Intratect IVIg Brochure

Intratect® and Intratect® 100 g/l

Safety through Quality

Human immunoglobulins for intravenous use

Intratect® I Table of contents 4
5
Table of contents 5
5
Intratect® und Intratect® 100 g/l – Safety through Quality
• High purity and naturalness 6
• Excellent safety profile and good tolerability 6
• User-friendly 7
7
The Intratect® process guarantees high quality and viral safety 10
• Viral safety begins with careful donor selection 11
• From the plasma pool to the final product 11
• The viral safety preparation procedure
• Protein-chemical characterisation 12
• Spectrum of selected anti-viral and anti-bacterial antibodies
• IgG subclass distribution and half-life 16
16
IN FOCUS: Patient safety
Added safety through the elimination of all coagulation factors 18
19
Multitalented immunoglobulin G – More than just infection protection 20
• Important mechanisms of action of IVIG 22
24
Safety through clinical efficacy – Studies with Intratect®
• Clinical study: Intratect® for primary antibody deficiency
• Clinical study: Intratect® 100 g/l for primary antibody deficiency
• Clinical study: Intratect® for primary immune thrombocytopenia
• Non-interventional study with Intratect® for primary
and secondary antibody deficiency syndromes

2

Intratect® I Table of contents

Immunoglobins stand for disease prevention and quality of life 26
From antibody deficiency to autoimmune disease 26
27
• Primary antibody deficiency syndromes 28
• Secondary antibody deficiency 28
• Autoimmune diseases
30
IN FOCUS: Patient-oriented treatment
Immediate bioavailability of IVIG – Ideal for patient-oriented application 34
38
Summary of product characteristics – Intratect® 42
Summary of product characteristics – Intratect® 100 g/l 43
References
List of abbreviations

3

Intratect® and Intratect® 100 g/l –
Safety through Quality

Immunoglobulin G antibodies are essential for that human pathogenic viruses are not transmit-
maintaining the immune system, inflammation ted and plasma components that trigger unde-
control and tissue regeneration. Antibody concen- sired coagulation activation or compromise toler-
trates help rebalance the immune system when ance are removed during the production process.
the body's own IgG antibody production or im-
mune cell communication is dysfunctional. Biotest's Intratect® production process satisfies
these rigorous criteria and is at the cutting edge
Highest demands are placed on the production of of technology for intravenous immunoglobulin G
IgG concentrates from human plasma to ensure concentrate production (IVIG).

4

Intratect® I Safety through Quality

High purity and naturalness

O The two-step process of the cation exchange chromatography guarantees 100 % immunoglobulin
purity.

O The IgG content of Intratect® and Intratect® 100 g/l is more than 98 %.The proportion of monomers
and dimers is more than 99 %, with a maximum of only 0.3 % polymers.The final product contains
no residual protein fragments.

O IgG subclass distribution that closely matches that of normal serum.
O The Intratect® process does not modify the IgG molecules. There is 99 % retention of the Fc part

function.
O Intratect® and Intratect® 100 g/l are sugar-free and isotonically stabilised with glycine.

Excellent safety profile and good tolerability

O Repeated donor plasma tests and a four-stage procedure to eliminate or inactivate viruses, includ-
ing nanofiltration (20 nm), ensure the highest degree of protection against the transmission of
human-pathogenic viruses.

O Biotest compounds have been certified under the QSEAL program since 2001.
O As Intratect® and Intratect® 100 g/l contain particularly low anti-A and anti-B isoagglutinin titers,

with proper administration there is minimum risk of haemolysis.
O All coagulation factors in the crude material are fully removed during the production process.

Intratect® and Intratect® 100 g/l are free of thrombogenic activity.

User-friendly

O Intratect® and Intratect® 100 g/l are ready to use solutions and can be kept for a period of two
years at 25 °C (room temperature).

O Each patient is different and the required IVIG amount must be individually calculated. This is
facilitated by different IVIG concentrations (5 % and 10 %) and five different package sizes.

Intratect® – more than just the sum of its quality characteristics

5

The Intratect® process guarantees
high quality and viral safety

All process developments for manufacture of and made available to the patient in a form with
intravenous immunoglobulin concentrates aim good tolerability. An important aspect in this re-
to conserve the natural structure of the IgG an- spect is the attainment of the highest possible
tibody without modifying it. Their efficacy and degree of safety with regard to the risk of trans-
immunbiological properties should be preserved mitting human-pathogenic viruses.

Viral safety begins with the right choice of donor

A number of measures are employed to prevent the transmission of viruses and other pathogens.

O Only plasma from officially licensed plasmaphereris and blood donor centres is used to produce
Intratect®. Plasma comes from Belgium, Germany, the Netherlands, Austria, Switzerland, Hungary
and the USA.

O Only plasma from healthy donors is used. In addition to a large number of specific donor selection
criteria, which also minimise the risk of infection with the new variant of Creutzfeldt-Jakob disease
(vCJD), donors must also test negative for hepatitis B viral antigens, as well as for antibodies against
the human immunodeficiency virus (HIV 1/2) and hepatitis C virus.

6

Intratect® I The Intratect® process guarantees high quality and viral safety

O Biotest also maintains a plasma quarantine period of at least 60 days. A first donation is not proc-
essed until the donor has volunteered a second time and virological screening is negative. Both
donation and donor are excluded if any screening results are positive.

O The plasma pools collected for processing are monitored twice using the nucleic acid amplification
test (NAT test).Tests are carried out for HCV RNA, HBV DNA, HIV RNA, HAV RNA and parvovirus B19
DNA.Testing is first carried out on a minipool with a limited number of plasmas and again later in
the whole plasma pool.

From the plasma pool to the final product

The source pool for manufacturing Intratect® tion of immunoglobulin G is via cation exchange
contains several thousand plasmas. In a first chromatography. Positively charged IgG antibod-
step, cryoprecipitate and coagulation factors are ies bind to the negatively charged column ma-
separated off and ethanol precipitation is used to trix. This first step separates off any impurities,
obtain various fractions (I/II/III). Fraction II is used which are discarded.The IgG antibodies are then
for manufacturing Intratect®. This is followed by removed from the matrix and collected as a pure
octanoic acid/calcium acetate and solvent/de- eluate fraction.
tergent treatments, which not only helps enrich
the immunoglobulins but also, and above all, Nanofiltration (20 nm) prior to final packaging
reduces any potential viral load and completely ensures the removal of even the smallest parti-
eliminates thrombogenic factors. Actual purifica- cles from the solution.

The virus reduction procedure

The development of virus and prion depletion Results of validation studies and test series (Ta-
processes, as well as the extensive quality tests ble 1) show Intratect® virus and prion clearance
required for crude materials and intermediate satisfies all current official requirements.
and final products are specified in numerous di-
rectives and are strictly monitored by national
(PEI) and international (EMA) agencies.

In accordance with the specifications of these
agencies, the manufacturing process steps un-
dergo continual validation studies to ensure they
effectively eliminate and inactivate viruses.

Also examined are the effects of minimal devia-
tions in the production process (for example, with
regard to temperature, pH-value, protein concen-
tration) on the outcome of virus reduction. The
process parameters then specified for the routine
process ensure process robustness, i.e. production
process reliability in terms of the capacity to in-
activate or eliminate viruses.

7

Intratect® I Intratect® procedure guarantees high quality and virus safety Virus elimination
Fig. 1: Intratect® manufacturing steps Virus inactivation

Plasma pool Elimination of thrombogenic factors
Separation of cryoprecipitate
and coagulation factors
Precipitation of fractions I, II, III
Separation of fractions I und III
Ethanol precipitation of fraction II
Ultra- and diafiltration
Treatment with octanoic acid
and calcium acetate
Solvent detergent treatment
Cation exchange chromatography
Nanofiltration (20 nm)
Ultra- and diafiltration
Steril final dispensing,
quality control, final packaging

8

Intratect® I The Intratect® process guarantees high quality and viral safety

Table 1: Capacity of the Intratect® production process to separate viruses and prions

Reduction factors (as log 10 value)

Production process HIV PRV BVDV Reo PPV MEV Prions

Precipitation an separation L 4.90 L 5.25 L 2.53 L 7.58 L 4.07 3.91 L 3.65
of fractions I/III

Treatment with octanoic L 5.72 L 6.36 L 4.71 n.a. n.a. n.a. n.a.
acid/calcium acetate

Solvent detergent L 4.43 L 4.57 L 4.82 n.a. n.a. n.a. n.a.
treatment

Nanofiltration (20 nm) – – L 4.49 L 4.72 3.82 L 6.33 L 4.07

Total reduction L 15.05 L 16.18 L 16.55 L 12.30 L 7.89 L 10.24 L 7.72
n.a. = not analysed

Table 2: Viruses used in validation studies

HIV Human immunodeficiency virus RNA virus with envelope 80 – 110 nm
PRV DNA virus with envelope 120 – 200 nm
BVDV Porcine pseudorabies virus RNA virus with envelope 40 – 60 nm
Reo (model virus for herpes viruses and HBV) RNA virus non-enveloped 60 – 80 nm
PPV Bovine viral diarrhea virus DNA virus non-enveloped 18 – 22 nm
MEV (model virus for HCV) RNA virus non-enveloped 22 – 30 nm
Reo virus
(model virus for non-enveloped viruses)
Porcine parvovirus
(model virus for human parvovirus B19)
Murine encephalomyelitis virus
(model virus for HAV)

In 2000, the Plasma Protein Therapeutics Association (PPTA) introduced a
certification program incorporating standards for plasma extraction, plasma
processing and quality controls.31
Biotest products have been certified in accordance with the QSEAL program
(Quality Standards of Excellence, Assurance and Leadership) since 2001.

9

Intratect® I The Intratect® process guarantees high quality and viral safety

Protein-chemical characterisation

Table 3: Protein-chemical characterisation of Intratect®

Parameter Intratect® 50 g/l* Intratect® 100 g/l*
Protein 50 g/l 100 g/l
Immunoglobulin 100 % 100 %
Monomers and dimers 99.8 % 99.7 %
Polymers 0.2 % 0.3 %
Fragments 0% 0%
IgG 98.8 % 98.4 %
IgA 1.0 % 1.3 %
IgM 0.1 % 0.2 %
Albumin 0.04 % 0%
Alpha-1-globulin 0% 0%
Alpha-2-globulin 0% 0%
Betaglobulin 0% 0%
Anti-A titre 1:16 1:16
Anti-B titre 1:8 1:8
Anti-D activity
Prekallikrein activator negative negativ e
Kallikrein 0 IU/ml** 0 IU/ml**
Prekallikrein 0 IU/ml** 0 IU/ml**
Proteolytic activity 0 IU/ml** 0 IU/ml**
Fibrinogen
Osmolality 0.5 U/l 1 U/l
Anticomplementary activity (ACA) 0% 0%
Fc-part function
300 mosmol/kg 328 mosmol/kg
0.6 CH50/mg 0.5 CH50/mg
98 % 99 %

Other excipients 300 mmol/l 305 mmol/l
Glycine l 10 mmol/l l 10 mmol/l
Natrium l 50 mmol/l l 50 mmol/l
Chloride

*) mean values from several batches, internal documentation
**) below detection limit

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Intratect® I The Intratect® process guarantees high quality and viral safety

Spectrum of selected anti-viral and anti-bacterial antibodies

Table 4: Spectrum of anti-viral and anti-bacterial antibodies

Antigen Intratect® 50 g/l Intratect® 100 g/l
Parvovirus B19 905 U/ml 1529 U/ml
Epstein-Barr virus (EBV, virus capsid) 845 U/ml 1807 U/ml
Hepatitis B virus 3.6 IU/ml 19 IU/ml
Measles virus 850 U/ml 1143 U/ml
Rubella virus 618 U/ml 1559 U/ml
Influenza virus type B 2643 U/ml
Enterococcus faecalis 1138 U/ml 1850 U/ml
Escherichia coli 836 U/ml 2095 U/ml
Haemophilus influenzae type B 925 U/ml 2051 U/ml
Anti-streptolysin-O activity 1188 IU/ml
Tetanus toxoid 1007 U/ml 1356 U/ml
Corynebacterium diphtheriae 500 IU/ml 3786 U/ml
Candida albicans 912 U/ml 2517 U/ml
1009 U/ml
1046 U/ml

IgG subclass distribution and half-life

The subclass distribution of Intratect® closely patients with a primary immune deficiency syn-
matches that of normal human serum. Half-life drome (PID). (Clinical Study Reports, 2003, 2012)
was determined in the course of clinical studies on

Table 5: IgG subclass distribution and half-life

IgG1 IgG2 IgG3 IgG4 Serum
(in %) (in %) (in %) (in %) half-life
1.5 – 8 0.6 – 10.4 (in days)
Normal range 36 – 81.5 14 – 47 21 – 28
3.4 2.5
Intratect® 50 g/l 57.6 36.6 3.2 2.4 27.2
34.1
Intratect® 100 g/l 59.4 35.0

11

Patient safety

IN FOCUS Added safety through the elimination
of all coagulation factors

Coagulation factors in immu- The crude plasma used in IVIG factors.These must be removed
noglobulin compounds can production contains differ- as quickly as possible if they are
compromise tolerability. If they ent coagulation factors, most to be prevented from triggering
enter the blood during IVIG of which are removed at the the coagulation cascade dur-
therapy they could trigger un- beginning of processing. The ing further processing. Other-
desired activation of the coag- removed factors are utilised wise, the proportion of coagula-
ulation cascade, which, in rare in the production of factor VIII tion factors in the final product
cases, could result in a throm- and factor IX compounds. could even increase.
boembolic event. Thromboem-
bolic events are, for example, Despite this, the plasma frac-
deep venous thromboses, pul- tions used to manufacture im-
monary embolisms, myocardial munoglobulins still contain a
infarctions or strokes.15,21 small proportion of coagulation

Fig. 2: Activation of coagulation cascade F XIIa, Kallikrein
F XIa HK
PK, HK, F XII
F XI

F IX F IXa F VIIIa
F VIII
TF F VIIa FX
F VII F Xa

F II F IIa

Fibrinogen Fibrin

(HK: high-molecular-weight kallikrein, PK: prekallikrein, TF: tissue factor, FII: prothrombin, FIIa: thrombin)

12

Earliest possible removal of thrombogenic factors during Intratect®
production

The production processes employed by Biotest comprise three independent phases, which gradually
reduce the remaining coagulation factors in the fraction II used to manufacture IVIG whilst preven-
ting the formation of new activated factors:
I Ethanol precipitation of fraction I/II/III
I Ethanol precipitation of fraction II
I Octanoic acid treatment of fraction II

Fig. 3: Reduction of the proportion of coagulation factors compared to the crude material
(results from tests on more than 50 Intratect® batches)

13

Patient safety

IN FOCUS Confidence through optimal testing of the final product

It is assumed that the main seconds is regarded as a sign of mation are measured as bench-
causes of thrombotic compli- residual activity on coagulation marks to correlate with the
cations are the prekallikrein ac- factors.13, 15 amount of FXIa initiator mol-
tivator (PKA, FXIIa) and the ac- ecules. Changes in the kinetics
tivated coagulation factor FXIa The thrombin generation test occurring following addition of
and kallikrein.13,15 depicts the kinetics involved in the IVIG to be tested then show
thrombin formation (FII) initi- any residual coagulation activ-
In accordance with the Europe- ated by FXIa. This involves mix- ity in the final product.21
an Pharmacopoeia, maximum
PKA activity in the final product
may not exceed 35 IU/ml IVIG.14
The PKA activity of Intratect®
and Intratect® 100 g/l is below
10 IU/ml.

The thrombogenic activity of
immunoglobulin compounds
was determined with the aid
of two different global tests,
NAPTT test (non-activated
partial thromboplastin time)
and TGT (thrombin generation
test).13,18,21

A NAPTT test optimised to test ing varying concentrations of In addition to coagulation fac-
IVIG depicts changes in human a specific control plasma (free tors, the presence of kallikrein
plasma coagulation time after of the coagulation factor FXI) in the final product can also
IVIG is added. Any remaining with FXIa to initiate the coagu- be established by determining
FXIa activity in the final product lation cascade. The amount of prothrombin complex activity.
reduces coagulation time com- thrombin formed and the time Chromogene tests are used.13
pared to the control plasma. A to peak (TTP) of thrombin for-
coagulation time below 200

14

NAPTT, TGT and determination of the prothrombin complex activity in Intratect®
(Mean values from more than 50 batches, internal documentation)

NAPTT determination*

NAPTT Undiluted solution Dilution 1:10
368 sec
Intratect® 328 sec 367 sec

Control plasma** 352 sec

*) Levels below 200 seconds are seen as critical15 **) platelet-poor plasma

Thrombin generation test (TGT) Time to achieve Thrombin
Maximum quantity of maximum quantity generation rate
generated thrombin
32 nM* 23 min** 4.0 nM/min

*) Levels above 350 nM are seen as critical **) Time should be longer than 11 minutes

Prothrombin complex activity

Factor II Factor VII Factor IX Factor X Kallikrein
l 0.05 IU/ml* l 0.05 IU/ml* l 0.05 IU/ml*
l 0.05 IU/ml* l 0.05 IU/ml*

*) Lowest detection limit

Summary

Intratect® and Intratect® 100 g/l are devoid of pro-coagulatory activ-
ity, as could be confirmed by determining the thrombogenic factors
with optimised global tests und with specific tests for individual fac-
tors in the final product.

15

Multitalented immunoglobulin G –
More than just infection protection

Intravenous immunoglobulins can do more than throughout the world.Today, its range of applica-
simply neutralise pathogens. Knowledge of the tions includes the prophylaxis and treatment of
immunoregulatory properties of IgG gained bacterial and viral infections, as well as the treat-
over the course of many years has made immu- ment of acute and chronic autoimmune diseases
noglobulin therapy a valued therapeutic option and severe inflammation.

The most important mechanisms of action of IVIG

The neutralisation of foreign antigens, bacteria, toxins, viruses and inflammatory mediators

Each millilitre of blood contains more than 1018 lating in the blood. Identification of the patho-
IgG molecules.The immense diversity of antibod- gens takes place in the variable region F(ab)2 of
ies in the human body enables the identification the antibody molecule. Particularly patients with
of 107 to 109 different antigen structures. These antibody deficiency syndromes require additional
include pathogens such as viruses, bacteria and immunoglobulin for prophylaxis against infec-
their toxins, and inflammation mediators circu- tion and to maintain the immune balance.5,20,35

16

Intratect® I Multitalented immunoglobulin G – more than just infection protection

Immunoregulation through interaction with Fcc receptors

Immunoglobulins are opsonins and form im- fested by increasing phagocyte activity, antigen
mune complexes with antigens. These bind to presentation, cytokine release and NK cell activ-
Fcc receptors on immunocompetent cells (mac- ity. Binding to inhibitory receptors (Fcc-IIB) pre-
rophages, dendritic cells, B and T cells, natural vents, for example, the autoantibody production
killer cells, endothelial cells) to trigger an immune in B cells.
response.
Blockade of Fcc receptors on macrophages and
The Fcc receptor-mediated phagocytosis of im- (autoreactive) B and T cells modulates autoim-
mune complexes is essential for the elimination mune and uncontrolled inflammatory reactions.
of pathogens and strengthens, for example, the
immune system by developing antibodies to In addition, IgG is also able to modulate recep-
combat invasive pathogens. tor expression in immunocompetent cells. In its
function as transport molecule it also indirectly
Depending on receptor properties this binding supports cell proliferation and maturation, con-
of Fcc receptors triggers an immunostimulatory tributing in this way to the regeneration of dam-
or inhibitory signal cascade. Stimulation is mani- aged tissue and the healing process.3,19,20,26

Interaction with the complement system fic damage to the body's own cells and tissue.The
activated complement factors C3b and C4b, and
The activation fragments of the complement sys- the C3a and C5a anaphylatoxins circulating in the
tem – C3b and C4b – act as opsonins and neutral- blood promote inflammatory processes and raise
ise pathogens, as does IgG. They are an essential vascular permeability.
component of innate immunity.
Immunoglobulins such as IgG, IgM and IgA regu-
The immune complexes formed from comple- late complement activity by capturing activated
ment and antigen bind to macrophages via Fcc factors (C3b, C4b) and reducing the formation of
receptors and cleaved off in the cell. The contact membranolytic complexes (C5a-C9) to protect
with T and B cells then results in the formation of healthy cells from destruction. Binding with ana-
antibodies against pathogens. phylatoxins inhibits inflammatory processes and
the bacterial function of neutrophil granulocytes
Uncontrolled complement activity during severe is maintained.4,9
bacterial infections or inflammatory autoim-
mune diseases is problematic. In the process, ex-
cess activation of complement causes non-speci-

Regulation of autoimmune and inflammatory processes

Immunoglobulins regulate the release of anti- lated by the neutralisation of autoantigens and
and pro-inflammatory mediators (for example, antibodies (idiotype-anti-idiotype interaction).
IFNc, TNFa, interleukins, growth factors), there- In addition, the IgG-mediated normalisation of
by contributing to the maintenance of immune the receptor repertoires of immune cells results
balance. This occurs through direct Fcc receptor in partial restoration of a normal immune system.
blockade and Fcc-mediated binding of immune This process is particularly important for the treat-
complexes on immune cells, as well as in interac- ment of chronic autoimmune diseases and the
tion with the complement, coagulation and nerv- restoration of therapeutic ability with resistance
ous systems. Autoimmune processes are modu- to long-term immunosuppressive therapies.19,20,26

17

Safety through clinical efficacy –
Studies with Intratect®

The clinical efficacy and tolerability of Intratect® (PID) in three open clinical trials.22,23,33 The efficacy
(50 g/l) and Intratect® 100 g/l were investigated of Intratect® (50 g/l) was also tested on patients
on patients with a primary antibody deficiency with primary immune thrombocytopenia (ITP).6

18

Intratect® I Safety through clinical efficacy – studies with Intratect®

Clinical study: Intratect® (50 g/l) for primary antibody deficiency

Fifty-one patients with PID, aged between 6 and as far as possible, any seasonal influences on
48, were substituted with 8 ml (400 mg) per kil- the health of the participating patients. A total
ogram BW Intratect® at intervals of 3 weeks (3 of 642 infusions were dispensed. The maximum
patients) or 4 weeks (48 patients). The 12-month infusion rate averaged 2.1 to 2.4 ml/kg/h (range
period of treatment was chosen to compensate, 1.0 to 5.9 ml/kg/h).

Table 6: Distribution of PID diagnoses Number of patients
20
Diagnosis 12
Common variable immunodeficiency (CVID) 5
Congenital agammaglobulinaemia 5
Congenital hypogammaglobulinaemia 5
Ataxia teleangiectasia 1
Hyper-IgM syndrome 1
Hyper-IgE syndrome 2
Severe combined immunodeficiency disease (SCID)
Selective IgG subclass deficiency

All patients had already substituted with various occurred in only 6 of 642 (0,9 %) infusions. In no
immunoglobulins before taking part in the trial single case was it necessary to discontinue par-
and had been diagnosed for at least 10 years. ticipation in the study due to adverse events.22

Results

An even average IgG trough level of 8 g/l was
maintained. In only 19 from 649 (2.9 %) deter-
minations was the value of the IgG trough level
below 6 g/l. This occurred in only 10 from 201
(5 %) of the determinations during the six-month
study period with different reference compounds.

The annual rate of severe bacterial infections was
0.02 and involved one case of cellulitis in the con-
nective tissue of the knee.The success criteria de-
scribed by the European Guideline for IVIG, which
specify that the frequency of severe bacterial in-
fections must be reduced to less than one event
per patient and year, were therefore fulfilled.11

The treatment with Intratect® was well tolerated.
Adverse events attributable to the Intratect® dose

19

Intratect® I Safety through clinical efficacy – studies with Intratect®

Clinical study: Intratect® 100 g/l for primary antibody deficiency

This study investigated the pharmacokinetics and In the first phase of the study (Part A) three infu-
tolerability of a ten-percent IVIG compound with sions with Intratect® 100 g/l were dispensed at
PID patients who regularly substituted (part A), intervals of three to four weeks.The infusion rate
as well as the tolerability of higher infusion rates was increased at 30-minute intervals from 0.3 to
(Part B).23 1.4 to a maximum of 2.0 ml/kg/h BW. The infu-
sion rate was increased to a maximum of 8 ml/
A total of 30 PID patients aged between 10 and 63 kg/h at the start of phase two (Part B, 4th to 6th
(median 34.5) took part in the open prospective infusions) to ascertain the maximum tolerable
study. 26 of the patients suffered from CVID and rate for each patient.The initial interval between
4 from congenital agammaglobulinaemia (XLA). increments was 30 minutes; this could then be
individually reduced.This individually determined
Prior to the study, all patients had been finely maximum rate was then used for the 5th and 6th
tuned to regular intravenous immunoglobulin. infusions.
The average amount dispensed in the three pre-
ceding infusions was 397.4 mg/kg BW (range: 56 IVIG dosage was between 200 and 800 mg/kg BW
to 727 mg/kg). IgG trough levels in the six months and based on the individual doses dispensed in
prior to beginning the study were between 4.9 the six months preceding the study.
and 11 g/l (median: 7.68 g/l).

Fig. 4: IgG serum levels and IgG subclass distribution after the 3rd infusion of Intratect® 100 g/l

20

Intratect® I Safety through clinical efficacy – studies with Intratect®

Results Investigations in the second study phase (Part B)
showed that 17 from 25 patients (68 %) tolerat-
All 30 patients completed the first part (Part A) ed an infusion rate of 6 ml/kg BW. Eight patients
of the study to investigate the pharmacokinetics, (32 %) tolerated an infusion rate of 8 ml/kg/h. In
25 patients also completed the second phase of 12 patients (48 %) the targeted infusion rate of
treatment (Part B). 8 ml/kg/h was not achieved, as the individual IVIG
dose was reached before the maximum infusion
With Intratect® 100 g/l, most patients also rate.
achieved a IgG trough level above 6 g/l. Only 2
patients had trough levels below 5 g/l, which cor-
responded to their previous values.

In Part A, the average IVIG dose per infusion was
411 mg/kg BW (range: 200 – 727 mg/kg). Median
IgG serum levels increased from 8.0 to 17.0 g/l
following infusion. Median IgG half-life was 34.1
days (range: 15.7 to 68.7 days).

The adverse events profile correlated with that
described in the European Core SmPC for the ad-
verse events of IVIG10, resp. typical events for PID
patients undergoing IVIG therapy, such as head-
aches, nasopharyngitis, arthralgia, back pain and
fatigue.

In 40 of the 165 infusions (24.2 %) adverse events
occurred in temporal connection with the study
(Parts A and B), during which no one died. A total
of three patients experienced four severe adverse
events during the same period, none of which
were connected to administration of the medi-
cation under investigation. (Clinical Study Report)

SUMMARY

Regular administration of Intratect® and Intratect® 100 g/l to patients with primary antibody
deficiency syndromes allow an even IgG serum level above 6 g/l to be achieved.

The safety profile is consistent to that of comparable intravenous immunoglobulin compounds.

Most patients tolerated an increased Intratect® infusion rate very well. It should, however,
be noted that the maximum tolerable infusion rate differs for each individual and should be
adapted to the patient's condition and specific risk factors.

21

Intratect® I Safety through clinical efficacy – studies with Intratect®

Clinical study: Intratect® (50 g/l) for primary immune thrombocytopenia

Typical for primary immune thrombocytopenia In a prospective clinical study, 24 adults with
(ITP) is a significantly reduced thrombocyte li- chronic ITP and thrombocyte levels ranging from
fecycle. The resulting thrombocyte loss can give 3/nl to 27/nl received Intratect® therapy.6
rise to complications in connection with bleeding;
this condition requires treatment. Fifteen patients were each given 1.0 g/kg BW
Intratect® on two days; nine patients were each
The only patients treated are those with acute given 0.4 g/kg on five days. Test criteria were a
haemorrhages and thrombocyte levels below 50/ thrombocyte increase to M 50/nl and a drop in
nl, and patients with chronic ITP and an increased the number of haemorrhages within 28 days.
risk of haemorrhage prior to an operation or be-
fore giving birth.

The success parameter for treatment is a doubling
of the initial thrombocyte level or a thrombocyte
increase of more than 50/nl within a few days.11

Table 7: Changes in the thrombocyte counts with Intratect®

Parameter Number of days

Time to rise to M 50/nl Mean Median
total (n=24)
at 1.0 g/kg/d for 2 days (n=15) 3.9 ± 2.4 3.0
at 0.4 g/kg/d for 5 days (n=9) 4.4 ± 2.8 2.5
2.9 ± 0.6 3.0

Duration of response M 50/nl 19.8 ± 7.8 22.5
total (n=24) 17.6 ± 8.0 18.0
at 1.0 g/kg/d for 2 days (n=15) 23.6 ± 6.3 22.5
at 0.4 g/kg/d for 5 days (n=9)

Duration of response over starting count 24.4 ± 3.6 25.5
total (n=24) 23.0 ± 3.7 22.5
at 1.0 g/kg/d for 2 days (n=15) 26.8 ± 1.7 27.0
at 0.4 g/kg/d for 5 days (n=9)

22

Intratect® I Safety through clinical efficacy – studies with Intratect®

Results Bleeding tendency decreased significantly just a
few days after administering Intratect®. After 7
22 of the 24 (91.7 %) patients responded to Intra- days, 72.2 % of patients experienced less haem-
tect® treatment. Significant thrombocyte in- orrhaging. Not until three weeks later did some
creases were found after an average of 3 days. On patients find they tended to bleed again.
average, the maximum increase of 224 ± 144/nl
thrombocytes was reached after 7.5 days. Average
response time to treatment was 25.5 days.

Fig. 5: Changed bleeding symptoms compared to the initial situation

80 72.2 72.2 unchanged
72.2 improved
Changes in bleeding tendency (%) worse
70
55.6
60
33.3
50 27.8

40 22.2

30 27.8 11.1
5.6
20
d 14 d 21 d 28
10 After start of treatment

0 d7

SUMMARY

Intratect® is able to reduce the bleeding tendency in ITP patients within just a few days
and to induce an increase in thrombocytes of over 50/nl that then lasts for several weeks. It
therefore meets the criteria of the European Guideline for the use of IVIG.11

23

Intratect® I Safety through clinical efficacy – studies with Intratect®

Non-interventional study with Intratect® (50 g/l) for primary and
secondary antibody deficiency syndromes

In a non-interventional study (NIS) between as for patients who had already been fine-tuned
2004 and 2010 a total of 21,995 Intratect® in- to this therapy.
fusions were documented. A total of 95 centres
participated in the study of 1,313 patients with Intratect® significantly raised the IgG trough
primary and secondary antibody deficiency syn- level.The trough IgG serum level of patients who
dromes who received immunoglobulin substitu- had never been treated with IVIG increased to
tion treatment on a regular basis. 6.62 g/l. Patients with previous IVIG treatment
showed an increase of 4 %.
Intratect® therapy proved beneficial for patients
that had not yet received IVIG treatment, as well

Fig. 6: IgG plasma level prior to the first and after the last Intratect® infusion (median)

The increase in the IgG trough level was accom- This investigation reaffirmed the excellent Intra-
panied by a significant improvement in the clini- tect® tolerability that had already been estab-
cal symptoms and a reduced incidence of infec- lished. The absolute number of adverse events
tion. This effect was particularly evident among brought about by therapy was 225, i.e. just 1 %
patients with no previous IVIG treatment. The of 21,995 infusions. In 97.1 % of cases, physicians'
infection incidence decreased among 72.7 % of assessment of Intratect® tolerability was ‘very
these patients. good’ or ‘good’.

24

Intratect® I Safety through clinical efficacy – studies with Intratect®

Fig. 7: Frequency of infection episodes*

* Doctor's evaluation after 3 infusions each

25

Immunoglobulins stand for
disease control and quality of life

From antibody deficiency to autoimmune disorder

Despite the large number of new drugs that have control inflammatory activity, help regenerate
significantly improved the chances particularly of damaged tissue and contribute toward maintain-
chronically ill patients, intravenous immunoglob- ing important organ function.
ulin remains a valuable and indispensable ther-
apy option. The spectrum of diseases for which they can be
used is extensive. It includes primary and second-
Immunoglobulins play a vital role in maintain- ary antibody deficiency diseases, as well as acute
ing cellular and humoral immune responses.They and chronic autoimmune disorders.

26

Intratect® I Immunoglobulins stand for disease control and quality of life

Primary antibody deficiency syndromes

The only chance of a more or less normal life for the patient protection from life-threatening in-
patients with a primary antibody deficiency syn- fections, prevents the recurrence of severe bacte-
drome is the finely tuned IgG substitution. rial infections, reduces the need for antibiotics,
aids healing and improves the quality of life.7,20
Congenital antibody deficiency syndromes in-
clude common variable immunodeficiencies
(CVID), severe combined immune deficiencies
(SCID), the DiGeorge syndrome, the X-linked ag-
ammaglobulinaemia (Morbus Bruton), the Wis-
kott-Aldrich syndrome and the selective IgA or
IgG subclass deficiencies.

The severely impaired antibody production is due
to genetic defects in the lymphocytes, granulo-
cytes, monocytes or thrombocytes and / or ma-
turity and functional disorders of immune cells.

Antibody deficiency can affect the entire immu-
noglobulin spectrum of individual immunoglobu-
lin classes (IgG, IgM, IgA) or IgG subclasses. Vul-
nerability to severe bacterial infections increases
with the severity of the condition. As inflamma-
tory responses often linger, wound healing and
tissue regeneration processes are sometimes also
affected.7,27

Substitution with intravenous immunoglobulins
adapted to the individual IgG serum level affords

Recommended therapy for secondary antibody deficiency

In patients with primary antibody deficiency diseases, the recommended IVIG dosage is 0.4 to
0.8 g/kg BW initially, followed by 0.2 to 0.8 g/kg BW at intervals of 2 to 4 weeks.10

Both the interval between infusions and the maintenance dose depend on the IgG half-life value,
which can be between 10 and 30 days. An IgG serum level of at least 6 g/l is required to achieve
a stable immune system and prophylaxis against infection.

Children usually require higher serum levels (above 8 g/l) to maintain age-appropriate growth
rates and the development of full organ functions.

27

Intratect® I Immunoglobulins stand for disease control and quality of life

Secondary antibody deficiency syndromes

Secondary (adaptive) antibody deficiencies of- The European Guidelines recommend using IVIG
ten occur as a result of malignant lymphomas for hypogammaglobulinaemia and recurrent
or during long-term administration of strong bacterial infections in connection with chronic
immunosuppressants. The associated dysfunc- leukaemia or multiple myeloma, following hae-
tions of immune cells in the blood and inade- matopoietic stem cell transplantation (HSCT),
quate cell-to-cell communication result in the as well as for children and juveniles with con-
inhibition of antibody production. The risk of genital AIDS and recurrent bacterial infections.10
infection increases with persistent hypogam-
maglobulinaemia and the ability to regenerate
tissue and control inflammation is reduced.

Recommended therapy for secondary antibody deficiency

Administration of an initial dose of 0.4 – 0.8 g/kg BW, followed by individually adapted main-
tenance therapy with 0.2 – 0.4 g/kg BW at intervals of two to three weeks.

The targeted IgG level necessary to stabilise the immune system and for prophylaxis against
infection is higher than 5 – 6 g/l.10

Autoimmune diseases

Autoimmune diseases are manifestations of mis- Immunoglobulins represent not only an anti-
directed immunological reactions to the body's infectious and anti-toxic component of the im-
own structures. They present with organ-specific mune defence, but above all, they also display
or systemic symptoms as acute or chronic illnesses. immunoregulatory and anti-inflammatory
properties. Their broad spectrum of actions also
Typical is the involvement of pathological anti- allows the therapeutic correction of immuno-
bodies and autoaggressive T and B cell clones logical dysfunctions of assorted aetiologies.
that cause destruction of body cells and tissues Immunoglobulins help restore the immune sys-
by apoptotic or lytic mechanisms.24,35 tem's equilibrium.2,9,24,26,35

The success story of intravenous immunoglobu- As the treatment of autoimmune diseases re-
lin therapy for the treatment of autoimmune quires high doses of IVIG to be effective, 1 – 2 g/
diseases goes back more than 25 years, when kg BW IVIG must be given per treatment cycle.
successful treatment of primary immune throm-
bocytopenia (ITP) was described for the first time. Acute autoimmune diseases, such as primary
Subsequently, clinically controlled studies have immune thrombocytopenia (ITP), Guillain-Barré
confirmed the efficacy of IVIG therapy in a vari- syndrome and Kawasaki syndrome usually only
ety of autoimmune and inflammatory diseases require one single dose of IVIG.
worldwide.2,3,12,17,19,27,30

28

Intratect® I Immunoglobulins stand for disease control and quality of life

Patients with relapsing-remitting forms and most cases, immunosuppressive medication can
chronic autoimmune diseases can usually be be considerably reduced, which also reduces the
successfully treated with corticosteroids or im- incidence of its adverse effects.The increased risk
munosuppressants. In cases that do not respond of infection associated with long-term suppres-
to this therapy or to a combination therapy, or if sion also diminishes after a certain time.
treatment induces adverse effects, most patients
(50 to 70 %) will show clinical improvement and Depending on the course of the illness, initially
therapeutic ability will be restored if treatment three to six cycles of 2 g/kg BW are given at in-
is supplemented with IVIG. tervals of 4 weeks. With clinical improvement
or stability the dosage can be reduced (0.2 to
Several cycles of IVIG therapy are required to 1.1 g/kg) and/or the interval extended. Treat-
achieve significant clinical improvement. Re- ment can be discontinued with sufficient clinical
generation processes, including the regulation improvement or when the patient is symptom-
of receptor expression following long-term sup- free. If a relapse occurs, it is advisable to give
pression, require several weeks. The partial res- IVIG at an early stage to stop the course of the
toration of immune equilibrium means that, in illness.1,2,8,12,30,34

Immunoglobulins can be used to effectively treat the following autoimmune diseases:*

O Peripheral autoimmune neuropathies (GBS, CIDP, MMN)
O Relapsing-remitting multiple sclerosis and the prevention of postpartum relapses
O Myasthenia gravis (myasthenic crisis)
O Refractory inflammatory myositis (dermato-/polymyositis and inclusion body myositis)
O Systemic vasculitides (Kawasaki syndrome, refractory SLE, primary vasculitides, mixed connective

tissue diseases (MCTD)/overlap syndrome)
O Autoimmune dermatoses (refractory pemphigus vulgaris and other blistering autoimmune

dermatoses)
O Autoimmune cytopenias (ITP, AIHA, autoimmune neutropenias)

*) With the exception of GBS, CIDP, MMN, ITP and Kawasaki syndrome, use is off-label 1, 2, 12, 17, 27, 30, 34, 36

Recommended therapy for autoimmune diseases

The IVIG dosage for the treatment of acute inflammatory autoimmune diseases is 1 – 2 g/kg
BW. Depending on the severity of the disease and the individual risk factors, this dose should be
split into two to five single doses.

IVIG is recommended as a supplementary therapy for chronically ill patients with a progressive
condition under immunosuppressants. After a monthly dose of 2 g/kg BW IVIG over three to
six months, the individually calculated maintenance dose depends on the patient's condition.

29

Patient-oriented treatment

IN FOCUS Immediate bioavailability of IVIG –
Ideal for patient-oriented use

In contrast to drugs given via is ideal for the neutralisation All compounds have a similar
subcutaneous or intramuscular and elimination of pathogens range of adverse events and in-
injection, intravenously given and inflammation mediators. cluded reactions such as head-
immunoglobulins are immedi- The effects at cell level (immu- aches, influenza-like symptoms,
ately bioavailable. This means, nomodulation, receptor expres- raised temperature, hypoten-
with entry into the blood, IgG sion) depend on a number of sion, nausea and joint or back
antibodies immediately neu- factors. pains.
tralise pathogens and inflam-
mation factors and activate The type and severity of the dis- Some of the complications ob-
the unspecific immune system. ease to be treated, accompany- served are in connection with
Through the Fcc-mediated ing or previous illnesses, organ the infusion rate or changes in
binding to vascular endothe- dysfunctions or the properties the viscosity of the blood fol-
lium and the immune cells of blood influence cellular re- lowing administration of im-
circulating in the blood, these sponses to immune therapies munoglobulins.
change their communication and also affect the tolerability
behaviour within just a few of IVIG.
hours.
Intravenous immunoglobulin
The more pure and concen- compounds are usually well tol-
trated the IVIG compound, the erated and, if properly applied,
quicker the desired effect. This produce few adverse events.

Infusion rates and IVIG concentration form an alliance

Clinics and physicians' surgeries A number of opportunities have Only an individual risk assess-
typically suffer from high work- now arisen in connection with ment before beginning thera-
loads and time pressure. They the introduction of 10 percent py can help avoid unnecessary
aim to treat each patient well, IVIG compounds. Whereas the complications.
but also efficiently. When seek- infusion volume and time have
ing to optimise work processes, decreased, the potential risk of
IVIG therapy infusion rates are adverse events for high dose
often a point of discussion. therapy has, however, increased.

30

To be determined: Inpatient or stationary treatment?

considerably higher doses of up
to 2 g/kg BW. To facilitate toler-
ability, this is usually given over
a five-day period.

The rule is, the more severe the
disease and organ dysfunction,
and the higher inflammatory
activity, the lower the infusion
rate. Economy of time is not
usually an important aspect of
stationary treatment.

Inpatients with a primary or infused relatively quickly. This Sufficient liquid intake is neces-
secondary antibody deficiency, saves time for both medical sary to avoid a rapid increase in
no further individual risk factors staff and patient. blood viscosity. In such cases, a
and whose daily dose does not patient could benefit from a five
exceed 0.2 to 0.4 g/kg BW IVIG Acute and/or seriously chroni- percent IVIG solution.
usually tolerate a ten percent cally ill patients require station-
IVIG compound that can be ary treatment, as they need The question of whether inpa-
tient or stationary treatment is
better depends largely on the
daily IVIG dose and the progress
of the disease.

31

Patient-oriented treatment

IN FOCUS To be determined: What are the individual risk factors?

IVIG infusions for patients with oral contraceptives or longer cur if the complement cascade
kidney dysfunctions or known periods of immobility. is activated and there is signi-
thromboembolic complications ficant inflammatory activity of
should take the lowest possible These are rare occurrences the reticular endothelial system
daily dose rather slowly. Too ra- (l 0.01 %), the causes of which (RES). Haemolytic reactions are
pid an increase in blood protein are as yet largely unknown. Ar- extremely rare.
content could result in adverse terial complications are most
reactions. likely to occur during administ- The proportion of anti-A or an-
ration of IVIG or within the first ti-B isoagglutinins in IVIG com-
Risk factors for thromboem- 24 hours, whereas venous com- pounds depends on the crude
bolic complications with IVIG plications do not usually arise plasma and is somewhat higher
administration are hypertonia, before day two or later.25,29,32 in 10 percent than in 5 percent
vascular diseases, premature compounds, which is due to the
cardiac infarct, stroke, deep IVIG compounds can contain production process.
venous thrombosis, severe hy- blood group antibodies (anti-A,
povolaemia or increased blood anti-B), which act as haemoly- Haemolysis-promoting fac-
viscosity due to other medica- sins (isoagglutinin) and bind tors are daily IVIG doses above
tion, hyperlipidaemia, hyperco- with red blood cells. Clinically 100 g or more than 2 g/kg BW,
agulopathy, diabetes mellitus, significant haemolysis can oc- a higher anti-A and anti-B IgG
titer (L 1:32) in the compound,
significant inflammatory ac-
tivity and high HLA sensitivity.
Patients with blood group A
(42.5 %) are more often affected
than those with blood groups B
or AB (14 resp. 6.5 %).16,28

Please note: the more risk fac-
tors involved, the lower the in-
fusion rate and daily IVIG dose
should be.

Opting for a 5 % instead of a
10 % immunoglobulin com-
pound often helps avoid com-
plications.

32

To be determined:What is the ideal (and safe) daily IVIG dose?

Whether in an outpatient or
stationary setting, the daily
IVIG dose must be adjusted to
the severity of the illness and
the patient's current general
condition.

Daily IVIG doses of up to 0.4 g/ severity of the illness. It must The weight of the patient must
kg BW are usually well tolerat- be ensured that temporary pro- also be taken into considera-
ed and can be given to patients tein load increases do not cause tion. Heavy patients some-
who are neither acutely ill nor organ dysfunctions, headaches, times tolerate higher daily IVIG
display additional risk factors nausea or other adverse events. doses (more than 30 – 50 g/d)
in an ambulatory setting. The The total dose should be spread less well. In such cases, it is ad-
decisive factor is, however, the over several days (0.4 to 0.5 g/ visable to reduce the infusion
actual condition of the patient kg per day). Opting for a 5 % rate to prevent the occurrence
on the day of infusion. Suffi- instead of a 10 % infusion solu- of complications.
cient liquid intake (drinking) tion is also a means of reducing
reduces the risk of headache the risk of adverse reactions.
and nausea.

If high-dose therapy (1 to 2 g/kg
BW) is required, the daily dose
must be adjusted to the pa-
tient's state of health and the

For the good of your patient, give careful consideration to:

I The concentration of the infusion solution: 5 % or 10 %
I Infusion rate: faster or slower
I IVIG dose: single dose or spread over several days

The more individual risks factors involved, the lower the infusion rate and
daily IVIG dose should be. A patient-oriented choice of IVIG concentrate
helps avoid complications.

33

Intratect® I SPC Intratect®

Summary of product characteristcs
Intratect®

1. NAME OF THE MEDICINAL PRODUCT Immunomodulation in adults, and children and adolescents
Intratect 50 g/l, solution for infusion (0 – 18 years) in:
2. QUALITATIVE AND QUANTITATIVE COMPOSITION • Primary immune thrombocytopenia (ITP), in patients at high risk of
Human normal immunoglobulin (IVIg)
One ml contains: bleeding or prior to surgery to correct the platelet count.
Human normal immunoglobulin 50 mg (purity of at least 96 % IgG) • Guillain Barré syndrome.
Each vial of 20 ml contains: 1 g • Kawasaki disease.
Each vial of 50 ml contains: 2.5 g 4.2 Posology and method of administration
Each vial of 100 ml contains: 5 g Replacement therapy should be initiated and monitored under the su-
Each vial of 200 ml contains: 10 g pervision of a physician experienced in the treatment of immunodefi-
Distribution of the IgG subclasses (approx. values): ciency.
IgG1 57 % Posology
IgG2 37 % The dose and dose regimen is dependent on the indication.
IgG3 3 % In replacement therapy the dose may need to be individualised for each
IgG4 3 % patient dependent on the pharmacokinetic and clinical response. The
The maximum IgA content is 2000 micrograms/ml. following dose regimens are given as a guideline:
Produced from the plasma of human donors. Replacement therapy in primary immunodeficiency syndromes
For a full list of excipients, see section 6.1. The dose regimen should achieve a trough level of IgG (measured before
3. PHARMACEUTICAL FORM the next infusion) of at least 5 to 6 g/l. Three to six months are required
Solution for infusion. after the initiation of therapy for equilibration to occur.The recommend-
The solution is clear to slightly opalescent and colourless to pale yellow. ed starting dose is 8 – 16 ml (0.4 – 0.8 g)/kg given once, followed by at
4. CLINICAL PARTICULARS least 4 ml (0.2 g)/kg given every three to four weeks.
4.1 Therapeutic indications The dose required to achieve a trough level of 5 – 6 g/l is of the order of
Replacement therapy in adults, and children and adolescents 4 – 16 ml (0.2 – 0.8 g)/kg/month. The dosage interval when steady state
(0 – 18 years) in: has been reached varies from 3 – 4 weeks.
• Primary immunodeficiency syndromes with impaired antibody produc- Trough levels should be measured and assessed in conjunction with the
incidence of infection.To reduce the rate of infection, it may be necessary
tion (see section 4.4). to increase the dosage and aim for higher trough levels.
• Hypogammaglobulinaemia and recurrent bacterial infections in pa- Hypogammaglobulinaemia and recurrent bacterial infections in patients
with chronic lymphocytic leukaemia, in whom prophylactic antibiotics
tients with chronic lymphocytic leukaemia, in whom prophylactic an- have failed; hypogammaglobulinaemia and recurrent bacterial infections
tibiotics have failed. in plateau phase multiple myeloma patients who have failed to respond
• Hypogammaglobulinaemia and recurrent bacterial infections in pla- to pneumococcal immunisation; congenital AIDS with recurrent bacterial
teau phase multiple myeloma patients who have failed to respond to infections.
pneumococcal immunisation. The recommended dose is 4 –8 ml (0.2 –0.4 g)/kg every three to four weeks.
• Hypogammaglobulinaemia in patients after allogeneic haematopoi- Hypogammaglobulinaemia in patients after allogeneic haematopoietic
etic stem cell transplantation (HSCT). stem cell transplantation
• Congenital AIDS with recurrent bacterial infections. The recommended dose is 4 – 8 ml (0.2 – 0.4 g)/kg every three to four
weeks. The trough levels should be maintained above 5 g/l.

Indication Dose Frequency of infusions
Replacement therapy in primary immunodeficiency starting dose:
0.4 – 0.8 g/kg every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/l
Replacement therapy in secondary immunodeficiency thereafter: every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/l
Congenital AIDS 0.2 – 0.8 g/kg every 3 – 4 weeks
Hypogammaglobulinaemia (l 4 g/l) in patients after 0.2 – 0.4 g/kg every 3 – 4 weeks to obtain IgG trough level above 5 g/l
allogeneic haematopoietic stem cell transplantation 0.2 – 0.4 g/kg
Immunomodulation: 0.2 – 0.4 g/kg on day 1,
Primary immune thrombocytopenia possibly repeated once within 3 days
0.8 – 1 g/kg for 2 – 5 days
Guillain Barré syndrome or for 5 days
Kawasaki disease 0.4 g/kg/d in divided doses over 2 – 5 days in association with acetylsalicylic acid
0.4 g/kg/d in one dose in association with acetylsalicylic acid
1.6 – 2 g/kg
or
2 g/kg

34

Intratect® I SPC Intratect®

Primary immune thrombocytopenia Hypersensitivity
There are two alternative treatment schedules: True hypersensitivity reactions are rare. They can occur in patients with
• 16 – 20 ml (0.8 – 1 g)/kg given on day one, this dose may be repeated anti-IgA antibodies.
IVIg is not indicated in patients with selective IgA deficiency where the
once within 3 days IgA deficiency is the only abnormality of concern.
• 8 ml (0.4 g)/kg given daily for two to five days. The treatment can be Rarely, human normal immunoglobulin can induce a fall in blood pres-
sure with anaphylactic reaction, even in patients who had tolerated pre-
repeated if relapse occurs. vious treatment with human normal immunoglobulin.
Guillain Barré syndrome Thromboembolism
8 ml (0.4 g)/kg/day over 5 days. There is clinical evidence of an association between IVIg administration
Kawasaki disease and thromboembolic events such as myocardial infarction, cerebral vas-
32 – 40 ml (1.6 – 2.0 g)/kg should be administered in divided doses over cular accident (including stroke), pulmonary embolism and deep vein
two to five days or 40 ml (2.0 g)/kg as a single dose. Patients should re- thromboses which is assumed to be related to a relative increase in blood
ceive concomitant treatment with acetylsalicylic acid. viscosity through the high influx of immunoglobulin in at-risk patients.
The dosage recommendations are summarised in the table. Caution should be exercised in prescribing and infusing IVIg in obese
Paediatric population patients and in patients with pre-existing risk factors for thrombotic
The posology in children and adolescents (0 – 18 years) is not different to events (such as advanced age, hypertension, diabetes mellitus and a his-
that of adults as the posology for each indication is given by body weight tory of vascular disease or thrombotic episodes, patients with acquired
and adjusted to the clinical outcome of the above mentioned conditions. or inherited thrombophilic disorders, patients with prolonged periods of
Method of administration immobilisation, severely hypovolaemic patients, patients with diseases
For intravenous use. which increase blood viscosity).
Intratect should be infused intravenously at an initial rate of not more In patients at risk for thromboembolic adverse reactions, IVIg products
than 1.4 ml/kg/hr for 30 minutes. should be administered at the minimum rate of infusion and dose prac-
If well tolerated (see section 4.4), the rate of administration may gradu- ticable.
ally be increased to a maximum of 1.9 ml/kg/hr for the remainder of Acute renal failure
the infusion. Cases of acute renal failure have been reported in patients receiving IVIg
4.3 Contraindications therapy. In most cases, risk factors have been identified, such as pre-
Hypersensitivity to the active substance or to any of the excipients (see existing renal insufficiency, diabetes mellitus, hypovolaemia, overweight,
section 4.4). concomitant nephrotoxic medicinal products or age over 65 years.
Hypersensitivity to human immunoglobulins, especially in patients with In case of renal impairment, IVIg discontinuation should be considered.
antibodies against IgA. While these reports of renal dysfunction and acute renal failure have
4.4 Special warnings and precautions for use been associated with the use of many of the licensed IVIg products con-
Certain severe adverse reactions may be related to the rate of infusion. taining various excipients such as sucrose, glucose and maltose, those
The recommended infusion rate given under section 4.2 must be closely containing sucrose as a stabiliser accounted for a disproportionate share
followed. Patients must be closely monitored and carefully observed for of the total number. In patients at risk, the use of IVIg products that
any symptoms throughout the infusion period. do not contain these excipients may be considered. Intratect does not
Certain adverse reactions may occur more frequently contain sucrose, maltose or glucose.
• in case of high rate of infusion, In patients at risk for acute renal failure, IVIg products should be admin-
• in patients who receive human normal immunoglobulin for the first istered at the minimum rate of infusion and dose practicable.
Aseptic meningitis syndrome (AMS)
time or, in rare cases, when the human normal immunoglobulin prod- Aseptic meningitis syndrome has been reported to occur in association
uct is switched or when there has been a long interval since the previ- with IVIg treatment.
ous infusion. Discontinuation of IVIg treatment has resulted in remission of AMS
Potential complications can often be avoided by ensuring that patients within several days without sequelae.
• are not sensitive to human normal immunoglobulin by initially inject- The syndrome usually begins within several hours to 2 days following
ing the product slowly (1.4 ml/kg/h corresponding to 0.023 ml/kg/min). IVIg treatment. Cerebrospinal fluid studies are frequently positive with
• are carefully monitored for any symptoms throughout the infusion pleocytosis up to several thousand cells per mm3, predominantly from
period. In particular, patients naive to human normal immunoglobulin, the granulocytic series, and elevated protein levels up to several hundred
patients switched from an alternative IVIg product or when there has mg/dl.
been a long interval since the previous infusion should be monitored AMS may occur more frequently in association with high-dose (2 g/kg)
during the first infusion and for the first hour after the first infusion, IVIg treatment.
in order to detect potential adverse signs. All other patients should be Haemolytic anaemia
observed for at least 20 minutes after administration. IVIg products can contain blood group antibodies which may act as
In case of adverse reaction, either the rate of administration must be haemolysins and induce in vivo coating of red blood cells with immu-
reduced or the infusion stopped. The treatment required depends on noglobulin, causing a positive direct antiglobulin reaction (Coombs' test)
the nature and severity of the adverse reaction. and, rarely, haemolysis. Haemolytic anaemia can develop subsequent
In case of shock, standard medical treatment for shock should be im- to IVIg therapy due to enhanced red blood cells (RBC) sequestration.
plemented. IVIg recipients should be monitored for clinical signs and symptoms of
In all patients, IVIg administration requires: haemolysis. (See section 4.8.)
• adequate hydration prior to the initiation of the infusion of IVIg
• monitoring of urine output
• monitoring of serum creatinine levels
• avoidance of concomitant use of loop diuretics

35

Intratect® I SPC Intratect®

Interference with serological testing Cases of reversible aseptic meningitis and rare cases of transient cutane-
After injection of immunoglobulin the transitory rise of the various pas- ous reactions have been observed with human normal immunoglobulin.
sively transferred antibodies in the patient's blood may result in mislead- Reversible haemolytic reactions have been observed in patients, espe-
ing positive results in serological testing. cially those with blood groups A, B, and AB. Rarely, haemolytic anaemia
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D requiring transfusion may develop after high dose IVIg treatment (see
may interfere with some serological tests for red cell antibodies for ex- also Section 4.4).
ample the direct antiglobulin test (DAT, direct Coombs' test).
Transmissible agents Increase in serum creatinine level and/or acute renal failure have been
Standard measures to prevent infections resulting from the use of me- observed.
dicinal products prepared from human blood or plasma include selection
of donors, screening of individual donations and plasma pools for specific Very rarely: Thromboembolic reactions such as myocardial infarction,
markers of infection and the inclusion of effective manufacturing steps stroke, pulmonary embolism, deep vein thromboses.
for the inactivation/removal of viruses. Despite this, when medicinal
products prepared from human blood or plasma are administered, the For safety with respect to transmissible agents, see 4.4.
possibility of transmitting infective agents cannot be totally excluded.
This also applies to unknown or emerging viruses and other pathogens. Details of further spontaneously reported adverse reactions:
The measures taken are considered effective for enveloped viruses such Cardiac disorders: Angina pectoris (very rare)
as HIV, HBV and HCV.The measures taken may be of limited value against General disorders and administrations site conditions: Rigors (very rare)
non-enveloped viruses such as HAV and parvovirus B19. Immune system disorders: Anaphylactic shock (very rare), allergic reac-
There is reassuring clinical experience regarding the lack of hepatitis tion (very rare)
A or parvovirus B19 transmission with immunoglobulins and it is also Investigations: Blood pressure decreased (very rare)
assumed that the antibody content makes an important contribution Musculoskeletal and connective tissue disorders: Back pain (very rare)
to the viral safety. Respiratory, thoracic and mediastinal disorders: Dyspnoe NOS (very rare)
It is strongly recommended that every time that Intratect is administered Vascular disorders: Shock (very rare)
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 Occasionally, hypersensitivity reactions have been observed including
product. various symptoms, such as:
4.5 Interactions with other medicinal products and other forms of in- chills, headache, dizziness, fever, vomiting, cutaneous reactions, nausea,
teraction arthralgia, low blood pressure and back pain.
Live attenuated virus vaccines:
Immunoglobulin administration may impair for a period of at least 6 Three clinical studies have been performed with Intratect: two in patients
weeks and up to 3 months the efficacy of live attenuated virus vaccines with primary immunodeficiencies (PID) and one in patients with im-
such as measles, rubella, mumps and varicella. After administration of mune thrombocytopenic purpura (ITP). In the two PID studies overall 68
this medicinal product, an interval of 3 months should elapse before patients were treated with Intratect and evaluated for safety.Treatment
vaccination with live attenuated virus vaccines. In the case of measles, period was 6 and 12 months respectively. The ITP study was performed
this impairment may persist for up to 1 year.Therefore patients receiving in 24 patients.
measles vaccine should have their antibody status checked.
4.6 Fertility, pregnancy and lactation These 92 patients received a total of 830 infusions of Intratect, whereby
Pregnancy a total of 51 suspected adverse drug reactions (ADRs) were recorded.
The safety of this medicinal product for use in human pregnancy has not The majority of these ADRs was mild to moderate and self-limiting. No
been established in controlled clinical trials and therefore should only serious ADRs were observed during the studies.
be given with caution to pregnant women and breast-feeding mothers.
IVIg products have been shown to cross the placenta, increasingly after The ADRs reported in the three studies are summarised and categorised
the third trimester. Clinical experience with immunoglobulins suggests according to the MedDRA System organ class and frequency below.
that no harmful effects on the course of pregnancy, or on the foetus and
the neonate are to be expected. Tabulated list of adverse reactions
Breast-feeding The table presented below is according to the MedDRA system organ
Immunoglobulins are excreted into the milk and may contribute to classification (SOC and Preferred Term Level).
protecting the neonate from pathogens which have a mucosal portal
of entry. Frequencies have been evaluated according to the following conven-
Fertility tion: very common (M 1/10); common (M 1/100 to l 1/10); uncom-
Clinical experience with immunoglobulins suggests that no harmful mon (M 1/1,000 to <1/100); rare (M 1/10,000 to l 1/1,000); very rare
effects on fertility are to be expected. (l 1/10,000); not known (cannot be estimated from the available data).
4.7 Effects on ability to drive and use machines
The ability to drive and operate machines may be impaired by some Frequency of Adverse Drug Reactions (ADRs) in clinical studies with
adverse reactions associated with Intratect. Patients who experience Intratect
adverse reactions during treatment should wait for these to resolve be-
fore driving or operating machines. MedDRA Adverse reaction Frequency
System Organ Class (SOC)
4.8 Undesirable effects
Summary of the safety profile Blood and lymphatic Haemolysis (mild) Uncommon
Adverse reactions such as chills, headache, dizziness, fever, vomiting, al- system disorders
lergic reactions, nausea, arthralgia, low blood pressure and moderate low
back pain may occur occasionally. Gastrointestinal disorders Nausea, vomiting, Uncommon
Rarely human normal immunoglobulins may cause a sudden fall in blood gastrointestinal pain
pressure and, in isolated cases, anaphylactic shock, even when the pa-
tient has shown no hypersensitivity to previous administration. General disorders and Pyrexia, chills, feeling hot Uncommon
administration site conditions

Investigations Body temperature Uncommon
Nervous system disorders increased, Coombs test
(indirect and direct) positive

Headache Common

Dysgeusia Uncommon

Skin and subcutaneous Papular rash Uncommon
tissue disorders

Vascular disorders Hypertension, thrombo- Uncommon
phlebitis superficial

36

Intratect® I SPC Intratect®

Description of selected adverse reactions 6.6 Special precautions for disposal and other handling
Product specific adverse reactions have not been reported.The reported The product should be brought to room or body temperature before use.
adverse reactions for Intratect are in the expected profile for human The solution should be clear or slightly opalescent and colourless or pale
normal immunoglobulins. yellow. Solutions that are cloudy or have deposits should not be used.
Paediatric population Any unused product or waste material should be disposed of in accord-
Frequency, type and severity of adverse reactions in children are expected ance with local requirements.
to be the same as in adults. 7. MARKETING AUTHORISATION HOLDER
4.9 Overdose Biotest Pharma GmbH
Overdose may lead to fluid overload and hyperviscosity, particularly in Landsteinerstraße 5
patients at risk, including elderly patients or patients with cardiac or 63303 Dreieich
renal impairment. Germany
Tel.: (+49) 06103 801 0
5. PHARMACOLOGICAL PROPERTIES Fax: (+49) 06103 801 150
5.1 Pharmacodynamic properties 8. MARKETING AUTHORISATION NUMBER(S)
Pharmacotherapeutic group: immune sera and immunoglobulins: im- –
munoglobulins, normal human, for intravascular administration, ATC 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
code: J06BA02 –
Human normal immunoglobulin contains mainly immunoglobulin G 10. DATE OF REVISION OF THE TEXT
(IgG) with a broad spectrum of antibodies against infectious agents. July 2011
Human normal immunoglobulin contains the IgG antibodies present in
the normal population. It is usually prepared from pooled plasma from
not fewer than 1000 donations. It has a distribution of immunoglobu-
lin G 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.
5.2 Pharmacokinetic properties
Human normal immunoglobulin is immediately and completely bioavail-
able 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.
Intratect has a half-life of about 27 days. This half-life may vary from
patient to patient, in particular in primary immunodeficiency.
IgG and IgG-complexes are broken down in cells of the reticuloendothe-
lial system.
5.3 Preclinical safety data
Immunoglobulins are normal constituents of the human body. In ani-
mals, single dose toxicity testing is of no relevance since higher doses
result in overloading. Repeated dose toxicity testing and embryo-foetal
toxicity studies are impracticable due to induction of, and interference
with antibodies. Effects of the product on the immune system of the
new-born have not been studied.
Since clinical experience provides no hint for tumorigenic and mutagenic
effects of immunoglobulins, experimental studies, particularly in heter-
ologous species, are not considered necessary.

6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Glycine, water for injections.
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not
be mixed with other medicinal products.
6.3 Shelf life
2 years.
After first opening, an immediate use is recommended.
6.4 Special precautions for storage
Do not store above 25 °C. Do not freeze.
Keep the vial in the outer carton in order to protect from light.
6.5 Nature and contents of container
20 ml or 50 ml or 100 ml or 200 ml of solution in a vial (Type II glass) with
a stopper (bromobutyl) and a cap (aluminium) – pack size of one vial.

37

Intratect® I SPC Intratect® 100 g/l

Summary of product characteristcs
Intratect® 100 g/l

1. NAME OF THE MEDICINAL PRODUCT Immunomodulation in adults, and children and adolescents
Intratect® 100 g/l (0 – 18 years) in:
solution for infusion • Primary immune thrombocytopenia (ITP), in patients at high risk of
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
Human normal immunoglobulin (IVIg) bleeding or prior to surgery to correct the platelet count.
One ml contains: • Guillain Barré syndrome.
Human normal immunoglobulin 100 mg (purity of at least 96 % IgG) • Kawasaki disease.
Each vial of 10 ml contains: 1 g 4.2 Posology and method of administration
Each vial of 50 ml contains: 5 g Replacement therapy should be initiated and monitored under the su-
Each vial of 100 ml contains: 10 g pervision of a physician experienced in the treatment of immunodefi-
Each vial of 200 ml contains: 20 g ciency.
Distribution of the IgG subclasses (approx. values): Posology
IgG1 57 % The dose and dose regimen is dependent on the indication.
IgG2 37 % In replacement therapy the dose may need to be individualised for each
IgG3 3 % patient dependent on the pharmacokinetic and clinical response. The
IgG4 3 % following dose regimens are given as a guideline:
The maximum IgA content is 1800 micrograms/ml. Replacement therapy in primary immunodeficiency syndromes
Produced from the plasma of human donors. The dose regimen should achieve a trough level of IgG (measured before
For a full list of excipients, see section 6.1. the next infusion) of at least 5 to 6 g/l. Three to six months are required
3. PHARMACEUTICAL FORM after the initiation of therapy for equilibration to occur.The recommend-
Solution for infusion. ed starting dose is 4 – 8 ml (0.4 – 0.8 g)/kg given once, followed by at least
The solution is clear to slightly opalescent and colourless to pale yellow. 2 ml (0.2 g)/kg given every three to four weeks.
4. CLINICAL PARTICULARS The dose required to achieve a trough level of 5 – 6 g/l is of the order of
4.1 Therapeutic indications 2 – 8 ml (0.2 – 0.8 g)/kg/month. The dosage interval when steady state
Replacement therapy in adults, and children and adolescents has been reached varies from 3 – 4 weeks.
(0 – 18 years) in: Trough levels should be measured and assessed in conjunction with the
• Primary immunodeficiency syndromes with impaired antibody produc- incidence of infection.To reduce the rate of infection, it may be necessary
to increase the dosage and aim for higher trough levels..
tion (see section 4.4). Hypogammaglobulinaemia and recurrent bacterial infections in patients
• Hypogammaglobulinaemia and recurrent bacterial infections in pa- with chronic lymphocytic leukaemia, in whom prophylactic antibiotics
have failed; hypogammaglobulinaemia and recurrent bacterial infections
tients with chronic lymphocytic leukaemia, in whom prophylactic an- in plateau phase multiple myeloma patients who have failed to respond
tibiotics have failed. to pneumococcal immunisation; congenital AIDS with recurrent bacterial
• Hypogammaglobulinaemia and recurrent bacterial infections in pla- infections.
teau phase multiple myeloma patients who have failed to respond to The recommended dose is 2 – 4 ml (0.2 – 0.4 g)/kg every three to four
pneumococcal immunisation. weeks.
• Hypogammaglobulinaemia in patients after allogeneic haematopoi- Hypogammaglobulinaemia in patients after allogeneic haematopoietic
etic stem cell transplantation (HSCT). stem cell transplantation
• Congenital AIDS with recurrent bacterial infections. The recommended dose is 2 – 4 ml (0.2 – 0.4 g)/kg every three to four
weeks. The trough levels should be maintained above 5 g/l.

Indication Dose Frequency of infusions
Replacement therapy in primary immunodeficiency starting dose:
0.4 – 0.8 g/kg every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/l
Replacement therapy in secondary immunodeficiency thereafter: every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/l
Congenital AIDS 0.2 – 0.8 g/kg every 3 – 4 weeks
Hypogammaglobulinaemia (l 4 g/l) in patients after 0.2 – 0.4 g/kg every 3 – 4 weeks to obtain IgG trough level above 5 g/l
allogeneic haematopoietic stem cell transplantation 0.2 – 0.4 g/kg
Immunomodulation: 0.2 – 0.4 g/kg on day 1,
Primary immune thrombocytopenia possibly repeated once within 3 days
0.8 – 1 g/kg for 2 – 5 days
Guillain Barré syndrome or for 5 days
Kawasaki disease 0.4 g/kg/d in divided doses over 2 – 5 days in association with acetylsalicylic acid
0.4 g/kg/d in one dose in association with acetylsalicylic acid
1.6 – 2 g/kg
or
2 g/kg

38

Intratect® I SPC Intratect® 100 g/l

Primary immune thrombocytopenia Hypersensitivity
There are two alternative treatment schedules: True hypersensitivity reactions are rare. They can occur in patients with
• 8 – 10 ml (0.8 – 1 g)/kg given on day one, this dose may be repeated once anti-IgA antibodies.
IVIg is not indicated in patients with selective IgA deficiency where the
within 3 days IgA deficiency is the only abnormality of concern.
• 4 ml (0.4 g)/kg given daily for two to five days. Rarely, human normal immunoglobulin can induce a fall in blood pres-
The treatment can be repeated if relapse occurs. sure with anaphylactic reaction, even in patients who had tolerated pre-
Guillain Barré syndrome vious treatment with human normal immunoglobulin.
4 ml (0.4 g)/kg/day over 5 days. Thromboembolism
Kawasaki disease There is clinical evidence of an association between IVIg administration
16 – 20 ml (1.6 – 2.0 g)/kg should be administered in divided doses over and thromboembolic events such as myocardial infarction, cerebral vas-
two to five days or 20 ml (2.0 g)/kg as a single dose. Patients should re- cular accident (including stroke), pulmonary embolism and deep vein
ceive concomitant treatment with acetylsalicylic acid. thromboses which is assumed to be related to a relative increase in blood
The dosage recommendations are summarised in the following table: viscosity through the high influx of immunoglobulin in at-risk patients.
Paediatric population Caution should be exercised in prescribing and infusing IVIg in obese
The posology in children and adolescents (0 – 18 years) is not different to patients and in patients with pre-existing risk factors for thrombotic
that of adults as the posology for each indication is given by body weight events (such as advanced age, hypertension, diabetes mellitus and a his-
and adjusted to the clinical outcome of the above mentioned conditions. tory of vascular disease or thrombotic episodes, patients with acquired
Method of administration or inherited thrombophilic disorders, patients with prolonged periods of
For intravenous use. immobilisation, severely hypovolaemic patients, patients with diseases
Intratect 100 g/l should be infused intravenously at an initial rate of not which increase blood viscosity).
more than 1.4 ml/kg/hr for 30 minutes. In patients at risk for thromboembolic adverse reactions, IVIg products
If well tolerated (see section 4.4), the rate of administration may gradu- should be administered at the minimum rate of infusion and dose prac-
ally be increased to a maximum of 1.9 ml/kg/hr for the remainder of ticable.
the infusion. Acute renal failure
4.3 Contraindications Cases of acute renal failure have been reported in patients receiving IVIg
Hypersensitivity to the active substance or to any of the excipients (see therapy. In most cases, risk factors have been identified, such as pre-
section 6.1). existing renal insufficiency, diabetes mellitus, hypovolaemia, overweight,
Hypersensitivity to human immunoglobulins, especially in patients with concomitant nephrotoxic medicinal products or age over 65 years.
antibodies against IgA. In case of renal impairment, IVIg discontinuation should be considered.
4.4 Special warnings and precautions for use While these reports of renal dysfunction and acute renal failure have
Certain severe adverse reactions may be related to the rate of infusion. been associated with the use of many of the licensed IVIg products con-
The recommended infusion rate given under section 4.2 must be closely taining various excipients such as sucrose, glucose and maltose, those
followed. Patients must be closely monitored and carefully observed for containing sucrose as a stabiliser accounted for a disproportionate share
any symptoms throughout the infusion period. of the total number. In patients at risk, the use of IVIg products that do
Certain adverse reactions may occur more frequently not contain these excipients may be considered. Intratect 100 g/l does
• in case of high rate of infusion, not contain sucrose, maltose or glucose.
• in patients who receive human normal immunoglobulin for the first In patients at risk for acute renal failure, IVIg products should be admin-
istered at the minimum rate of infusion and dose practicable.
time or, in rare cases, when the human normal immunoglobulin prod- Aseptic meningitis syndrome (AMS)
uct is switched or when there has been a long interval since the previ- Aseptic meningitis syndrome has been reported to occur in association
ous infusion. with IVIg treatment.
Potential complications can often be avoided by ensuring that patients Discontinuation of IVIg treatment has resulted in remission of AMS
• are not sensitive to human normal immunoglobulin by initially inject- within several days without sequelae.
ing the product slowly (1.4 ml/kg/h corresponding to 0.023 ml/kg/min), The syndrome usually begins within several hours to 2 days following
• are carefully monitored for any symptoms throughout the infusion IVIg treatment. Cerebrospinal fluid studies are frequently positive with
period. In particular, patients naive to human normal immunoglobulin, pleocytosis up to several thousand cells per mm3, predominantly from the
patients switched from an alternative IVIg product or when there has granulocytic series,and elevated protein levels up to several hundred mg/dl.
been a long interval since the previous infusion should be monitored AMS may occur more frequently in association with high-dose (2 g/kg)
during the first infusion and for the first hour after the first infusion, IVIg treatment.
in order to detect potential adverse signs. All other patients should be Haemolytic anaemia
observed for at least 20 minutes after administration. IVIg products can contain blood group antibodies which may act as
In case of adverse reaction, either the rate of administration must be haemolysins and induce in vivo coating of red blood cells with immu-
reduced or the infusion stopped. The treatment required depends on noglobulin, causing a positive direct antiglobulin reaction (Coombs' test)
the nature and severity of the adverse reaction. and, rarely, haemolysis. Haemolytic anaemia can develop subsequent
In case of shock, standard medical treatment for shock should be im- to IVIg therapy due to enhanced red blood cells (RBC) sequestration.
plemented. IVIg recipients should be monitored for clinical signs and symptoms of
In all patients, IVIg administration requires haemolysis. (See section 4.8.)
• adequate hydration prior to the initiation of the infusion of IVIg Interference with serological testing
• monitoring of urine output After injection of immunoglobulin the transitory rise of the various pas-
• monitoring of serum creatinine levels sively transferred antibodies in the patient's blood may result in mislead-
• avoidance of concomitant use of loop diuretics ing positive results in serological testing.

39

Intratect® I SPC Intratect® 100 g/l

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D Rarely human normal immunoglobulins may cause a sudden fall in blood
may interfere with some serological tests for red cell antibodies for ex- pressure and, in isolated cases, anaphylactic shock, even when the pa-
ample the direct antiglobulin test (DAT, direct Coombs' test). tient has shown no hypersensitivity to previous administration.
Transmissible agents Cases of reversible aseptic meningitis and rare cases of transient cutane-
Standard measures to prevent infections resulting from the use of ous reactions have been observed with human normal immunoglobulin.
medicinal products prepared from human blood or plasma include se- Reversible haemolytic reactions have been observed in patients, espe-
lection of donors, screening of individual donations and plasma pools cially those with blood groups A, B, and AB. Rarely, haemolytic anaemia
for specific markers of infection and the inclusion of effective manu- requiring transfusion may develop after high dose IVIg treatment (see
facturing steps for the inactivation/removal of viruses. Despite this, also Section 4.4).
when medicinal products prepared from human blood or plasma are Increase in serum creatinine level and/or acute renal failure have been
administered, the possibility of transmitting infective agents cannot observed.
be totally excluded. This also applies to unknown or emerging viruses Very rarely: Thromboembolic reactions such as myocardial infarction,
and other pathogens. stroke, pulmonary embolism, deep vein thromboses.
The measures taken are considered effective for enveloped viruses such For safety information with respect to transmissible agents, see sec-
as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and tion 4.4.
hepatitis C virus (HCV). The measures taken may be of limited value Details of further spontaneously reported adverse reactions:
against non-enveloped viruses such as hepatitis A virus and parvovirus Cardiac disorders: Angina pectoris (very rare)
B19. General disorders and administrations site conditions: Rigors (very rare)
There is reassuring clinical experience regarding the lack of hepatitis Immune system disorders: Anaphylactic shock (very rare), allergic reac-
A or parvovirus B19 transmission with immunoglobulins and it is also tion (very rare)
assumed that the antibody content makes an important contribution Investigations: Blood pressure decreased (very rare)
to the viral safety. Musculoskeletal and connective tissue disorders: Back pain (very rare)
It is strongly recommended that every time that Intratect 100 g/l is Respiratory, thoracic and mediastinal disorders: Dyspnoe NOS (very rare)
administered to a patient, the name and batch number of the product Vascular disorders: Shock (very rare)
are recorded in order to maintain a link between the patient and the Occasionally, hypersensitivity reactions have been observed including
batch of the product. various symptoms, such as:
Paediatric population chills, headache, dizziness, fever, vomiting, cutaneous reactions, nausea,
The special warnings and precautions for use mentioned for the adults arthralgia, low blood pressure and back pain.
should also be considered for the paediatric population. Suspected Adverse Drug Reactions reported in completed clinical trials:
4.5 Interactions with other medicinal products and other forms of in- Three clinical studies have been performed with Intratect 50 g/l: two in
teraction patients with primary immunodeficiencies (PID) and one in patients with
Live attenuated virus vaccines: immune thrombocytopenic purpura (ITP). In the two PID studies overall
Immunoglobulin administration may impair for a period of at least 6 68 patients were treated with Intratect 50 g/l and evaluated for safety.
weeks and up to 3 months the efficacy of live attenuated virus vaccines Treatment period was 6 and 12 months respectively. The ITP study was
such as measles, rubella, mumps and varicella. After administration of performed in 24 patients.
this medicinal product, an interval of 3 months should elapse before These 92 patients received a total of 830 infusions of Intratect 50 g/l,
vaccination with live attenuated virus vaccines. In the case of measles, whereby a total of 51 adverse drug reactions (ADRs) were recorded.
this impairment may persist for up to 1 year.Therefore patients receiving With Intratect 100 g/l one clinical study has been performed in patients
measles vaccine should have their antibody status checked. with PID. 30 patients were treated with Intratect 100 g/l over 3 to 6
Paediatric population months and evaluated for safety. These 30 patients received a total of
It is expected that the same interaction mentioned for the adults may 90 infusions of Intratect 100 g/l, whereof a total of 13 infusions (14.4 %)
also occur in the paediatric population. were associated with adverse drug reactions (ADRs).
4.6 Fertility, pregnancy and lactation The majority of these ADRs was mild to moderate and self-limiting. No
Pregnancy serious ADRs were observed during the studies.
The safety of this medicinal product for use in human pregnancy has not Tabulated list of adverse reactions
been established in controlled clinical trials and therefore should only The table presented below is according to the MedDRA system organ
be given with caution to pregnant women and breast-feeding mothers. classification (SOC and Preferred Term Level).
IVIg products have been shown to cross the placenta, increasingly during Frequencies have been evaluated according to the following conven-
the third trimester. Clinical experience with immunoglobulins suggests tion: very common (M 1/10); common (M 1/100 to l 1/10); uncom-
that no harmful effects on the course of pregnancy, or on the foetus and mon (M 1/1,000 to <1/100); rare (M 1/10,000 to l 1/1,000); very rare
the neonate are to be expected. (l 1/10,000); not known (cannot be estimated from the available data).
Breast-feeding
Immunoglobulins are excreted into the milk and may contribute to Frequency of Adverse Drug Reactions (ADRs) in clinical studies with
protecting the neonate from pathogens which have a mucosal portal Intratect 50 g/l
of entry.
Fertility MedDRA Adverse reaction Frequency
Clinical experience with immunoglobulins suggests that no harmful System Organ Class (SOC)
effects on fertility are to be expected.
4.7 Effects on ability to drive and use machines Blood and lymphatic Haemolysis (mild) Uncommon
The ability to drive and operate machines may be impaired by some system disorders
adverse reactions associated with Intratect 100 g/l. Patients who experi-
ence adverse reactions during treatment should wait for these to resolve Gastrointestinal disorders Nausea, vomiting, Uncommon
before driving or operating machines. gastrointestinal pain
4.8 Undesirable effects
Summary of the safety profile General disorders and Pyrexia, chills, feeling hot Uncommon
Adverse reactions such as chills, headache, dizziness, fever, vomiting, al- administration site conditions
lergic reactions, nausea, arthralgia, low blood pressure and moderate low
back pain may occur occasionally. Investigations Body temperature Uncommon
increased, Coombs test
(indirect and direct) positive

40

Intratect® I SPC Intratect® 100 g/l

Nervous system disorders Headache Common distributed relatively rapidly between plasma and extravascular fluid,
Dysgeusia Uncommon after approximately 3 – 5 days equilibrium is reached between the intra-
Skin and subcutaneous Papular rash Uncommon and extravascular compartments.
tissue disorders Intratect 100 g/l has a half-life of about 34 days. This half-life may vary
Vascular disorders Hypertension, thrombo- Uncommon from patient to patient, in particular in primary immunodeficiency.
phlebitis superficial IgG and IgG-complexes are broken down in cells of the reticuloendothe-
lial system.
Frequency of Adverse Drug Reactions (ADRs) in a clinical study with 5.3 Preclinical safety data
Intratect 100 g/l Immunoglobulins are normal constituents of the human body. Repeated
dose toxicity testing and embryo-foetal toxicity studies are impractica-
MedDRA Adverse reaction Frequency ble due to induction of, and interference with antibodies. Effects of the
System Organ Class (SOC) Palpitations Common product on the immune system of the new-born have not been studied.
Cardiac Disorders Since clinical experience provides no hint for tumorigenic and mutagenic
effects of immunoglobulins, experimental studies, particularly in heter-
Gastrointestinal disorders Diarrhoea, abdominal pain Common ologous species, are not considered necessary.
6. PHARMACEUTICAL PARTICULARS
General disorders and Discomfort, fatigue, chills Common 6.1 List of excipients
administration site conditions Glycine, water for injections.
6.2 Incompatibilities
Immune system disorders Infusion related reaction, Common In the absence of compatibility studies, this medicinal product must not
hypersensitivity be mixed with other medicinal products.
6.3 Shelf life
Nervous system disorders Headache, sensory Common 2 years.
disturbance After first opening, an immediate use is recommended.
6.4 Special precautions for storage
Musculosketal and connective Arthralgia, back pain, Common Do not store above 25 °C. Do not freeze.
tissue disorders bone pain, myalgia Keep the vial in the outer carton in order to protect from light.
6.5 Nature and contents of container
Skin and subcutaneous tissue Pain of skin Common 10 ml or 50 ml or 100 ml or 200 ml of solution in a vial (Type II glass) with
disorders a stopper (bromobutyl) and a cap (aluminium) – pack size of one vial. Not
all pack sizes may be marketed.
Vascular disorders Hyperaemia, hypertension Common 6.6 Special precautions for disposal and other handling
The product should be brought to room or body temperature before use.
Description of selected adverse reactions The solution should be clear or slightly opalescent and colourless or pale
Product specific adverse reactions have not been reported.The reported yellow. Solutions that are cloudy or have deposits should not be used.
adverse reactions for Intratect are in the expected profile for human Any unused product or waste material should be disposed of in accord-
normal immunoglobulins. ance with local requirements.
Paediatric population 7. MARKETING AUTHORISATION HOLDER
Frequency, type and severity of adverse reactions in children are expected Biotest Pharma GmbH
to be the same as in adults. Landsteinerstraße 5
4.9 Overdose 63303 Dreieich
Overdose may lead to fluid overload and hyperviscosity, particularly in Germany
patients at risk, including elderly patients or patients with cardiac or Tel.: (+49) 06103 801 0
renal impairment. Fax: (+49) 06103 801 150
Paediatric population 8. MARKETING AUTHORISATION NUMBER(S)
In the paediatric population at risk, e.g. with cardiac or renal impairment, –
overdose may lead to fluid overload and hyperviscosity as with any other 9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
intravenous immunoglobulins. –
5. PHARMACOLOGICAL PROPERTIES 10. DATE OF REVISION OF THE TEXT
5.1 Pharmacodynamic properties September 2012
Pharmacotherapeutic group: immune sera and immunoglobulins: im-
munoglobulins, normal human, for intravascular administration, ATC
code: J06BA02
Human normal immunoglobulin contains mainly immunoglobulin G
(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 donations. It has a distribution of immunoglobu-
lin G 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.
Paediatric population
The pharmacokinetic properties in the paediatric population are ex-
pected to be the same as in adults.
5.2 Pharmacokinetic properties
Human normal immunoglobulin is immediately and completely bioavail-
able in the recipient's circulation after intravenous administration. It is

41

Intratect® I Bibliography

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pemphigus: high-dose i.v. immunoglobulin therapy and its ficiencies: more than mere replacement therapy
mode of action for treatment of pemphigus Clin. Exp. Immunol. (2011) 164 (Suppl. 2): 2–5
J. Dermatol. (2010) 37: 239–245
21) König H, Etscheid M: Untersuchungen zur Thrombogenität
2) Arnson Y et al.: Intravenous immunoglobulin therapy for von therapeutischen Immunglobulinen
autoimmune diseases BfArM/PEI Bull. Arzneimittelsicherheit (2011) 2: 22–25
Autoimmunity: (2009) 42: 1–8
22) Kreuz W. et al.: A multi-centre study of efficacy and safety of
3) Ballow M: The IgG molecule as a biological immune response Intratect, a novel intravenous immunoglobulin preparation
modifier: mechanisms of action of intravenous immune Clin. Exp. Immunol. (2010) 161: 512–517
serum globulin in autoimmune and inflammatory disorders
J. Allergy Clin. Immunol. (2011) 127: 315–323 23) Krivan G et al: Open prospective trial investigating phar-
macokinetics, tolerability and safety of a new 10 % human
4) Basta M: Ambivalent effect of immunoglobulins on the immunoglobulin for intravenous infusion (IVIg) in patients
complement system: activation versus inhibition with primary immunodeficiency disease (PID)
Mol. Immunol. (2008) 45: 4073–4079 15th Biennial Meeting of the Eur. Soc. for Immunodeficiencies
(ESID), Florence, Oct. 2012, Poster and Abstract No. 230
5) Bayry J et al.: Intravenous immunoglobulin for infectious
diseases: back to the pre-antibiotic and passive prophylaxis? 24) Lau AC et al.: Intravenous immunoglobulin and salicylate
Trends Pharmacol. Sci. (2004) 25: 306–310 differentially modulate pathogenic processes leading to
vascular damage in a model of Kawasaki disease
6) Colovic M et al.: Clinical efficacy and safety of a novel intra- Arthritis Rheum. (2009) 60: 2131–2141
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Intratect® I List of abreviations

List of abbreviations

AIHA Autoimmune haemolytic anaemia
BW Bodyweight
CIDP Chronic inflammatory demyelinating polyneuropathy
CVID Common variable immunodeficiency
EMA European Medicines Agency
FDA Food and Drug Administration (US)
GBS Guillain-Barré syndrome
HAV Hepatitis A virus
HBC Hepatitis B virus
HCV Hepatitis C virus
HIV Human immunodeficiency virus
ITP Primary immune thrombocytopenia (idiopathic thrombocytopenic purpura)
IVIG Intravenous immunoglobulin G
CPP Cryo-poor (depleted) plasma
MMN Multifocal motor neuropathy
NAPTT non-activated partial thromboplastin time
NAT Nucleic acid amplification technique
PEI Paul-Ehrlich Institute (German federal institute of vaccines and biomedical drugs)
PID Primary immunodeficiency disease
PKA Prekallikrein activator
TGT Thrombin generation test
vCJD Variant form of Creutzfeldt-Jakob disease

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