European Journal of Pharmacology 747 (2015) 96–104

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European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar

Review

Is there evidence for recommending specific intravenous immunoglobulin formulations? A systematic review of head-to-head randomized controlled trials Anna Maria Buehler n, Uri P. Flato, Cleusa P. Ferri, Jefferson G. Fernandes Hospital Alemao Oswaldo Cruz, Institute of Health Education and Science, Rua João Juliao, 245, First floor, 01323-903 Sao Paulo, SP, Brazil

art ic l e i nf o

a b s t r a c t

Article history: Received 8 October 2014 Received in revised form 11 November 2014 Accepted 12 November 2014 Available online 10 December 2014

Intravenous immunoglobulins (IVIG) have been used for several licensed and off-label indications. Each IVIG product is a unique formulation of IgG and excipients, making them distinct products. How these differences impact on individual IVIG product efficacy and safety are not well established but can be investigated by head-to-head randomized controlled trials (RCT). A systematic review of head-to-head RCT comparing different formulations of IVIG, regardless of the target condition and outcomes investigated. Two reviewers screened 4084 citations retrieved from MEDLINE, Embase, Cochrane and LILACS, and 23 citations were fully-text evaluated. Eight trials were included. The clinical conditions, outcomes and risk of bias were assessed. Of the eight trials included only two investigated products that are currently on the market. One evaluated two Grifols brands used in patients with primary immunodeficiency and another evaluated two Baxter brands used in patients with chronic inflammatory demyelinating polyradiculoneuropathy. There were no differences between the formulations for the outcomes evaluated. In the other trials, either the manufacturers were acquired by other companies or the formulation was withdrawn from the market. As consequence, evidence concerning these products could not be considered. The quality of the studies was low, showing high risk of bias. Direct evidence about the different IVIGs is scarce and, at present, there is no scientific evidence that can be applied for a specific brand or formulation. Further comparative effectiveness studies are highly desirable for a better understanding of the differences in safety and efficacy of IVIGs. & 2014 Elsevier B.V. All rights reserved.

Keywords: Intravenous immunoglobulins Head-to-head randomized controlled trials Efficacy Systematic review

Contents 1. 2.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 Materials and methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 2.1. Study design . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 2.2. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 2.3. Eligibility criteria and data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 2.4. Risk of bias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3. Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.1. Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.2. Characteristics of the studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 3.3. Outcomes results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 3.4. Risk of bias. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

n

Corresponding author. Tel.: þ 55 11 999604002. E-mail addresses: [email protected] (A.M. Buehler), [email protected] (U.P. Flato), [email protected] (C.P. Ferri), [email protected] (J.G. Fernandes). http://dx.doi.org/10.1016/j.ejphar.2014.11.033 0014-2999/& 2014 Elsevier B.V. All rights reserved.

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Appendix A. Supporting information . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

1. Introduction

2. Materials and methods

Human intravenous immunoglobulins (IVIG) have been used for several decades as the mainstay treatment for primary immunodeficiency diseases (PID) (Berger, 2004; Bruton, 1952; CunninghamRundles et al., 1984; Janeway et al., 1953). The second important use of IVIG therapy is in autoimmune or inflammatory diseases (Kazatchkine and Kaveri, 2001). Immunoglobulin for clinical use is obtained from large pools of human plasma, with the pool size ranging from a minimum of 1000 donors to up to 60,000 donors, this information being as proprietary by each manufacturer (Knezevic-Maramica and Kruskall, 2003). Currently, a wide variety of diseases can be treated with IVIG and the licensed indications of the IVIG vary between the regulatory agencies of each country. There are also the off-label indications, which outnumber the number of formal indications, covering a large number of areas of medicine such as hematological, neurological, dermatological, oncological and obstetrical diseases (Leong et al., 2008). Commercially available IVIG products differ substantially regarding; the processes of production, purification and viral inactivation, IgA content and the stabilizers used (which might affect their efficacy), tolerability and costs (Gelfand, 2006; Lemm, 2002; Siegel, 2005). Depending on the characteristics of the formulation and the patients' profile, one brand is often preferable over another. For example, different IgA contents influence the risk of systemic reactions in PID patients with IgA deficiency and anti-IgA antibodies (Burks et al., 1986; Manlhiot et al., 2008). Hyperosmolar solutions may be avoided in patients having cardiac disease or at risk of a thromboembolic event (Reinhart and Berchtold, 1992). Sucrose or glucose stabilizers contents have been associated with renal failure in patients with chronic kidney disease (Cayco et al., 1997; Chapman et al., 2004). There are many opportunities during the manufacturing process where differences between products can be introduced. Nowadays, the decision making process about which trade name to use for a patient with a specific condition is based on these differences matched with the patient0 s risk factors. Although there have been many experimental research (Bayrakci et al., 2005; Szenczi et al., 2006), pharmacokinetic (Ballow et al., 2003; Berger et al., 2010; Koleba and Ensom, 2006) and observational studies (Manlhiot et al., 2010; Moy et al., 2010; Nadeau et al., 2010; Stein et al., 2009) as well as several narrative reviews summarizing this evidence (Cherin and Cabane, 2010; Feldmeyer et al., 2010; Gelfand, 2006; Gurcan et al., 2010; Haque, 1992; Knezevic-Maramica and Kruskall, 2003; Kotitschke and Harbauer, 1992; Lemm, 2002; Mark, 2011; Prins et al., 2007), there is uncertainty regarding the superiority of one IVIG formulation over another from direct comparison between different commercial trade names. The best evidence of efficacy is provided by randomized, head-to-head studies, comparing alternative interventions. This direct comparison establishes an evidence base for choosing or excluding a treatment, improving the quality of health care services and saving money (Lehmacher and Wolff, 2011; O'Connor, 2010). To our knowledge, this is the first systematic review aiming to identify direct comparisons between at least two different IVIG trade names, regardless of the target condition or outcome investigated.

2.1. Study design A systematic review of the head-to-head randomized controlled trials comparing at least two different trade names of IVIG, regardless of the target condition and outcome investigated. This review was conducted in accordance with PRISMA guideline (preferred reporting items for systematic reviews and metaanalyses) (Moher et al., 2009), using a predefined protocol. 2.2. Search strategy We searched for studies in MEDLINE, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE and LILACS, up to June 2014 with no limits of language or period. We combined terms using the controlled vocabulary from each database (Mesh for MEDLINE and Cochrane Library, Emtree for EMBASE and DeCS for LILACS) and their synonyms as free text words. In order to maximize the sensitivity of the search, we combined only terms related to the intervention (derivatives of the Mesh “Immunoglobulins, Intravenous”), associating those which distinguished the different trade names (e.g., pharmaceutical

Identification

Records identified through database searching (n = 4084)

Records after duplicates removed

Screening

(n =3870)

) Records screened

Records excluded (n = 3829)

(n = 3870)

Eligibility

Full-text articles excluded: (n =31) Full-text articles assessed for eligibility

Included

(n = 40)

Studies included in qualitative synthesis

7 RCT not directly comparing different brands formulations 9 non comparatives studies 14 narrative reviews 1 systematic reviews of RCT not directly comparing different brands formulations

(n = 9) Fig. 1. Flowchart of the included studies.

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Table 1 Characteristics of the studies. Study

Randomized controlled trial description, and sample size (N:I/C)

Clinical condition

Follow-up Intervention period of outcome assessment

Control

Kuitwaard et al. (2010)

Equivalence trial multicentric, Netherlands, efficacy trial (27: 13/14) Superiority cross-over trial multicentric Spain, Tolerability trial (35:18/17)

Chronic inflammatory demyelinating polyradiculoneuropathy

6–16 weeks Four infusions of 10% liquid IVIG (Kiovig, (mean 10 Baxter AG, Vienna, weeks) Austria).

(ODSS)a Four infusions of 5% freeze-dried IVIG (Gammagard S/D, Baxter AG, Vienna, Austria)

(MD:  0.004 (–0.4 to 0.4)), p ¼0.98

Only described as above 80% in most cases patients or investigators, (p ¼ 0.179 for patient; p¼ 0.122 for investigator; between the groups) 35/39 ¼90% vs 35/42 RR: 1.08 (0.91;1.28)b 29/39 vs 25/42 p¼ 0.115 RR: 1.25 (0.92;1.70) b

Matamoros et al. (2005)

Bussel et al. Noninferiority (2004) trial. Multicenter, International USA, Tolerability trial (97:48/ 49)

Primary efficacy outcome

Primary (n¼ 22) and Not secondary (n¼ 13) specified immunodeficiencies. (6–16 months)

Three infusions of 10% liquid IVIG (Flebogamma 10%, Instituto Grifols)

Investigators and Three infusions of 5% liquid IVIG (Flebogamma patients subjective efficacy (measured as 5%, Instituto Grifols) patient physical wellbeing by an analogue visual scale)

Idiopathic (immune) 21 days for thrombocytopenic efficacy purpura 6 months for adverse reactions

Two infusions of IVIG-C caprylate/ chromatography purification (Gamunexs 10%, Bayer)

Two infusions of IVIG S/ D 10% liquid solvent/ detergent purification (Gamimunes N, 10%, Bayer)

Mean 10.2 infusions of IVIG-C 10% caprylate/ chromatography purification (Gamunex, 10% Bayer)

Mean 10.7 infusions of IVIG-SD 10% solvent/ detergent purification (Gamimunes N, 10% Bayer).

Two infusions of IVIG (Polyglobin N; Tropon Biologische Praparate; Cologne, Germany)

Three infusions of IVIG MA (Pentaglobin; Biotest; Dreieich, Germany)

9 months

Percentage of patients whose platelet count increased fromr20  109/L to Z 50  109/L within 7 days percentage of patients with maintenance of platelet count Z 50  109/L for at least 7 days Proportion of patients with at least one validated episode of acute sinusitis, acute exacerbation of chronic sinusitis, or pneumonia proportion of patients with all infections (both validated and clinically defined) Annual infection rate Reduction of APACHE Score the improvement rate under therapy (defined as rate of patients with a decrease in APACHE II score of 4 7 from day 1to day 5) in-hospital mortality

Roifman et al. (2003)

Noninferiority trial. Multicentric International Canada, safety and efficacy trial (146:73/ 73)

Primary immunodeficiency

Pilz et al. (1997)

Superiority trial Unicentric Germany, efficacy trial (27:14/13)

Postcardiac surgical 4 days ICU patients at High risk for sepsis (APACHE scoreZ 24)

Steele et al. (1987)

Primary Superiority cross-over trial immunodeficiency Unicentric USA, efficacy trial (10:5/5)

6 months

6 infusions of unmodified IVIG with no specification of the IgG concentration containing 5% sucrose and lyophylizated (Revlon Health Care Group, Tuckahoe, NY)

6 infusion of modified IVIG with no specification of the IgG concentration (mIVIG) alkylated and stabilized with 10% maltose (Gamimune, Cutter Laboratories, Inc. Berkeley, CA)

Pirofsky (1987)

Primary Superiority cross-over trial immunodeficiency Multicentric USA, Tolerability trial (39)

6 months

3 infusions of unmodified IVIG 5% stabilized with 10% maltose at pH 4.25 (Cutter Biological)

Ochs et al. (1980)

Primary Superiority cross-over trial immunodeficiency Multicentric USA, safety trial (30)

6 months

3 infusions of 5% IVIG 10% maltose (Cutter Laboratories, Inc.; Berkeley, CA)

3 infusions of modified IVIG with no specification of the IgG concentration (mIVIG), pH 6.8 (Gamimune, Cutter Biological, Berkeley, CA) Patient acceptability 3 infusions of 10% IVIG 0.3 mol/L glycine (Cutter Laboratories, Inc.; Berkeley, CA)

Results

9/73 vs 17/73 p¼ 0.06 RR: 0.53 (0.25;1.11)b 11/73 vs 24/73 p¼ 0.012 RR: 0.46 (0.24;0.87) 0.18 vs 4.3 p¼ 0.023

IVIG MA:  5.2 (  12.5 to 2.1) vs IVIG:  6.9 (  13.4 to  0.4) p¼ 0.51 IVIG MA: 54% ( 25 to 81%) vs IVIG: 57% (29–82%) p ¼ 0.86 IVIG MA: 31% (9–61%) vs IGIV: 29% (8–58%); p¼ 0.90 Native: 664 mg/dL Mean (SD) IgG level (204) vs mIVIG: immediately after infusion Mean (SD) IgG 743 mg/dL (197) Native: 338 mg/dL level 4 weeks after infusion Hospitalization (209) vs mIVIG: 392 mg/dL (198) (number of patients) Native: 0 (0%) vs Sick days (number of mIVIG: 2/5 (40%) days) Missed work/ school (number of days) Native: 116 days vs mIVIG: 218 daysNative: 3 days vs mIVIG: 29 days Total elevation mean Native pH 4.25: serum levels of IgGs. 852 mg/dL mIVIG pH 6.8: 813 mg/dL.

IVIG-maltose 5%: 27/ 29 (93.10%) and 2/29 (6.9%) had no preference.

IVIG: intravenous immunoglobulin; (a) ODSS, overall disability sum score (range 0–12) a higher value indicates more limitations; (b) calculated by systematic review authors.

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preparations, drug compounding, therapeutic equivalency and known brand names). (for full strategy in MEDLINE, see Supplementary Appendix 1). We placed no language, time or filter for study design restrictions.

2.3. Eligibility criteria and data extraction We have included randomized controlled trials which directly compared at least two different formulations of intravenous immunoglobulin used in any target condition for any outcome investigated. We excluded trials comparing IVIG with placebo or an active treatment other than IVIG. Two investigators independently assessed the eligibility of the studies by screening the title and abstract. Studies considered eligible by the two reviewers were selected for full text evaluation, using a standard eligibility criteria form to register the reasons for exclusion. Any disagreement was resolved by consensus. We collected standardized data regarding patient characteristics (e.g. total number, average age, gender, previous IVIG dosage and body mass index); characteristics of the interventions (trade names and/or the highlighted formulation characteristics, IVIG scheme, dose, infusion rate, number of infusions and period of time between two infusions); outcomes and measurements of association.

2.4. Risk of bias Two independent reviewers assessed the risk of bias using the Cochrane Handbook criteria(Higgins, 2009). For each trial, the following domains were classified as low risk (þ), high risk ( ) or unclear risk (?) of bias: random sequence generation, allocation concealment, blinding of participants, personal and outcome assessors, incomplete outcome data, selective outcome reporting and other potential threats to validity (conflicts of interest).

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3. Results 3.1. Search strategy A total of 4084 citations were retrieved from the electronic search and 3928 titles and abstracts were screened based on titles and abstracts after removal of duplicates (Fig. 1). We selected 23 references for full text assessment, from which eight trials met our inclusion criteria (Bussel et al., 2004; Kuitwaard et al., 2010; Matamoros et al., 2005; Ochs et al., 1980; Pilz et al., 1997; Pirofsky, 1987; Roifman et al., 2003; Steele et al., 1987). The main reasons for exclusion were experimental/in vitro studies, observational studies and narratives reviews. We were not able to do meta-analysis because there were no identical trade names or common outcomes investigated by the trials.

3.2. Characteristics of the studies The characteristics of the studies are summarized in Table 1 and the scheme of IVIG administration is described in Table 2. The studies investigated IVIG in four different clinical conditions: primary immunodeficiency (Ochs et al., 1980; Pirofsky, 1987; Roifman et al., 2003; Steele et al., 1987; Matamoros et al., 2005), chronic inflammatory demyelinating polyradiculoneuropathy (Kuitwaard et al., 2010), thrombocytopenic purpura (Bussel et al., 2004) and in post cardiac surgery patients in Intensive Care Unit (ICU) and at high risk for sepsis (Pilz et al., 1997) (Table 1). Of the eight trials, only the studies by Kuitwaard et al. and by Matamoros et al. investigated IVIG trade names that are currently on the market (Kuitwaard et al., 2010; Matamoros et al., 2005). Regarding the others trials, most of the products either had their manufacturers acquired by other companies or did not describe in enough detail the formulations to allow us to establish some current trade name. In other situations, the brand was withdrawn from the market. As a consequence, evidence related to these

Table 2 Interventions scheme. Treatment Kuitwaard et al. (2010)

10 infusions in three phases: Not described. Just mentioned all patients treated according to their 1) Open label phase with one Gammagard S/D infusion individual established IVIG dosage prior to study entry. 2) Double-blind phase: patients randomised to receive four infusions of Gammagard S/D or Kiovig 3) Open-label phase with five Kiovig infusions Dose: 200 and 400 mg/kg every 2–4 weeks and fixed at 400 mg/kg fortnightly for patients previously submitted to bone marrow transplant infusion rate: 0.01–0.02 ml/kg/min for the first 30 min followed by a continuous increase until a maximum rate of 0.04 ml/kg/min. Total dose divided over two infusions on consecutive days Dose: 1 g/kg/day – (mean 987.3 (77.8) at IGIV-C group and mean 968.2 (78.5) at IVIG-S/D group) infusion rate: STarting of 0.01–0.02 mL/kg/min for 30 min. If well tolerated, gradually increased to a maximum of 0.08 mL/kg/min (0.06 mL/kg/min at Canadian centers) Single daily dose every 3–4 weeks for 9 months Dose: ranged 100–600 mg/kg body weight Infusion rate: NR Patients allocated to IVIG (Polyglobin N) received 2 infusions, Doses: IV IgG (Polyglobin N) total dose of 18 mg/kg, divided in 12 mg/kg and one per day. 6 mg/kg doses. Patients allocated to IV IgGMA (Pentaglobin) received IV IgGMA (Pentaglobin) total dose of 15 mg/kg, divided in 5 ml/kg does 3 infusions, one per day. Total period of treatment: 4 days Infusion rate: NR 6 infusion of each IVIG, then crossed-over to more 6 infusion Dose: 200 mg/kg Infusion rate: NR of each IVIG. Infusions were separated by 4 weeks interval 3 infusions every 4 weeks and then the patients crossed over Dose: 400 mg/kg ( 8 mL/kg) Infusion rate: starting of 0.01–0.02 ml/kg/min to more 3 infusions of the other IgG formulation. (0.5–1.0 mg/kg/min) to a maximum rate of 0.04 ml/kg/min (2.0 mg/kg/min). 3 infusions every 4 weeks and then the patients crossed over Dose: 100–150 mg/kgInfusion rate: 40–60 mg/kg/h to more 3 infusions of the other IgG formulation.

Matamoros et al. (2005) Two infusions of 5% gamma globulin before randomization and three infusions of 10% or 5% gamma globulin after randomization. Bussel et al. (2004)

Roifman et al. (2003) Pilz et al. (1997)

Steele et al. (1987) Pirofsky (1987) Ochs et al. (1980)

Dose and infusion rate

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products could not be used and we will only consider the following detailed description of the trials having IVIG brands currently on the market. (For the full description of the other trials, see Supplementary Appendix 1.) In the study by Kuitwaard et al. (2010) the authors compared four infusions of 10% liquid IVIG (Kiovigs, Baxter) to four infusions of 5% freeze-dried lyophilized IVIG (Gammagards S/D, Baxter) (Kuitwaard et al., 2010). Before randomization, all the patients had received one infusion of Gammagard S/D. After the randomized phase all the patients received five infusions of Kiovigs (Table 2). There was no description of the doses or the infusion rate. The mean follow-up period of the study was10 weeks. Matamoros et al. (2005) compared three infusions of 10% liquid IVIG (Flebogammas, Grifols) to three infusions of 5% liquid IVIG (Flebogammas, Grifols) (Matamoros et al., 2005). Before this randomized phase, all the patients had received two infusions of 5% Flebogammas. The doses varied from a range of 200 mg/kg to 400 mg/kg, administrated every 2–4 weeks.

mentioned that satisfaction was above 80% in both cases. They also investigated the tolerance and the hematological and biochemical parameters, finding no differences between the concentrations. All trials reported adverse effects, but these events were not common across the trials (Table 4). Fatigue, headache and muscle and joint pain were the most frequent events reported, occurring in more than 60% of the patients. There were no serious adverse effects described in any of the trials.

3.3. Outcomes results

4. Discussion

The primary efficacy outcomes of the trials are shown in Table 1 and the secondary outcomes are described in Table 3. Kuitwaard et al. (2010) investigated the improvement in the Overall Disability Sum Score (ODSS) scale, which is used to evaluate the patients' disability and was validated in patients with immune mediated sensory-motor polyneuropathies. As a result, they found no difference between the two IVIG concentrations. They also applied impairment and quality of life scales showing no differences between the formulations. Matamoros et al. (2005) considered as an efficacy outcome the well-being of the patients measured by analog visual scale and assessed from the point of view of the own patient and of the physician. They did not describe the numeric estimates and only

Although we identified eight trials directly comparing two different trade names of IGIV, we could only consider the evidence from two trials investigating trade names that are currently on the market. The comparison of 10% Kiovigs (Baxter) and the 5% freeze-dried lyophilized Gammagard S/D (Baxter) showed no significant differences in the morbidity of the patients with chronic inflammatory demyelinating polyradiculoneuropathy. Also, there were no significant differences in tolerance or patient well-being for the comparison of the liquid formulations Flebogammas 5% and Flebogammas 10% (Grifols) in patients with primary and secondary immunoglobulin deficiency. The findings provided by the other trials have little applicability since we cannot guarantee that the formulations used in the trials

3.4. Risk of bias All the studies showed high risk of bias for at least one of the domains evaluated (Table 5). The study of Kuitwaard et al. (2010) was well designed and reported random sequence generation and allocation concealment. However, it showed a high risk of bias due to the presence of conflict of interest. The study of Matamoros et al. (2005) showed high risk of bias of allocation concealment, blind scheme and selective reporting.

Table 3 Secondary outcomes investigated and qualitative results.

Kuitwaard et al. (2010)

Matamoros et al. (2005)

Secondary outcomes

Descriptive results

FSS (fatigue severity scale ranged from 0 to7; a higher score indicates more fatigue) ISS (INCAT sensory sum score ranged from 0 to20; a higher score indicates more sensory deficits)MRC (Medical Research Council ranged from 0 to 60, a higher value indicates better muscle strength)RHS (Rotterdam handicap scale ranged from 9 to 36; a higher score indicates less handicap)SF-36 ( short form (36) health survey; all separate items ranged from 0 to100, a higher scores indicate better health or less bodily pain)Vigorimeter (range 0e160) a higher value indicates better muscle strength. tolerance (based on the presence/absence of adverse drug reactions), haematological/biochemical analysis and serum immunoglobulin levels

No significant differences were found between the two preparations for all other outcome measures, including impairment scales regarding muscle strength and sensory symptoms, and scales measuring handicap, fatigue and quality of life.

Bussel et al. (2004)

Viral safety (HAV, HCV, HBV, HIV, Parvovirus B19)Laboratory analyses included CBC, indirect and Direct Antiglobulin (Coombs') Test (DAT), blood type, serum chemistries, and urine analysis.

Roifman et al. (2003)

Clinically defined, non-validated infections time to first infection, lung function parameters, infusion viral infection

Pilz et al. (1997) Steele et al. (1987)

Mechanical ventilation required; mean duration of ICU treatment IgG for viral, protozoan and bacterial pathogens (4 weeks after sixth infusion)Antibiotics taken; opsonizing antibodies against Streptococcus pneumoniae Laboratory parameters (liver, urine, blood counts, HBsAg)

Pirofsky 1987 Ochs et al. (1980)

Vital signs (systolic and diastolic blood pressure, temperature, pulse and respiration)Necessity to decrease the rate or interrupt any infusion

Haematological and biochemical parameters were similar in both groups no difference in the IgG and IgG subclass levels IgA and IgM levels were also measured, there being no significant differences between groups No evidence of any transmission of these 5 viruses was observed. The mean changes from baseline for hemoglobin, hematocrit and RBC concentration were not different and the magnitude of these changes were small and not considered to be clinically significant. No differences in clinically defined, non-validated infections time to first infection results not reported; no changes in any lung parameters including FVC and FEV were noted; antigen were not detected in either group No differences between groups No differences between groups Greater opsonizing antibodies were apparent for native IgG until the third infusion and then equal between the groups. Variations seen during the study were generally transient, not clinically significant and did not differ between the groups. No differences between groups 59% of the IGIV 10% patients had to be slowed or stopped the infusions vs 0% in IGIV-maltose 5% group.

Table 4 Adverse effects. Kuitwaard et al. (2010)

Matamoros et al. (2005)

Bussel et al. (2004)

Roifman et al. (2003)

Steele et al. (1987)

Pirofsky (1987)

Ochs et al. (1980)

Kiovig Flebo(n ¼14) gamma 10% (n¼ 18)

Flebogamma 5% (n ¼35)

IGIV-C 10% (Gamunex) (n¼ 48)

IGIV-S/D 10% Gamimune N (n¼ 49)

IGIV-C 10% (Gamunex) (n¼ 87)

IGIV-S/D 10% Gamimune N (n¼ 85)

Unmodified IVIG (n¼ 5)

Gamimune N (n¼ 5)

Native IGIV 5% mIGIV pH IGIV pH 4.25 (n¼ 39) 6.8 (n ¼39) maltose 5% (n ¼39)

IGIV 10% (n¼ 39)

Any event Fatigue

NR 10 (77%)

NR NR

25 (52%) NR

27 (55%) NR

80 (92%) NR

80 (94%) NR

NR NR

NR NR

5 (12.8%) NR

2(5.1) NR

NR NR

NR NR

Muscle /joint/ pain Nausea Headache Vomiting Fever Itching Chills Back/ neck pain Dizziness Flushing Skin rash/ erithema Pain at infusion area Tightness of chest Asthenia Hypertension episode

8 (62%)

NR NR 10 NR (71%) 9 (64%) NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

1 (3)

19 (66)

NR 8 (62%) NR NR 5 (38%) 6 (46%) 3 (23%)

NR 6 (43%) NR NR 6 (43%) 1 (7%) 6 (43%)

2 (6%) 2 (6%) 1 (3%) NR NR 0 (0) NR

5 (10%) 24 (50%) 6 (13%) 5 (10%) NR NR 3 (6%)

4 (8%) 24 (49%) 8 (16%) 5 (10%) NR NR 4 (8%)

NR 6.9%/ infusion NR NR NR NR NR

NR 8.0%/ infusion NR NR NR NR NR

NR NR NR 2 (20%) NR NR NR

NR NR NR 5 (50%) NR NR NR

NR NR NR NR NR NR NR

NR NR NR NR NR NR NR

1 (3) NR NR NR NR 0 (0) NR

13 (45) NR NR NR NR 14 (48) NR

5 (38%) 3 (23%) 3 (23%)

4 (29%) NR 5 (36%) NR 5 (36%) 1 (6%)

NR NR 0 (0)

1 (2%) NR 3 (6%)

3 (6%) NR 0 (0%)

NR NR NR

NR NR NR

NR NR NR

NR NR NR

NR NR NR

NR NR NR

NR 1 (3) NR

NR 9 (31) NR

3 (23%)

4 (29%) NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

1 (6%)

0 (0)

NR

NR

NR

NR

NR

NR

NR

NR

0 (0)

6 (21)

NR NR

NR NR

NR 1 (6%)

NR 0 (0)

2 (4%) NR

3 (6%) NR

NR NR

NR NR

NR NR

NR NR

NR NR

NR NR

NR NR

NR NR

NR: not reported.

2 (1.1%) 0 (0%) 0 (0%) NR NR 3 (17%) NR

A.M. Buehler et al. / European Journal of Pharmacology 747 (2015) 96–104

Gammagard S/D (n¼ 13)

101

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Table 5 Risk of bias. Study

Allocation Random Sequence generation (selection concealment (selection bias) bias)

Blinding of participants and personnel (performance bias)

Incomplete Blinding of outcome assessment (detection outcome data (attrition bias) bias)

Selective reporting (reporting bias)

Other bias: conflicts of interest

Kuitwaard et al. 2010 Matamoros et al. 2005 Bussel et al. 2004 Roifman et al. 2003 Pilz et al. 1997 Steele et al. 1987 Pirofsky 1987 Ochs et al. 1980

þ

þ

þ

þ

þ

þ



?

?





þ



?

þ

þ

þ

þ







þ

þ

þ

?







?

?







þ

?

?

?

þ

þ

þ

þ

?

?

?

?



þ

þ



?

?

þ









( þ) Low risk of bias; (  ) high risk of bias; (?)uncertain risk of bias.

are still on the market. The studies described only one specific characteristic of the formulation, such as the differences in pH, type of sugar content, or the method of viral inactivation, not providing detailed descriptions of content would have allowed us to link them with some equivalent current trade name. Additionally, we found studies in which the manufacturer laboratories either do not exist anymore (e.g. Revlon Health Care Group) or were acquired by another pharmaceutical company (e.g., Cutter Biological, Bayer). There are other limitations in the current evidence that deserve to be commented on. Clearly, the head-to-head evidence for the different IVIG formulations is scarce. Not all the formal indications and the most common off-labels indications were assessed by the trials. Also, not all the currently available products were investigated in the same clinical setting. The included studies have serious methodological limitations. Much of the information necessary to internally validate the results was either not adequately reported or showed high risk of bias, which may compromise the findings. The sample size of all included studies was small, with no guarantee of adequate power to detect real differences between the products for the specific outcomes (the parameters used to calculate the sample size were not described by the trials). In most of the studies, the definition of outcomes was either surrogate outcomes or was not clinically relevant. The range of the adverse effects reported by the trials was also limited, based on descriptive data with no formal testing for differences between the groups. Also, the adverse effects were not commonly reported across the trials and there was no report of any serious adverse effect. In fact, it is accepted that IVIGs are generally well tolerated. The majority of reactions are mild in severity and are reversible by slowing or temporarily stopping the infusion, and often occur during or after one of the first infusions of an IVIG product (Dantal, 2013; Orange et al., 2006). Most of the limitations of the existing evidence could be attributed to issues related to the process of registration of a new IVIG product in the regulatory agencies, especially the United States (US) Food and Drug Administration Agency (FDA). Until March 2000, the safety and efficacy of a new IVIG product in primary immune deficiency (PID) must be proven by a prospective, randomized, double-blind, parallel-group, non-inferiority study in at least 80 subjects head-to-head comparing the test

product to a US-licensed IVIG product. The primary efficacy outcome had to be the comparison of the serious infection rate over a period of 12 months. After March 2000, the FDA presented an alternate clinical trial design for the evaluation of IVIG safety and efficacy in PID: a single-arm, 12-month, open study of approximately 50 PID patients with safety and efficacy targets based on previous trials (http://www.fda.gov/ohrms/dockets/ac/00/transcripts/3603t2a.pdf) (March 17, 2000). Thereafter, many of the current brands have been licensed using this alternative approach (Berger, 2007; Berger et al., 2010; Church et al., 2006; Moy et al., 2010; Ochs et al., 2004; Stein et al., 2009; Wasserman et al., 2012). From the eight trials included, only the trial by Roifman et al. (2003) evaluated infections episodes. The brand Gamunexs was shown to be superior to Gamimunes and have more cost benefit (Mahadevia et al., 2005). As a consequence, the manufacturer at that time (Bayer) replaced Gamimunes with Gamunexs. Nowadays, the pharmaceutical company Grifols has bought the biological division of Bayer, which still markets the Gamunexs brand. In the absence of robust head-to-head evidence on the efficacy of the formulations in several settings, other indirect factors are considered when making the decision about which brand to use with patients. The specific differences in the manufacturing process between plasma procurement and the final IGIV product, IgG contents and excipients used (such as stabilizers, sugars and preservatives) may impact on the tolerability profile of the different brands of the IVIG. Depending on the patient-risk profile, one brand may be preferred over another. Some of these characteristics are associated with serious adverse effects and include thromboembolic events, hemolysis and hemolytic anemia, which is associated with stabilizers, such sucrose, glucose, maltose, D-sorbitol, mannitol, glycine and L-proline (Dantal, 2013; Orange et al., 2006). Special attention should be given for renal impairment related to IVIGs stabilized with sucrose, which is well established and includes acute renal failure, osmotic nephrosis and renal insufficiency (Chapman et al., 2004; Shah, 2005; Shah and Vervan, 2005). Costs are another important concern that must be considered in the choice of trade name. Concerns about reimbursement rate, product preparation time, storage and shelf life, and the incidence and costs associated with management of adverse events may impact on the decisions. For example, the 10% concentrated infusion permits the administration of double the amount of the

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active ingredient in the same time compared to the 5% concentrated product, and may consequently reduce infusion time, reduced volume overload and clinical deterioration in cardiac patients, and hospital expenses (Kallenberg CGM, 2007; Shah, 2005). Also, shorter infusion time decreases nursing time, which reduces costs for the health care center (Kallenberg CGM, 2007). Even considering all these factors which may affect the choice of one or another product, there are limited economic data available, most of them evaluating the cost of infections among patients with primary immunodeficiency disease (Menzin et al., 2014; Soares et al., 2012).

5. Conclusions Head-to-head randomized controlled trials comparing different IVIG trade names are very scarce and there is no evidence that allow drawing any conclusion about the different IVIGs formulations. Further comparative effectiveness studies are highly desirable to better understand the differences in safety and efficacy between them. Meanwhile, healthcare providers have to understand each product0 s characteristic differences and how these may impact on the patients' tolerability, preferences and costs to make their decisions.

Acknowledgements This work was funded by Hospital Alemao Oswaldo Cruz.

Appendix A. Supporting information Supplementary data associated with this article can be found in the online version at http://dx.doi.org/10.1016/j.ejphar.2014.11.033. References March 17, 2000. FDA Blood Products Advisory Committee 65th Meeting. In: FDA (Ed.). Transcript, Miller Reporting Company, Inc., Silver Spring, Maryland. Ballow, M., Berger, M., Bonilla, F.A., Buckley, R.H., Cunningham-Rundles, C.H., Fireman, P., Kaliner, M., Ochs, H.D., Skoda-Smith, S., Sweetser, M.T., Taki, H., Lathia, C., 2003. Pharmacokinetics and tolerability of a new intravenous immunoglobulin preparation, IGIV-C, 10% (Gamunex, 10%). Vox Sang., 202–210. Bayrakci, B., Ersoy, F., Sanal, O., Kilic, S., Metin, A., Tezcan, I., 2005. The efficacy of immunoglobulin replacement therapy in the long-term follow-up of the B-cell deficiencies (XLA, HIM, CVID). Turk. J. Pediatr. 47, 239–246. Berger, M., 2004. Subcutaneous immunoglobulin replacement in primary immunodeficiencies. Clin. Immunol. 112, 1–7. Berger, M., 2007. A multicenter, prospective, open label, historically controlled clinical trial to evaluate efficacy and safety in primary immunodeficiency diseases (PID) patients of Flebogamma 5% DIF, the next generation of Flebogamma. J. Clin. Immunol. 27, 628–633. Berger, M., Pinciaro, P.J., Althaus, A., Ballow, M., Chouksey, A., Moy, J., Ochs, H., Stein, M., 2010. Efficacy, pharmacokinetics, safety, and tolerability of Flebogamma 10% DIF, a high-purity human intravenous immunoglobulin, in primary immunodeficiency. J. Clin. Immunol. 30, 321–329. Bruton, O.C., 1952. Agammaglobulinemia. Pediatrics 9, 722–728. Burks, A.W., Sampson, H.A., Buckley, R.H., 1986. Anaphylactic reactions after gamma globulin administration in patients with hypogammaglobulinemia. Detection IgE antibodies IgA. N. Engl. J. Med. 314, 560–564. Bussel, J.B., Eldor, A., Kelton, J.G., Varon, D., Brenner, B., Gillis, S., Angiolillo, A., Kulkarni, R., Abshire, T.C., Kelleher, J., Group, I.-C.i.I.S., 2004. IGIV-C, a novel intravenous immunoglobulin: evaluation of safety, efficacy, mechanisms of action, and impact on quality of life. Thromb. Haemost. 91, 771–778. Cayco, A.V., Perazella, M.A., Hayslett, J.P., 1997. Renal insufficiency after intravenous immune globulin therapy: a report of two cases and an analysis of the literature. J. Am. Soc. Nephrol. 8, 1788–1794. Chapman, S.A., Gilkerson, K.L., Davin, T.D., Pritzker, M.R., 2004. Acute renal failure and intravenous immune globulin: occurs with sucrose-stabilized, but not with D-sorbitol-stabilized, formulation. Ann. Pharmacother. 38, 2059–2067. Cherin, P., Cabane, J., 2010. Relevant criteria for selecting an intravenous immunoglobulin preparation for clinical use. BioDrugs 24, 211–223. Church, J.A., Leibl, H., Stein, M.R., Melamed, I.R., Rubinstein, A., Schneider, L.C., Wasserman, R.L., Pavlova, B.G., Birthistle, K., Mancini, M., Fritsch, S., Patrone, L.,

103

Moore-Perry, H.J., Ehrlich, H.J., Group, U.-P.-I.S., 2006. Efficacy, safety and tolerability of a new 10% liquid intravenous immune globulin [IGIV 10%] in patients with primary immunodeficiency. J. Clin. Immunol. 26, 388–395. Cunningham-Rundles, C., Siegal, F.P., Smithwick, E.M., Lion-Boule, A., CunninghamRundles, S., O'Malley, J., Barandun, S., Good, R.A., 1984. Efficacy of intravenous immunoglobulin in primary humoral immunodeficiency disease. Ann. Intern. Med. 101, 435–439. Dantal, J., 2013. Intravenous immunoglobulins: in-depth review of excipients and acute kidney injury risk. Am. J. Nephrol. 38, 275–284. Feldmeyer, L., Benden, C., Haile, S.R., Boehler, A., Speich, R., French, L.E., Hofbauer, G. F., 2010. Not all intravenous immunoglobulin preparations are equally well tolerated. Acta Derm. Venereol. 90, 494–497. Gelfand, E.W., 2006. Differences between IGIV products: impact on clinical outcome. Int. Immunopharmacol. 6, 592–599. Gurcan, H.M., Keskin, D.B., Ahmed, A.R., 2010. Information for healthcare providers on general features of IGIV with emphasis on differences between commercially available products. Autoimmun. Rev. 9, 553–559. Haque, K.H., 1992. Does the commercial type of IVIG used make a difference? Pediatrics 89, 806–807. Higgins, J.P.T.G.S., 2009. Cochrane Handbook for Systematic Reviews of Interventions. Willey-Blackwell. Janeway, C.A., Apt, L., Gitlin, D., 1953. Agammaglobulinemia. Trans. Assoc. Am. Physicians 66, 200–202. Kallenberg CGM, L.M., 2007. Cost considerations in choosing an intravenous immunoglobulin preparation. EJHP Pract. 2, 66–68. Kazatchkine, M.D., Kaveri, S.V., 2001. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N. Engl. J. Med. 345, 747–755. Knezevic-Maramica, I., Kruskall, M.S., 2003. Intravenous immune globulins: an update for clinicians. Transfusion 43, 1460–1480. Koleba, T., Ensom, M.H.H., 2006. Pharmacokinetics of intravenous immunoglobulin: a systematic review. Pharmacotherapy 26, 813–827. Kotitschke, R., Harbauer, G., 1992. Evaluating the safety with reference to intravenous tolerance of immunoglobulins. Beitr. Infusionsther. 30, 203–207. Kuitwaard, K., Berg, L.H., Vermeulen, M., Brusse, E., Cats, E.A., Kooi, A.J., Notermans, N.C., Pol, W.L., Schaik, I.N., Nes, S.I., Hop, W.C., Doorn, P.A., 81, 2010. Randomised controlled trial comparing two different intravenous immunoglobulins in chronic inflammatory demyelinating polyradiculoneuropathy. J. Neurol. Neurosurg. Psychiatry 81, 1374–1379. Lehmacher, W., Wolff, S., 2011. The relevance of head-to-head trials to patientcentred clinical research. Z. Evid. Fortbild. Qual. Gesundhwes 105, 639–645. Lemm, G., 2002. Composition and properties of IVIg preparations that affect tolerability and therapeutic efficacy. Neurology 59, S28–32. Leong, H., Stachnik, J., Bonk, M.E., Matuszewski, K.A., 2008. Unlabeled uses of intravenous immune globulin. Am. J. Health Syst. Pharm. 65, 1815–1824. Mahadevia, P.J., Strell, J., Kunaprayoon, D., Gelfand, E., 2005. Cost savings from intravenous immunoglobulin manufactured from chromotography/caprylate (IGIV-C) in persons with primary humoral immunodeficiency disorder. Value Health 8, 488–494. Manlhiot, C., Tyrrell, P.N., Liang, L., Atkinson, A.R., Lau, W., Feldman, B.M., 2008. Safety of intravenous immunoglobulin in the treatment of juvenile dermatomyositis: adverse reactions are associated with immunoglobulin A content. Pediatrics 121, e626–630. Manlhiot, C., Yeung, R.S., Chahal, N., McCrindle, B.W., 2010. Intravenous immunoglobulin preparation type: association with outcomes for patients with acute Kawasaki disease. Pediatr. Allergy Immunol. 21, 515–521. Mark, S.M., 2011. Comparison of intravenous immunoglobulin formulations: product, formulary, and cost considerations. Hosp. Pharm. 46, 668–676. Matamoros, N., De Gracia, J., Hernandez, F., Pons, J., Alvarez, A., Jimenez, V., 2005. A prospective controlled crossover trial of a new presentation (10% vs. 5%) of a heat-treated intravenous immunoglobulin. Int. Immunopharmacol. 5, 619–626. Menzin, J., Sussman, M., Munsell, M., Zbrozek, A., 2014. Economic impact of infections among patients with primary immunodeficiency disease receiving IVIG therapy. Clin. Outcomes Res.: CEOR 6, 297–302. Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., Group, P., 2009. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. J. Clin. Epidemiol. 62, 1006–1012. Moy, J.N., Scharenberg, A.M., Stein, M.R., Suez, D., Roberts, R.L., Levy, R.J., Ballow, M., Fasano, M.B., Dash, C.H., Leach, S.J., 2010. Efficacy and safety of a new immunoglobulin G product, Gammaplex((R)), in primary immunodeficiency diseases. Clin. Exp. Immunol. 162, 510–515. Nadeau, J.O., Bhibhatbhan, A., McDougall, D., Toth, C., 2010. Identification and comparison of adverse events for preparations of IVIG in patients with neuromuscular diseases. Clin. Neurol. Neurosurg. 112, 467–469. O'Connor, A.B., 2010. Building comparative efficacy and tolerability into the FDA approval process. J. Am. Med. Assoc. 303, 979–980. Ochs, H.D., Buckley, R.H., Pirofsky, B., Fischer, S.H., Rousell, R.H., Anderson, C.J., Wedgwood, R.J., 1980. Safety and patient acceptability of intravenous immune globulin in 10% maltose. Lancet, 1158–1159. Ochs, H.D., Pinciaro, P.J., Octagam Study, G., 2004. Octagam 5%, an intravenous IgG product, is efficacious and well tolerated in subjects with primary immunodeficiency diseases. J. Clin. Immunol. 24, 309–314. Orange, J.S., Hossny, E.M., Weiler, C.R., Ballow, M., Berger, M., Bonilla, F.A., Buckley, R., Chinen, J., El-Gamal, Y., Mazer, B.D., Nelson Jr., R.P., Patel, D.D., Secord, E., Sorensen, R.U., Wasserman, R.L., Cunningham-Rundles, C., Primary Immunodeficiency Committee of the American Academy of Allergy, A., Immunology,

104

A.M. Buehler et al. / European Journal of Pharmacology 747 (2015) 96–104

2006. Use of intravenous immunoglobulin in human disease: a review of evidence by members of the Primary Immunodeficiency Committee of the American Academy of Allergy, Asthma and Immunology. J. Allergy Clin. Immunol. 117, S525–553. Pilz, G., Appel, R., Kreuzer, E., Werdan, K., 1997. Comparison of early IgM-enriched immunoglobulin vs polyvalent IgG administration in score-identified postcardiac surgical patients at high risk for sepsis. Chest 111, 419–426. Pirofsky, B., 1987. Clinical use of a new pH 4.25 intravenous immunoglobulin preparation (gamimune-N). J. Infect. 15 (Suppl 1), 29–37. Prins, C., Gelfand, E.W., French, L.E., 2007. Intravenous immunoglobulin: properties, mode of action and practical use in dermatology. Acta Derm. Venereol. 87, 206–218. Reinhart, W.H., Berchtold, P.E., 1992. Effect of high-dose intravenous immunoglobulin therapy on blood rheology. Lancet 339, 662–664. Roifman, C.M., Schroeder, H., Berger, M., Sorensen, R., Ballow, M., Buckley, R.H., Gewurz, A., Korenblat, P., Sussman, G., Lemm, G., Stein, M., Stark, D., Ermitano, M.L., Desroches, A., Mazer, B., Church, J., Ballas, Z., Filipovich, A., Friday, G., Graffino, D., Haysman, M., Knutsen, A., Richmond, W., Rubinstein, A., Marquinez, F., McNeil, D., Skoda-Smith, S., 2003. Comparison of the efficacy of IGIV-C, 10% (caprylate/chromatography) and IGIV-SD, 10% as replacement therapy in primary immune deficiency: a randomized double-blind trial. Int. Immunopharmacol. 3, 1325–1333. Shah, S., 2005. Pharmacy considerations for the use of IGIV therapy. Am. J. Health Syst. Pharm. 62, S5–11.

Shah, S., Vervan, M., 2005. Use of i.v. immune globulin and occurrence of associated acute renal failure and thrombosis. Am. J. Health Syst. Pharm. 62, 720–725. Siegel, J., 2005. The product: all intravenous immunoglobulins are not equivalent. Pharmacotherapy 25, 78S–84S. Soares, M.O., Welton, N.J., Harrison, D.A., Peura, P., Shankar- Hari, M., Harvey, S.E., Madan, J.J., Ades, A.E., Palmer, S.J., Rowan, K.M., 2012. An evaluation of the feasibility, cost and value of information of a multicentre randomised controlled trial of intravenous immunoglobulin for sepsis (severe sepsis and septic shock): incorporating a systematic review, meta-analysis and value of information analysis. Health Technol. Assess. 16, 1–186. Steele, R.W., Augustine, R.A., Steele, R.W., Tannenbaum, A.S., Charlton, R.K., 1987. A comparison of native and modified intravenous immunoglobulin for the management of hypogammaglobulinemia. Am. J. Med. Sci. 293 (2), 69–74. Stein, M.R., Nelson, R.P., Church, J.A., Wasserman, R.L., Borte, M., Vermylen, C., Bichler, J., IgPro10 in, P.I.D.s.g., 2009. Safety and efficacy of Privigen, a novel 10% liquid immunoglobulin preparation for intravenous use, in patients with primary immunodeficiencies. J. Clin. Immunol. 29, 137–144. Szenczi, A., Kardos, J., Medgyesi, G.A., Zavodszky, P., 2006. The effect of solvent environment on the conformation and stability of human polyclonal IgG in solution. Biologicals 34, 5–14. Wasserman, R.L., Church, J.A., Stein, M., Moy, J., White, M., Strausbaugh, S., Schroeder, H., Ballow, M., Harris, J., Melamed, I., Elkayam, D., Lumry, W., Suez, D., Rehman, S.M., 2012. Safety, efficacy and pharmacokinetics of a new 10% liquid intravenous immunoglobulin (IVIG) in patients with primary immunodeficiency. J. Clin. Immunol. 32, 663–669.