bandages, peripheral sterile Intravenous (IV) infusion set and intravenous infusion pump as the use of permanent indwelling ports or central venous lines are usually discouraged due to the risk of infection (especially in antibody deficient patients) and thrombotic events . A specific intravenous line for the only use of IVIG is required and administration of concomitant medications through the same IV line should be avoided.

- Intravenous saline fluids for hydration.

- Appropriate waste disposal.

- Premedication as deemed necessary by the physician and/or IVIG specific products.

- Prescription of symptomatic treatment for headache, fever, flu-like symptoms should be done and drugs available for use if needed.

- Emergency equipment and drugs for treatment of a potential anaphylaxis should be readily available for use during the infusion.

(Please also refer to TEC12, B0012).

Refer to domain search and domain methodology section.

Detailed documentation of IVIG infusions should include the patient’s current health status and any changes in this status in the period between IVIG infusions; the name, dose and the lot numbers of the product; any pre-medications which were given; time duration of the infusion and specific rate titrations which were made; and any problems or adverse reactions  the patient experienced during the infusion and how they were managed.

Prior to the first administration { NZ Clinical Immunology Group, 2013; ACT Health, 2013; Octapharma 2014; Baxter 2011;Younger, 2012 }{32,33,36,37}:

- Serological testing for prior exposure to or infection with known blood pathogens (such as EBV, CMV, HBV, HCV, HIV) and appropriate vaccinations should be considered

Prior to each administration:

- A signed informed and written consent should be obtained from the patient, who should have received full information on the description of IVIG, their nature of blood product, the associated risks and benefits as well as alternatives to this treatment.

- The prescription from the physician for

•          the IVIG with the date, the identification of the patient, the particular IVIG product, the dose based on the patient weight, rate and duration of infusion

•          a premedication if needed.

•          specific instructions must be in place in case adverse events occur (headache, flu-like symptom, allergic reaction, malaise, nausea).

- Record of brand and assessment that it matches the physician prescription, the manufacturer, lot number, expiry date, dose of the product and identification of the patient.

For each administration:

- The integrity and quality of the IVIG should be assessed prior to the use, all refrigerated products should be at room temperature, the reconstitution of the product should be done per manufacturer’s guidelines, prescriber’s orders and following aseptic technique.

- The health status and the body weight of the patient prior to the infusion should be assessed and recorded. The dosage of the product should be adapted in case of any significant change of the body weight.

- The administration of the product should be carefully monitored and observed for any symptoms or alteration of vital signs throughout the infusion period and for at least 20 minutes after administration. In addition, a monitoring of the renal function and of the diuresis is required as well as a good hydration of the patient. As certain adverse reactions are more frequent in case of a high rate of infusion, during the first administration of IVIG, in case of switch between specific products and /or re-challenge infusion, or depending on patient medical condition and pre-existing risk factors, a low initial rate of infusion - which depends of each product - should be respected and may be gradually increased if the infusion is well tolerated by the patient. Should an adverse reaction happening (e.g. hypersensitivity with anaphylactic reaction, hyperviscosity complications such as thromboembolic events, acute renal failure, aseptic meningitis syndrome, haemolysis), then the vital signs should be checked and documented, the rate of infusion should be decreased or stopped and standard medical treatment should be implemented.

After the administration:

- Records of the infusion and declaration of any adverse reaction.

- Assess and record the need for a premedication for future infusions and ensure its prescription and availability for the next infusion.

- Records of the discard of any remaining product.

- Every 6 to 12 months:

-           Long term complications of IVIG such as renal impairment, hemolytic anemia.

-           Blood-borne infections.

Refer to domain search and domain methodology section.

Please refer to TEC10 (B0010).

Refer to domain search and domain methodology section.

Manufacturing and Preparation

Quality controls are required to guarantee the consistency of IVIG batches and to limit the risks of adverse reactions that have shown to be linked to the presence of certain proteins (e.g. IgA) or to biological⁄ microbial (e.g. endotoxins) or chemical (e.g. residues of viral inactivation treatments) impurities. A set of quality control assays are needed to guide manufacturers in the development of IVIG preparations, to control the conditions of production and to guarantee the quality, safety and consistency of the products. In fact, international and national Pharmacopoeias define quality assays that must be performed by manufacturers, and all assay methods should be validated {WHO, 2013} {38}. Reference preparations and WHO standards, based on plasma preparations or purified fractions, are available from the National Institute for Biological Standards and Control (NIBSC, UK), the Center for Biologics Evaluation and Research, Food and Drug Administration (CBER ⁄FDA, US), or from the European Directorate for the Quality of Medicines and HealthCare (EDQM, France). Batches should comply with the quality specifications defined and approved from regulators in the marketing authorization file of each product. Since IVIG products are manufactured using components of human blood, they may potentially contain the causative agents of hepatitis and other viral diseases, potentially even Creutzfeldt-Jacob Disease (CJD). For that reason prescribed manufacturing procedures at the plasma collection centers and plasma-testing laboratories need to be designed in that way that they reduce the risk of transmitting viral infection. Risk reducing measures include careful selection of donors for plasma pools, testing for viral markers at multiple stages which allow for the detection of plasma viruses {Baxter, 2011}{36}, and the application of rigorously validated methods of testing. Quality controls for plasma derivatives include determination of chemical parameters (like pH), protein content, content of stabilizers and residues of chemicals used for the production or viral inactivation and various safety parameters (e.g. protein identity, visual appearance) {Radosevich M, 2010}{39}.

Maintenance, storage and transport

Immunoglobulin products are supplied as solutions or as lyophilized products that need to be stored appropriately. Some IGs products require refrigeration whereas others can be stored at room temperature. As such, lyophilized products are generally stored at room temperature before reconstitution. However, all liquid IVIG products optimally require refrigerated transport and storage between 2°C and 8°C. Lower temperatures are likely to damage the product, and any IVIG liquid which has been frozen should be discarded {NZ Clinical Immunology Group, 2013}{32}. IVIG products should ideally be stored in accredited blood fridges that meet required standards. Domestic fridges and ward fridges should not be used for storage since these refrigerators are not closely monitored and accepted temperature range cannot be guaranteed. Blood products should be transported in dedicated and validated containers and be stored within glass containers, which are closed with rubber stoppers {ACT Health, 2013}{33}. It is important to follow the manufacturer’s specifications regarding storage of each product, since the recommendations may vary per IG product {NZ Clinical Immunology Group, 2013}{32}. While being stored and transported, the IVIGs should be protected from light {ACT Health, 2013}{33}.

Examples for Storage:

Kiovig (Baxter)

- Store in a refrigerator for the duration of the shelf life (36 months) (2°C – 8°C). Do not freeze.

- At room temperature: Kiovig may be stored at room temperature (below 25°C) for up to 12 months within the first 24 months. However, once stored at room temperature, the product must remain stored at room temperature and must be used within the first 24 months from the date of manufacture. The total storage time of Kiovig depends on the point of time the vial is transferred to room temperature. The new expiration date must be recorded on the package when the product is transferred to room temperature. Product cannot be stored at room temperature after 24 months from date of manufacture. Once the product has been stored at room temperature, the product should not be re-refrigerated {Baxter, 2011} {36}.

Octagam (Octapharma)

- Store in a refrigerator for the duration of the shelf life (48 months) (2°C – 8°C). Do not freeze.

- At room temperature: Octagam may be removed from the refrigerator for a single period of up to 3 months (without exceeding the expiry date) and stored at a temperature below 25°C. At the end of this period, the product should not be refrigerated again and should be disposed of {Octapharma, 2014} {35}. In certain cases, Octagam may be stored for 24 months at +2°C to +25°C from the date of manufacture {Octapharma, 2007} {34}. The date at which the product was taken out of the refrigerator should be recorded {Octapharma, 2014} {35}.

Use and documentation

Before administering IVIGs, it needs to be sure that the patient is not allergic to IGs, and not to the any of the ingredients in the product. Appropriate vaccinations should be considered for immune competent patients who receive regular/repeated treatment with IVIGs {Octapharma, 2014}{35}. It is strongly recommended that every time the patient receives a dose of IVIG the name, dose and batch number of the product are recorded in order to maintain a record of the batches used. The integrity (protective seals) and the quality of the product should always be assessed. IVIG products should not be used if the solution is cloudy, has deposits or is colored intensively. If the protective seals are not intact, the dispensing pharmacy should be notified and the product should not be given. The products should neither be used after the expiry date stated on the label {Octapharma, 2014; Baxter, 2011}{35,36}. All (refrigerated) products should be at room temperature before infusion, as adverse effects can be associated with the administration of products that are too cold. The products should be allowed to brought to room temperature by themselves and not by heating (e.g. in microwave) since this may degrade the product. However, once a product has been brought to room temperature it may not be returned to the fridge. The date the product is removed from refrigeration should be noted on the packet. It is important to note that each product should be administered once removed from refrigeration and it is for a single use in one patient only, and therefore any remaining product should be discarded and recorded as such {Baxter, 2011}{36}.

IVIG products are not generic and there are notable differences among them. They must be considered as individual therapies and choice of or decision to change a particular IVIG product needs to be done with caution {Gelfand EW, 2005; 2006}{40,41}. In the case of the product is diluted, the preparation should be used as soon as practicable, in order to reduce microbiological hazard, as the product does not contain antimicrobial preservative. If storage is necessary, the diluted preparation should be stored at 2°C to 8°C for not more than 24 hours. It is possible for lyophilized products to be prepared at more than one concentration depending on the amount of diluent added. Possibilities for different concentrations should however be specified in the manufacturer’s prescribing information. Lyophilized products should ideally be reconstituted in the infusion clinic. It is critically important to be aware of and to follow manufacturer’s guidelines, prescriber’s orders and aseptic technique when reconstituting these products {Younger MEM, 2012}{37}. IVIGs should be administered through a designated intravenous infusion, and should not be mixed with other medications or piggybacked into other infusions {Baxter, 2011}{36}. Since sterility of the IVIG is a concern, the solution should not be reconstituted until IV access has been established and it is ready to be administered. After adding the appropriate diluent to the powder by gently rotations, the vials should not be shaken to mix the solution, since this may damage the immunoglobulin proteins. Instead, the diluent should be able to dissolve the powder. It may take 5 up to 20 minutes for the powder to completely be absorbed into solution. Depending on the manufacturer, IVIG may only be stable in solution for a few hours {Rosenthal K, 2007}{42}

Another quality assurance process includes detailed documentation of IVIG infusions. This should include the patient’s current health status and any changes in this status in the period between IVIG infusions; the name, dose and the lot numbers of the product; any pre-medications which were given; time duration of infusion and specific rate titrations which were made; and any problems or adverse reactions the patient experienced during the infusion and how they were managed {Younger MEM, 2012}{37}.

Refer to domain search and domain methodology section.

The health professional using IVIG requires specific knowledge and skills in order to be competent to treat patients with IVIGs. A hospital based IVIG program should provide education, training and protocols for staff to ensure the appropriate management and use of IVIGs, including for transport, storage, use of equipment and infusion techniques. The number of training sessions may vary between personnel depending upon their experience. Usually two up to eight sessions, individualized or in groups, are required. The training should include education related to documentation, patient consent, difference among IVIG brands, selection of a brand on the basis of patients’ risk factors, contraindications, needs, action plans for adverse events, rapid infusion protocols, and setup of infusion pumps, tubing and filter equipment {Reid B, 2006}{43}. IVIG can be given in the hospital, doctor’s office, or patient’s home. In any setting, nurses administer 90% of the transfusions {White-Reid K, 2008}{29}. They should complete an accredited blood transfusion education program and be assessed upon their competency {ACT Health, 2013}{33}. Accredited nurses are responsible for checking blood and blood products, administering IVIG, monitoring patients during transfusion, and carrying out the appropriate actions should an adverse effect occur, ensuring adequate documentation in the medical notes, and reporting of transfusion reactions or other incidences related to the transfusion {ACT Health, 2013}{33}. Protocols including a list of recommendations for the administration of IVIGS to help nurses and institutions are valuable. These protocols should list the importance of providing information to patients and their families and obtaining patient consent for IVIG use after outlining its risks and benefits. Other key features should be the verification of the prescription and indications for IVIGs, a list of contraindications to IVIG use, the assessment of the patients’ medical history and health conditions before IVIG infusion, the identification of patients at risk for adverse reactions, the careful choice of IVIG brands and infusion protocols that are appropriate for the patients’ conditions, the equipment needed to perform the infusion and control checks of the product, the necessary preparations before the infusion starts, how the infusion should be carried out, how to deal with adverse reactions and how to complete the infusion, and post-transfusion care, {Reid B, 2006; Malcolmson C, 2014} {43,44}.

Training for administering IVIG {National Blood Authority, 2014}{45}

After having obtained training for administering IVIGs, one should be able to:

- describe the transportation and storage requirements of the specific IVIG

- define IVIG administration and location of site of infusion

- list the appropriate infusion sites and understand the rotation of sites

- demonstrate care of the infusion site

- describe appropriate supplies necessary to complete the procedure

- use the pump and the alternative “push method”

- check the product, prepare the product, and to report wastage or nonuse

- prepare the infusion site and draw up the product from single or multiple vials and prime tubing

- demonstrate insertion of subcutaneous catheter and act appropriately if blood is present

- demonstrate appropriate aseptic techniques

- perform accurate administration the treatment, and remove and dispose the needle safely

- understand potential situations/reactions which could result from the infusion

- manage any reaction to the treatment correctly.

  Whether the nurse is administering an intravenous infusion or teaching patients or caregivers to administer subcutaneous infusions, safety has to be the first priority. Guidelines prior to, during and after administration of IVIG should be carefully followed. In that sense, core pre-infusion assessments may include assessment of the appropriateness of the IVIG for the patient, product integrity and product temperature, and the patients’ health status. An important intra-infusion assessment may include a continuous assessment of the patient for any symptoms to ensure that the infusion is being tolerated {Baxter, 2011; Younger MEM, 2012}{36,37}. Core post-infusion assessments may include an assessment for any irritation or adverse reaction to the infusion and an assessment for pre-medications for future assessments. These guidelines should be offered to help infusion nurses, but also patients and givers to minimize problems and adverse effects, and safely provide a successful infusion experience for the patient {Younger MEM, 2012}{37}.

One needs to be familiar with the complications of IVIG treatment, possible adverse effects and post-infusion reactions, and one needs to know which interventions are effective in case the patient experiences particular adverse effects {Younger MEM, 2012}{37}. IVIG is not a generic drug and IVIG products are not interchangeable, thus a specific IVIG product needs to be tailored to patient characteristics to insure safety {Gelfand EW, 2005; 2006}{40,41}. Communication of potential issues and problems so that they can be proactively addressed is critical {Younger MEM, 2012}{31}. Training and experience is crucial in order to decrease the risk of adverse events. When an IVIG infusion is given the first time, more attention is needed since adverse events may occur. However, if a patient has already received several infusions, it is known how the patient reacts and thus doses etc. are adjusted. Since the manufacture for the individual product is different, individual patients may experience different adverse events to different products and may experience adverse events in some, but not in other products {Gelfand EW, 2005; 2006}{40,41}. Premedication is usually only given if there has been a previous adverse reaction. In case of an adverse reaction, the rate of infusion must either be reduced or infusion stopped. Lower doses may be administered on a more frequent basis. Risk of adverse events can also be reduced by ensuring adequate hydration and by paying attention to particular requirements depending upon the health condition and its associated increased risks. The treatment required depends on the nature and severity of the (risk of the) adverse reaction {Baxter, 2011; NHS Health Scotland, 2012}{36,46}. Lastly, anyone involved with the administration of IVIG to patients must be well informed about the manufacturing and regulation, proper dose and administration, adverse events, appropriate assessments and related patient education {Chipps E, 1994}{47}.

Refer to domain search and domain methodology section.

Patients should be eligible for IVIGs only in case they give consent for transfusion of blood and/or blood products. One or several patient and/or family education sessions may be required to inform patients and/or his or her family about what IVIG are and what they are used for, the fact that IVIGs are not licensed for use in the treatment of Alzheimers’ disease and mild-cognitive-impairment (off-label use), what one needs to know before using IVIGs, how and how often it is administered, the approximate duration of each infusion times depending on the patient’s assigned dose and body mass, potential risks and benefits of its use, the potential of virus transmissions, contra-indications (e.g. deficiency of Immunoglobulin A with anti-IgA antibodies, anaphylactic reaction) and contra-indications with other medications, so that informed consent may be obtained {Relkin NR, 2009; Gysler M, 2012}{13,48}. Information about such things as new modalities of treatment, legislative initiatives and insurance issues may also be valuable. Patients and their families should equally be provided with written information brochures concerning the IVIGs. A risk assessment may be carried out to ensure the patient and/or his/her family understand the need for treatment and how it is administered.

In case patients (and their family) agree upon an IVIG treatment, they should be informed about the fact that just as each patient may require a different IVIG, each may also require an individualized infusion regimen in order to achieve the desired outcome. IVIG is given through an intravenous infusion at an individualized rate, dose and time. If the treatment is successful, it may be repeated. At present IVIG is usually only given in hospital, thus no training and training materials need to be provided to the patient for using IVIG. However, in case patients may be able to receive IVIG for treating Alzheimer’s disease or mild-cognitive-impairment subcutaneously in the future, the patients (depending upon their cognitive functioning) or their caregivers might be able to administer the product outside the hospital setting. This will be especially the case for those patients who are receiving IVIG without adverse events or with mild adverse reactions that can easily be managed {American Academy of Allergy Asthma & Immunology, 2011}{49}. In that case special training should be provided to patients and their families about how subcutaneous IVIG should be given in a safe and aseptic manner, including associated risks and benefits. In any administration of IVIG, another important education topic is ensuring that the patient and his/her family understand adverse reactions and/or its signs and complications, as well as how to react to adverse reactions. The possibility of rare adverse events such as stroke, thrombotic events and acute renal failure, which have been reported with IVIG should be discussed {Dodel R, 2010, Patwa HS, 2012; ACT Health, 2013} {9,27,33}. Patients over 65 years of age with particular co-morbidities are mostly at risk for adverse events. In these patients, there should be special attention for the potential risks and benefits of IVIG weighed against those of alternative therapies {Baxter, 2011}{36}. In case of the existence of an augmented risk, patients should know that they will be administered with IVIG products at the minimum concentration available and the minimum rate of infusion practicable. Life attenuated vaccines should be deferred up to three months after the administration of IVIG. Patients receiving measles vaccine should have their antibody status checked. {ACT Health, 2013}{36}. The ability to drive and operate machines may be impaired by some adverse reactions associated with IVIGs. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines. Last but not least, a consent form documenting agreement to undergo treatment with IVIG and discussion of potential adverse effects must be completed by the patient and the responsible physician. Patients should be informed that they have the right to stop the treatment any time they wish {Younger MEM, 2012}{37}.