BioDrugs (2013) 27:393400

DOI 10.1007/s40259-013-0044-3

ADIS DRUG EVALUATION

Immune Globulin (Human) 10 % Liquid: A Review of its Use

in Primary Immunodeficiency Disorders
Paul L. McCormack

Published online: 24 May 2013

Springer International Publishing Switzerland 2013

Abstract Human immune globulin (IG) 10 % liquid

(Gammagard Liquid) is a ready-to-use, highly purified, and
concentrated immunoglobulin (Ig)G solution approved in
the US for both intravenous and subcutaneous antibody
replacement therapy in patients aged C2 years with primary
humoral immunodeficiency. Intravenous IG 10 % liquid
every 34 weeks for C12 months, at median serum IgG
trough levels of 9.611.2 g/L, completely prevented acute
serious bacterial infections (SBIs) in a phase III clinical trial.
Weekly subcutaneous IG 10 % liquid at a dose equal to
137 % of the equivalent weekly intravenous dose, which was
earlier determined to produce the same IgG exposure, produced higher serum trough IgG levels and lower peak IgG
levels than intravenous administration, and also effectively
reduced SBIs; the infection rate was 0.067 SBIs/subject/
year, which met the US FDA efficacy criterion of \1 SBI/
subject/year. The rates for non-serious infections of any kind
were low for both intravenous and subcutaneous therapy.
Both intravenous and subcutaneous IG 10 % liquid were safe
and generally well tolerated. Systemic adverse reactions
were more frequent with intravenous therapy and local
infusion-site reactions were more frequent with subcutaneous therapy, but the latter reduced over time. Most adverse
reactions were of mild or moderate intensity. Thus, IG 10 %

liquid is an effective and generally well-tolerated preparation for both intravenous and subcutaneous IgG replacement
therapy in patients with primary immunodeficiency disorders involving antibody deficiency. It offers the benefits of a
ready-to-use, liquid preparation and the convenience of
home-based therapy in appropriate patients.

The manuscript was reviewed by: S. Baldovino, CMID, Centro

Universitario di Ricerche di Immunologia Clinica, Universita` di
Torino, Ospedale G. Bosco, Turin, Italy; M.G. Danieli, Department
of Scienze Cliniche e Molecolari, Clinica Medica, Torrette di
Ancona, Italy; S. Gupta, School of Medicine, University of
California, Irvine, CA, USA; P. Wood, Department of Clinical
Immunology, St Jamess University Hospital, Leeds, UK.

Most adverse events are of mild or moderate intensity;

serious adverse reactions are infrequent or non-existent

P. L. McCormack (&)
Adis, 41 Centorian Drive, Private Bag 65901, Mairangi Bay,
North Shore 0754, Auckland, New Zealand
e-mail: demail@springer.com

Immune globulin (human) 10 % liquid (Gammagard Liquid) for antibody replacement therapy in
patients with primary immunodeficiency disorders:
a summary
A highly purified, ready-to-use, human IgG preparation
approved for both intravenous and subcutaneous
antibody replacement therapy
In the pivotal clinical trial, intravenous administration
every 34 weeks prevented acute serious bacterial
infections (SBIs)
Weekly subcutaneous administration produced higher
trough and lower peak serum IgG levels than
intravenous administration, and an SBI rate that met US
FDA criteria for efficacy
Both intravenous and subcutaneous administration are
generally well tolerated.

Subcutaneous therapy is associated with a lower

frequency of treatment-related systemic adverse events
and a higher frequency of local infusion-site reactions
than intravenous therapy, although local reactions
reduce over time on therapy
Subcutaneous administration offers the benefits of
home-based therapy in appropriate patients

394

1 Introduction
Lifelong immunoglobulin (antibody) replacement therapy, combined with judicious use of antibiotics, is the
only effective treatment for many primary immunodeficiency disorders (PID) involving antibody deficiency,
such as X-linked agammaglobulinemia and common
variable immunodeficiency [13]. These disorders are
the result of genetic mutations causing B-cell dysfunction (or combined T- and B-cell dysfunction) and
inadequate antibody production [4]. PID may manifest
in childhood or adulthood, and patients are prone to
recurrent bacterial infections, particularly sinusitis and
other respiratory tract infections [1, 2, 5]. PID are relatively rare, but are considered to be under-diagnosed
and under-reported in registries; prevalence rates are
highly variable between countries or regions, ranging
from \1 per 100,000 of population up to 12.4 per
100,000 of population [68].
Intravenous administration of immunoglobulin (Ig)G
has been the gold standard therapy in PID with impaired
humoral immunity and allows the administration of high
doses of IgG [9]. However, subcutaneous immunoglobulin (IGSC) therapy has become widely accepted, and is
associated with fewer systemic adverse reactions and
higher trough levels of IgG with less fluctuation in
serum IgG levels than intravenous immunoglobulin
(IGIV) as a result of more frequent administration of
lower doses [2]. IGSC also allows for self-administration at home, providing convenience and independence
that translates into increased quality of life in many
patients [2].
Human immune globulin (IG) 10 % liquid (Gammagard Liquid) is a ready-to-use, highly purified, and
concentrated IgG solution for infusion that is approved
in the US for either intravenous or subcutaneous
administration in the treatment of patients aged
C2 years with primary humoral immunodeficiency [10].
This immune globulin preparation is also licensed in the
EU under the brand name Kiovig for the intravenous
treatment of patients with PID involving impaired
antibody production [11]. Throughout this article, the
term IG 10 % liquid refers solely to the Gammagard
Liquid or Kiovig preparations. This article reviews
the efficacy and tolerability of IG 10 % liquid, administered by either the intravenous or subcutaneous route,
in the treatment of patients with PID involving antibody
deficiency, and briefly overviews its pharmacologic
properties.

P. L. McCormack

Data sources: Medical literature (including published

and unpublished data) on human immune globulin
10 % liquid (Gammagard Liquid [or Kiovig]) was
identified by searching databases including MEDLINE
(from 1946) and EMBASE (from 1996) [searches last
updated 10 May 2013], bibliographies from published
literature, clinical trial registries/databases and websites
(including those of regional regulatory agencies and the
manufacturer). Additional information (including contributory unpublished data) was also requested from the
company developing the drug.
Search terms: Human immune globulin, immune
globulin, immune globulin 10 %, immunoglobulin G,
gammagard, gammagard liquid, kiovig, primary
immunodeficiency.
Study selection: Studies in patients with primary
immunodeficiency disorders who received human
immune globulin 10 % liquid. Inclusion of studies was
based mainly on the methods section of the trials. When
available, large, well-controlled trials with appropriate
statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also
included.
Keywords: Gammagard Liquid, immune globulin
10 % liquid, primary immunodeficiency disorders,
therapeutic efficacy, tolerability, pharmacodynamics,
pharmacokinetics.

2 Pharmacodynamic Properties
IG 10 % liquid is a highly purified, concentrated, ready-touse IgG solution prepared from large pools of human
plasma [10]. Donor plasma is screened against potential
infectious agents and the manufacturing process includes
three separate validated virus inactivation/removal steps
[10]. IG 10 % liquid contains 100 mg/mL of protein, of
which C98 % is immunoglobulin (almost exclusively
IgG). The average concentration of IgA is 37 lg/mL and
IgM is present in only trace amounts. IG 10 % liquid
contains a broad spectrum of IgG antibodies, and retains
Fc and Fab functions. The proportions of IgG subclasses in
the preparation are similar to those in normal plasma. It is
stabilized/buffered with glycine 0.25 M and does not
contain any added sugars, sodium or preservatives. The
osmolality of IG 10 % liquid (240300 mOsmol/kg water)
is similar to that of normal plasma (285295 mOsmol/kg
water) [10].

Immune Globulin (Human) 10 % Liquid: A Review

Higher serum IgG concentrations resulting from higher

doses of IGIV therapy in patients with PID have been
shown to be associated with a decreased incidence of
infections [1214]. A retrospective analysis of studies
using subcutaneous IG preparations, including IG 10 %
liquid, found that there were strong correlations between
dose and serum IgG trough level, and between serum IgG
trough level and annualized rate of overall infection,
although the relationship between dose and annualized rate
of overall infection was not significant, possibly owing to a
lack of statistical power [15].
Although it varied by product and by batch, IgG
replacement therapies, including IG 10 % liquid, contained
small amounts of IgG-class anti-A (geometric mean titers
of 6.217.4) and anti-B (geometric mean titers of 3.412.3)
isoagglutinins (this study was published as an abstract) and
so could potentially cause hemolysis in patients with PID
receiving high intravenous doses at rapid infusion rates
[16].

3 Pharmacokinetic Properties
3.1 Intravenous Administration
In the pivotal phase III clinical trial of intravenous IG 10 %
liquid administered every 2128 days for 12 months in
patients (n = 61) with PID (see Sect. 4.1), the median
weight-adjusted dose per subject was 455 mg/kg, the mean
infusion rate was 4.3 mL/kg/h, and the median trough IgG
levels ranged from 9.6 to 11.2 g/L over the total treatment
period [17]. Only one patient experienced an IgG trough
level \4.5 g/L (i.e., 4.11 g/L), which occurred prior to the
first infusion of the study, following a pre-study IGIV dose
of 434 mg/kg [17].
Pharmacokinetic parameters were assessed in the phase
III trial after the fourth intravenous dose in 57 patients. The
median peak (Cmax) and trough (Cmin) IgG levels were 20.5
and 10.3 g/L, respectively, while the median area under the
plasma concentration-time curve (AUC) from time zero to
21 days (AUC21d) was 29,139 mg
days/dL. The median
elimination half-life was 35 days, the median incremental
recovery ([mg/dL peak plasma concentration 30 min after
infusion]/[mg/kg administered]) was 2.3 and the median
in vivo recovery was 112 % [17].
Similarly, in patients with PID (n = 22) receiving
intravenous IG 10 % liquid at a mean dose of 0.41 g/kg
every 3 weeks in a European trial, the median Cmax and
Cmin values assessed after the third, fourth or fifth infusion
were 16.3 and 8.48 g/L, respectively [18]. The median
AUC21d was 545 g
h/dL and the median terminal halflife was 30.1 days. The median incremental recovery was
1.85.

395

3.2 Subcutaneous Administration

The bioavailability of IG 10 % liquid is lower after subcutaneous administration than after intravenous administration [10]. Pharmacokinetic assessment of the first 15
patients aged C12 years in Period 2 of the pivotal US study
(see Sect. 4.2 for treatment details) after switching from
intravenous to subcutaneous IG 10 % liquid (at a weekly
subcutaneous dose of 130 % of the weekly equivalent
intravenous dose) determined that pharmacokinetic equivalence would require a weekly subcutaneous dose equal to
137 % of the weekly intravenous dose [19]. For this
assessment, equivalence was defined as a subcutaneous
AUC over the dose interval (AUCs) equal to 80125 % of
the intravenous AUCs standardized to a 7-day interval [19].
After individually adapting subcutaneous dosages and
treating for 12 weeks (Period 4) in this study, the mean
weekly subcutaneous dose in patients aged C12 years
(n = 32) was 182.6 mg/kg compared with an initial mean
intravenous dose of 133.2 mg/kg [19]. The mean Cmax was
lower (13.93 vs. 22.40 g/L) and the mean Cmin was higher
(12.02 vs. 10.50 g/L) after subcutaneous versus intravenous administration [19]. Cmax was attained 2.9 days after
subcutaneous administration and the mean clearance was
2.023 mL/kg/day [10]. The median trough IgG level after
subcutaneous administration was 12.60 g/L. The mean
AUCs was 9,176 mg
days/dL after subcutaneous administration compared with 9,958 mg
days/dL after intravenous administration (standardized to a 7-day interval). The
geometric mean ratio of subcutaneous to intravenous AUC
was 95.2 % and met the criteria for equivalence [19]. The
mean adjusted dose at the end of treatment was 137.3 % of
the intravenous dose in patients aged C12 years compared
with 141.0 % in those aged\12 years, indicating that there
was little difference in dose requirements for children [10,
19].

4 Therapeutic Efficacy
The efficacy of IG 10 % liquid in the treatment of PID
involving antibody deficiency has been assessed in two
pivotal, multicenter, noncomparative trials conducted in
the US, one using intravenous administration [17] and the
other subcutaneous administration [19], with supporting
data from a smaller noncomparative study conducted in
Scandinavia using intravenous administration [18].
4.1 Intravenous Administration
Patients (n = 61) in the pivotal US study of intravenous IG
10 % liquid had a median age of 34 years (range 672 years)
and had been diagnosed with PID, consisting predominantly

396

(90 % of patients in whom a specific diagnosis was documented) of common variable immunodeficiency, hypogammaglobulinemia, and X-linked agammaglobulinemia.
They had been receiving IGIV every 2128 days at a dose of
300600 mg/kg for C4 months and were seronegative for
hepatitis B surface antigen, hepatitis C virus or human
immunodeficiency virus [17]. Those with selective, complete IgA deficiency were excluded.
Patients received intravenous IG 10 % liquid every
2128 days for C12 months at a dose (300600 mg/kg)
equivalent to their previous IGIV as long as the minimum
trough IgG level was maintained at [4.5 g/L [17]. The
maximum tolerated infusion rate (up to a maximum of
5.0 mL/kg/h) was determined for each patient by incremental rate elevation over 30 min during the first treatment
visit. The primary efficacy endpoint was the rate (number/
subject/year) of validated (i.e., met predefined, specific
diagnostic requirements) acute serious bacterial infections
(SBIs), including bacteremia/sepsis, bacterial pneumonia,
bacterial meningitis, osteomyelitis/septic arthritis, and
visceral abscess [17]. The rate of SBIs was compared with
a rate of \1.0 SBI/subject/year, which is recommended by
the US FDA as the threshold below which immunoglobulin
replacement therapy can be considered to have demonstrated substantial efficacy [20].
None of the 61 patients reported a validated SBI during
C12 months of treatment, thereby demonstrating significant efficacy for IG 10 % liquid [17]. Four patients (6.6 %)
reported other predefined, validated, common bacterial
infections (otitis media [two cases], gastroenteritis, and
urinary tract infection), which were non-serious, of moderate severity, and resolved fully without the need for
hospitalization. The mean rate of validated, non-serious
common infections was 0.07 infections/subject/year (95 %
CI 0.020.17). There were 224 non-validated infections
(i.e., infections that did not fulfill the criteria for SBI or
other predefined, validated bacterial infections) producing
a non-validated infection rate of 3.4 infections/subject/year
[17]. These infections most commonly consisted of sinusitis, nasopharyngitis, bronchitis, and upper respiratory tract
infections.
In the European trial involving 22 adults (aged
2670 years) with PID (predominantly common variable
immunodeficiency) from six study sites in Sweden and
Finland, who received nine intravenous infusions of IG
10 % liquid (300450 mg/kg every 21 days at a rate of
B8 mL/kg), there were no serious infections, and the
median rate of mild or moderate infections (59 episodes in
total) was 0.48 infections/subject/month [18]. The infections included all types and consisted mostly of respiratory
tract infections, gastrointestinal infections and ear infections. In comparison, there were 30 infections, one of
which was serious and required hospitalization, during a

P. L. McCormack

pretreatment run-in phase in which patients received three

intravenous infusions of reconstituted IGIV 10 % [18].
4.2 Subcutaneous Administration
The pivotal US study assessing subcutaneous administration of IG 10 % liquid enrolled 49 patients, aged C2 years
(range 377 years), with PID, consisting predominantly
(92 % of patients) of common variable immunodeficiency,
hypogammaglobulinemia, and X-linked agammaglobulinemia [19]. Patients had to have been treated with intravenous or subcutaneous immunoglobulin replacement
therapy at a dose of 3001,000 mg/kg/4 weeks for
C3 months prior to the study and to have a serum trough
level of IgG [4.5 g/L at the last pre-study assessment.
Eleven patients had previous IGSC experience [19].
Initially, all patients received intravenous IG 10 %
liquid every 34 weeks for 13 weeks (Period 1) and then
received weekly subcutaneous IG 10 % liquid at 130 % of
the weekly equivalent of the intravenous dose (to compensate for the reduced bioavailability of subcutaneous
administration) for C12 weeks (Period 2) [19]. The subcutaneous dose was subsequently adjusted to 137 % of the
intravenous dose (based on a pharmacokinetic analysis
performed during Period 2) over 6 weeks (Period 3), after
which patients subcutaneous doses were adjusted individually and continued for 12 weeks (Period 4). After
completing all four treatment periods, patients were eligible to continue subcutaneous treatment with IG 10 %
liquid in an extension study (duration &5 months at the
time of analysis) [19].
Subcutaneous infusions were started at a rate of 5 mL/h/
site and gradually increased over subsequent infusions to a
maximum of 20 (\40 kg bodyweight) or 30 (C40 kg
bodyweight) mL/h/site, with a maximum dose of 20
(\40 kg bodyweight) or 30 (C40 kg bodyweight) mL/site.
There was no limitation on the number of subcutaneous
infusion sites used, although a maximum limit of eight
simultaneous sites is now recommended in the prescribing
information; 75 % of infusions used B5 sites and 3 % of
infusions used 810 sites [19]. Among the 47 patients who
received subcutaneous IG 10 % liquid, 2,294 infusions
were administered, and the median duration of subcutaneous treatment was 379 days [19]. The mean weekly dose
administered during the entire subcutaneous treatment
period ranged from 181.9 to 190.7 mg/kg. At the end of the
fourth treatment period, the mean serum IgG trough level
was 12.02 g/L.
During subcutaneous treatment there were three episodes of validated acute SBIs (all bacterial pneumonia),
giving an annualized rate of 0.067 SBIs/subject/year, well
below the FDA-recommended efficacy threshold of 1.0
SBI/subject/year [19]. The upper limit of the 99 %

Immune Globulin (Human) 10 % Liquid: A Review

confidence interval was 0.134, also well within the FDArecommended threshold of \1.0. None of the SBIs or other
infections occurring during subcutaneous therapy required
hospitalization.
The rate for all infections, including bacterial, viral,
fungal and protozoal infections, during subcutaneous
therapy was 4.1 infections/subject/year [19]. Therapeutic
antibiotics were taken by 36 subjects for an average of
37.3 days/subject/year and prophylactic antibiotics were
taken by 12 patients for an average of 12.9 days/subject/
year. Fifty three percent of patients missed C1 day from
work or school and the annualized rate was 4 days/subject/
year [19]. Subcutaneous therapy was distributed over all
four seasons and the rates for all infections in winter,
spring, summer and fall were 2.3, 2.7, 2.6 and 4.0 infections/subject/year, respectively [19].

5 Tolerability
The tolerability data for IG 10 % liquid are derived from
the clinical trials in patients with PID discussed in Sect. 3,
primarily using values for adverse reactions (i.e., drugrelated adverse events) as stated in the US prescribing
information [10], supplemented with information from a
small study of IGIV conducted in the Netherlands [21].
The US prescribing information for IG 10 % liquid, like
all IGIV products, carries a black box warning against
acute renal dysfunction and acute renal failure in predisposed patients [10]. These adverse effects occur more
commonly with IGIV products containing sucrose; IG
10 % liquid does not contain sucrose. In patients at risk of
renal dysfunction or failure, IG 10 % liquid should be
administered at the lowest infusion rate practicable [10].
5.1 Intravenous Administration
In the pivotal US trial of intravenous IG 10 % liquid, there
were 15 serious adverse events (in eight patients) and 400
non-serious adverse reactions [10]. Two of the serious
adverse events (two episodes of aseptic meningitis in one
patient) were considered possibly related to the infusion; 13
were considered not drug-related [17]. None of the serious
adverse events were life-threatening. Of the non-serious
adverse reactions, 381 were mild or moderate in intensity
and 19 were severe [10]. All of the severe reactions were
transient and resolved without complication. Headache was
the most commonly observed adverse reaction (Table 1).
Active screening prior to, during, and after the study found
no evidence of viral transmission [17].
In the multicenter study conducted in Sweden and Finland
(n = 22), the proportion of infusions associated with adverse
reactions was 4 % (8/194 infusions) [18]. The reported

397
Table 1 Treatment-related adverse reactions or adverse events
occurring during or within 72 h of infusion, and associated with
C0.7 % of infusions (n = 1,812) in patients (n = 61) with PID during treatment with intravenous immune globulin 10 % liquid in the
pivotal US trial [10]
Adverse event

Infusions (%)

Patients (%)

Headache

5.2

48

Fatigue

1.8

23

Fever

1.5

28

Nausea

0.9

18

Chills

0.8

13

Rigors

0.8

13

Diarrhea

0.7

15

Pain in extremity

0.7

12

Migraine

0.7

adverse reactions were headache (9 % of patients), fever/

pyrexia (9 %), urticaria (5 %), infusion-site pain (5 %), vertigo (5 %), pruritus (5 %) and flushing of face/neck (5 %). All
adverse events were non-serious. Two patients had a positive
direct Coombs test at the end of treatment with IG 10 %
liquid, but one was positive prior to treatment with IG 10 %
liquid. No patient presented with signs of hemolysis [18].
In a study conducted in the Netherlands in which 14
patients with primary humoral immunodeficiency were
switched from lyophilized IGIV 6 % to IG 10 % liquid, all
adverse events occurring within 72 h of infusion were nonserious, and were numerically less frequent with IG 10 %
liquid (7 events in 3 patients over 28 infusions) than with
the previous lyophilized IGIV 6 % (20 events in 3 patients
over 28 infusions) [21].
5.2 Subcutaneous Administration
There were no serious adverse reactions reported during
treatment with subcutaneous IG 10 % liquid in the pivotal
US study [19]. Of the 348 non-serious adverse reactions,
eight reactions were severe, 112 were moderate, and 228
were mild [10]. The most common adverse events occurring during or within 72 h of infusion were local reactions,
headache, fever, fatigue, vomiting and upper abdominal
pain [19]. The incidence of adverse reactions or temporally
associated adverse events reported during treatment with
subcutaneous IG 10 % liquid are shown in Table 2.
Local infusion-site adverse reactions, other than infections, were classified as either mild (81 %) or moderate
(19 %), and consisted of rash, erythema, edema, hemorrhage, irritation, pain, hematoma, pruritus, and swelling
[10, 19]. The incidence of local reactions per infusion was
2.8 % in patients nave to subcutaneous treatment and
1.1 % in those who had previously received subcutaneous
therapy [10]. The proportion of patients experiencing local

398

P. L. McCormack

Table 2 Treatment-related adverse reactions or adverse events

occurring during or within 72 h of infusion, and associated with
C0.3 % of infusions (n = 2,294) in patients (n = 47) with PID during treatment with subcutaneous immune globulin 10 % liquid in the
pivotal US study [10]
Adverse event

Infusions (%)

Patients (%)

Local reactions

2.4

45

Headache

1.4

40

Fever

0.5

19

Fatigue

0.5

15

Increased heart rate

0.5

Upper abdominal pain

0.4

11

Vomiting

0.3

11

Asthma

0.3

Nausea

0.3

Increased systolic BP

0.3

BP blood pressure

reactions appeared to decrease over time during subcutaneous treatment [19]. The rate of local reactions per infusion decreased from 4.9 % at the start of subcutaneous
therapy to 1.5 % at the end of the study, and to 1.1 % in the
extension period [10].

6 Dosage and Administration

IG 10 % liquid is indicated in the US as antibody
replacement therapy in patients aged C2 years with
primary humoral immunodeficiency, including, but not
limited to, CVID, X-linked agammaglobulinemia, congenital agammaglobulinemia, WiskottAldrich syndrome,
and SCID [10]. IG 10 % liquid may be administered
intravenously or subcutaneously in the treatment of PID.
6.1 Intravenous Administration
The recommended intravenous dosage of IG 10 % liquid for
the treatment of PID is 300600 mg/kg every 34 weeks
based on clinical response [10]. The recommended initial
intravenous infusion rate is 0.5 mL/kg/h (0.8 mg/kg/min) for
30 min, which can be increased every 30 min, if tolerated, up
to 5 mL/kg/h (8 mg/kg/min). The optimum serum IgG trough
level required to keep patients free of infection is not known
and may differ between individuals [22]. IgG trough levels in
combination with clinical response should be used to guide
dose adjustment [10, 22].
6.2 Subcutaneous Administration
Subcutaneous IG 10 % liquid is generally administered
weekly at one or more body sites simultaneously. Suggested

sites are the abdomen, thighs, upper arms or lower back.

Since the bioavailability of subcutaneous IG is less than that
of intravenous IG, the recommended initial weekly dose is
137 % of the previous intravenous dose divided by the
number of weeks between intravenous doses [10]. When the
subcutaneous dose is adjusted in this way to provide an AUC
comparable to that during intravenous therapy, the serum
IgG trough level during weekly subcutaneous therapy is
approximately 2.81 g/L higher than the last trough level
during stable intravenous therapy [10]. The maintenance
dose is based on clinical response and the target serum IgG
trough level, using the trough level prior to the final intravenous dose as a guide in those patients switching from
intravenous to subcutaneous administration.
The recommended initial subcutaneous infusion rate at
each site is 20 mL/h with a maximum of 30 mL/site for
patients with a bodyweight C40 kg, and 15 mL/h with a
maximum of 20 mL/site in those with a bodyweight
\40 kg [10]. The recommended infusion rates for maintenance therapy are 2030 mL/h/site for a bodyweight
C40 kg and 1520 mL/h/site for a bodyweight \40 kg,
with the same maximum doses per site. The recommended
maximum number of sites to be used simultaneously is
eight.
Local prescribing information should be consulted for
detailed information, including contraindications, precautions, drug interactions, and use in special patient populations.

7 Current Status of Immune Globulin 10 % Liquid

in Primary Immunodeficiency Disorders
IG 10 % liquid is approved in the US for both intravenous
and subcutaneous administration in the treatment of PID
with antibody deficiency [10]. There is another fully liquid
10 % IgG immune globulin preparation approved in the US
for both intravenous and subcutaneous administration in
patients with primary immunodeficiency (marketed under
two brand names: Gamunex-C [23] and GammakedTM
[24]). It is preservative- and sucrose-free, stabilized with
glycine, contains 46 lg/mL of IgA and uses viral inactivation steps that differ from those for IG 10 % liquid. In
addition, there is a liquid 20 % IgG immune globulin
preparation approved in the US for subcutaneous administration only (Hizentra [25]). It is also preservative- and
sucrose-free, is stabilized with L-proline and contains
polysorbate 80 and B50 lg/mL of IgA. An earlier liquid
16 % IgG subcutaneous immune globulin preparation
(Vivaglobin [26]) was discontinued in the US by the
manufacturer of the 20 % liquid subcutaneous immune
globulin product [27].
Indirect comparison suggests that these subcutaneous
immune globulin preparations have similar efficacy [28],

Immune Globulin (Human) 10 % Liquid: A Review

although none has been directly compared with any other

in controlled clinical trials. According to the prescribing
information, the rates for any infection observed in pivotal
clinical trials were 2.88 infections/subject/year for the
other 10 % liquid preparation after intravenous administration (the prescribing information lacks efficacy data for
subcutaneous administration) [23, 24] and 2.76 infections/
subject/year for the subcutaneous 20 % liquid preparation
[25], compared with 4.1 infections/subject/year for subcutaneous IG 10 % liquid in the pivotal US study (Sect. 4.2).
Indirect comparison does, however, suggest that they may
differ in their tolerability profiles, for reasons that are not
immediately obvious other than that they derive from
separate trials with different protocols and procedures [28].
For instance, the reported incidence in the prescribing
information of local infusion-site reactions (as a percentage
of infusions) after subcutaneous administration was 2.4 %
with IG 10 % liquid compared with 58.4 % for the 20 %
liquid preparation and 59 % for the other 10 % liquid
preparation. Similarly, the proportions of patients experiencing local infusion-site reactions were 45 % for IG 10 %
liquid, 75 % for the other 10 % liquid preparation and
100 % for the 20 % liquid preparation [10, 2325].
While IGIV with 5 or 10 % IgG preparations has been
the mainstay of therapy for these disorders, it generally
requires treatment at a hospital or specialist infusion center,
may face problems with regard to venous access, and is
associated with systemic adverse reactions, such as fever,
headache, fatigue, and chills in a sizeable proportion of
infusions, variously reported as 514 % [2]. IGSC provides
the convenience and flexibility of self-administration at
home in those without a fear of needles and is associated
with a lower incidence of systemic adverse events, usually
reported as B1 % of infusions [2]. Fluid volume limitations
associated with subcutaneous administration require more
frequent administration of smaller doses, which results in
less fluctuation in serum IgG levels over the dose interval
compared with IGIV and produces higher trough IgG
levels, albeit with lower peak IgG levels. However, IGSC
usually requires the simultaneous use of multiple sites for
infusion depending upon the dose administered and results
in a higher incidence of local infusion-site reactions than
IGIV, although these reduce over time on therapy [2, 29].
The administration details for IG 10 % liquid are similar
to those of the other 10 % immune globulin preparation,
recommending subcutaneous infusion of approximately
2030 mL/site, depending upon bodyweight, at a rate of
1530 mL/h/site and with a maximum of eight sites
simultaneously (or a maximum infusion rate of
160240 mL/h for all sites) [23, 24]. The 20 % immune
globulin preparation delivers the same quantity of IgG in
half the volume, allowing for smaller infusion volumes,
although the recommended volume per site is lower at

399

1525 mL/site using an infusion rate of 1525 mL/h/site

over a maximum of four sites simultaneously (for a maximum infusion rate of 50 mL/h for all sites) [25].
IgG replacement therapy improves health-related quality
of life (HR-QOL), normalizing it to a level similar to that
of healthy individuals, and home-based therapies further
improve HR-QOL and patient satisfaction with treatment
in both adults and children (or their parents) [2, 30].
In clinical trials, IG 10 % liquid, after either intravenous
or subcutaneous administration, was highly effective in
limiting acute SBIs, with rates of 0.0 (intravenous) or 0.067
(subcutaneous) SBIs/subject/year (Sect. 4). The rates for
non-serious infections of all kinds were also low with both
treatment modalities, ranging from 3.4 to 5.8 infections/
subject/year (Sect. 4).
Both intravenous and subcutaneous IG 10 % liquid were
safe and generally well tolerated (Sect. 5). Serious adverse
events were infrequent or non-existent. Systemic adverse
reactions were more frequent with intravenous administration, while local infusion-site reactions were more frequent
with subcutaneous administration (Sect. 5). Most adverse
reactions with either route of administration were of mild or
moderate intensity. The incidence of local infusion-site
reactions associated with subcutaneous administration progressively decreased with increasing time spent on therapy.
The use of intravenous IG 10 % liquid was estimated to
save approximately 1,010/patient annually compared with
intravenous IGIV 6 % lyophilized in the Netherlands as a
result of eliminating the reconstitution step and reducing
the mean infusion time by 0.81 h per patient [21]. In
addition, a survey conducted in Sweden in 1997 estimated
that IGSC would save $US10,100 per patient-year compared with IGIV [31].
Thus, IG 10 % liquid is an effective and generally
well-tolerated preparation for both intravenous and subcutaneous IgG replacement therapy in patients with PID
involving antibody deficiency. It offers the benefits of a
ready-to-use liquid preparation and the convenience of
home-based therapy in appropriate patients.
Disclosure The preparation of this review was not supported by any
external funding. During the peer review process, the manufacturer of
the agent under review was offered an opportunity to comment on this
article. Changes resulting from comments received were made by the
author on the basis of scientific and editorial merit.

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