Intratect IVIg Brochure

Intratect ® and Intratect ® 100 g/l 

Safety through Quality 

Human immunoglobulins for intravenous use

Intratect® I Table of contents 

Table of contents 

Intratect® und Intratect® 100 g/l – Safety through Quality 4 

• High purity and naturalness 5 

• Excellent safety profile and good tolerability 5 

• User-friendly 5 

The Intratect® process guarantees high quality and viral safety 6 

• Viral safety begins with careful donor selection 6 

• From the plasma pool to the final product 7 

• The viral safety preparation procedure 7 

• Protein-chemical characterisation 10 

• Spectrum of selected anti-viral and anti-bacterial antibodies 11 

• IgG subclass distribution and half-life 11 

IN FOCUS: Patient safety 

Added safety through the elimination of all coagulation factors 12 

Multitalented immunoglobulin G – More than just infection protection 16 

• Important mechanisms of action of IVIG 16 

Safety through clinical efficacy – Studies with Intratect® 18 

• Clinical study: Intratect® for primary antibody deficiency 19 

• Clinical study: Intratect® 100 g/l for primary antibody deficiency 20 

• Clinical study: Intratect® for primary immune thrombocytopenia 22 

• Non-interventional study with Intratect® for primary 24 

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 

• Primary antibody deficiency syndromes 27 

• Secondary antibody deficiency 28 

• Autoimmune diseases 28 

IN FOCUS: Patient-oriented treatment 

Immediate bioavailability of IVIG – Ideal for patient-oriented application 30 

Summary of product characteristics – Intratect® 34 

Summary of product characteristics – Intratect® 100 g/l 38 

References 42 

List of abbreviations 43 

3

Intratect® and Intratect® 100 g/l – 

Safety through Quality 

Immunoglobulin G antibodies are essential for 

maintaining the immune system, inflammation 

control and tissue regeneration. Antibody concentrates 

help rebalance the immune system when 

the body's own IgG antibody production or immune 

cell communication is dysfunctional. 

Highest demands are placed on the production of 

IgG concentrates from human plasma to ensure 

that human pathogenic viruses are not transmitted 

and plasma components that trigger undesired 

coagulation activation or compromise tolerance 

are removed during the production process. 

Biotest's Intratect® production process satisfies 

these rigorous criteria and is at the cutting edge 

of technology for intravenous immunoglobulin G 

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, including 

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 

intravenous immunoglobulin concentrates aim 

to conserve the natural structure of the IgG antibody 

without modifying it. Their efficacy and 

immunbiological properties should be preserved 

and made available to the patient in a form with 

good tolerability. An important aspect in this respect 

is the attainment of the highest possible 

degree of safety with regard to the risk of transmitting 

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 processed 

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® 

contains several thousand plasmas. In a first 

step, cryoprecipitate and coagulation factors are 

separated off and ethanol precipitation is used to 

obtain various fractions (I/II/III). Fraction II is used 

for manufacturing Intratect®. This is followed by 

octanoic acid/calcium acetate and solvent/detergent 

treatments, which not only helps enrich 

the immunoglobulins but also, and above all, 

reduces any potential viral load and completely 

eliminates thrombogenic factors. Actual purification 

of immunoglobulin G is via cation exchange 

chromatography. Positively charged IgG antibodies 

bind to the negatively charged column matrix. 

This first step separates off any impurities, 

which are discarded. The IgG antibodies are then 

removed from the matrix and collected as a pure 

eluate fraction. 

Nanofiltration (20 nm) prior to final packaging 

ensures the removal of even the smallest particles 

from the solution. 

The virus reduction procedure 

The development of virus and prion depletion 

processes, as well as the extensive quality tests 

required for crude materials and intermediate 

and final products are specified in numerous directives 

and are strictly monitored by national 

(PEI) and international (EMA) agencies. 

Results of validation studies and test series (Table 

1) show Intratect® virus and prion clearance 

satisfies all current official requirements. 

In accordance with the specifications of these 

agencies, the manufacturing process steps undergo 

continual validation studies to ensure they 

effectively eliminate and inactivate viruses. 

Also examined are the effects of minimal deviations 

in the production process (for example, with 

regard to temperature, pH-value, protein concentration) 

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 inactivate 

or eliminate viruses. 

7

Intratect® I Intratect® procedure guarantees high quality and virus safety 

Fig. 1: Intratect® manufacturing steps 

Plasma pool 

Separation of cryoprecipitate 

and coagulation factors 

Virus elimination 

Virus inactivation 

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 

Elimination of thrombogenic factors 

Cation exchange chromatography 

Nanofiltration (20 nm) 

Ultra- and diafiltration 

Steril final dispensing, 

quality control, final packaging 

8


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 

of fractions I/III 

Treatment with octanoic 

acid/calcium acetate 

Solvent detergent 

treatment 

L 4.90 L 5.25 L 2.53 L 7.58 L 4.07 3.91 L 3.65 

L 5.72 L 6.36 L 4.71 n.a. n.a. n.a. n.a. 

L 4.43 L 4.57 L 4.82 n.a. n.a. n.a. n.a. 

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 

Porcine pseudorabies virus 

(model virus for herpes viruses and HBV) 

DNA virus with envelope 

120 – 200 nm 

BVDV 

Bovine viral diarrhea virus 

(model virus for HCV) 

RNA virus with envelope 

40 – 60 nm 

Reo 

Reo virus 

(model virus for non-enveloped viruses) 

RNA virus non-enveloped 

60 – 80 nm 

PPV 

Porcine parvovirus 

(model virus for human parvovirus B19) 

DNA virus non-enveloped 

18 – 22 nm 

MEV 

Murine encephalomyelitis virus 

(model virus for HAV) 

RNA virus non-enveloped 

22 – 30 nm 

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


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 negative negativ e 

Prekallikrein activator 0 IU/ml** 0 IU/ml** 

Kallikrein 0 IU/ml** 0 IU/ml** 

Prekallikrein 0 IU/ml** 0 IU/ml** 

Proteolytic activity 0.5 U/l 1 U/l 

Fibrinogen 0 % 0 % 

Osmolality 300 mosmol/kg 328 mosmol/kg 

Anticomplementary activity (ACA) 0.6 CH 50 /mg 0.5 CH 50 /mg 

Fc-part function 98 % 99 % 

Other excipients 

Glycine 300 mmol/l 305 mmol/l 

Natrium l 10 mmol/l l 10 mmol/l 

Chloride l 50 mmol/l l 50 mmol/l 

*) mean values from several batches, internal documentation 

**) below detection limit 

10


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 1138 U/ml 2643 U/ml 

Enterococcus faecalis 836 U/ml 1850 U/ml 

Escherichia coli 925 U/ml 2095 U/ml 

Haemophilus influenzae type B 1007 U/ml 2051 U/ml 

Anti-streptolysin-O activity 500 IU/ml 1188 IU/ml 

Tetanus toxoid 912 U/ml 1356 U/ml 

Corynebacterium diphtheriae 1009 U/ml 3786 U/ml 

Candida albicans 1046 U/ml 2517 U/ml 

IgG subclass distribution and half-life 

The subclass distribution of Intratect® closely 

matches that of normal human serum. Half-life 

was determined in the course of clinical studies on 

patients with a primary immune deficiency syndrome 

(PID). (Clinical Study Reports, 2003, 2012) 

Table 5: IgG subclass distribution and half-life 

IgG1 

(in %) 

IgG2 

(in %) 

IgG3 

(in %) 

IgG4 

(in %) 

Serum 

half-life 

(in days) 

Normal range 36 – 81.5 14 – 47 1.5 – 8 0.6 – 10.4 21 – 28 

Intratect® 50 g/l 57.6 36.6 3.4 2.5 27.2 

Intratect® 100 g/l 59.4 35.0 3.2 2.4 34.1 

11

Patient safety 

IN FOCUS 

Added safety through the elimination 

of all coagulation factors 

Coagulation factors in immunoglobulin 

compounds can 

compromise tolerability. If they 

enter the blood during IVIG 

therapy they could trigger undesired 

activation of the coagulation 

cascade, which, in rare 

cases, could result in a thromboembolic 

event. Thromboembolic 

events are, for example, 

deep venous thromboses, pulmonary 

embolisms, myocardial 

infarctions or strokes. 15,21 

The crude plasma used in IVIG 

production contains different 

coagulation factors, most 

of which are removed at the 

beginning of processing. The 

removed factors are utilised 

in the production of factor VIII 

and factor IX compounds. 

Despite this, the plasma fractions 

used to manufacture immunoglobulins 

still contain a 

small proportion of coagulation 

factors. These must be removed 

as quickly as possible if they are 

to be prevented from triggering 

the coagulation cascade during 

further processing. Otherwise, 

the proportion of coagulation 

factors in the final product 

could even increase. 

Fig. 2: Activation of coagulation cascade 

PK, HK, F XII 

F XIIa, Kallikrein 

F XI 

F XIa 

HK 

TF 

F IX 

F IXa 

F VIIIa 

F VIII 

F VII 

F VIIa 

F X 

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 preventing 

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 

causes of thrombotic complications 

are the prekallikrein activator 

(PKA, FXIIa) and the activated 

coagulation factor FXIa 

and kallikrein. 13,15 

In accordance with the European 

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. 

seconds is regarded as a sign of 

residual activity on coagulation 

13, 15 

factors. 

ing varying concentrations of 

a specific control plasma (free 

of the coagulation factor FXI) 

with FXIa to initiate the coagulation 

cascade. The amount of 

thrombin formed and the time 

to peak (TTP) of thrombin formation 

are measured as benchmarks 

to correlate with the 

amount of FXIa initiator molecules. 

Changes in the kinetics 

occurring following addition of 

the IVIG to be tested then show 

any residual coagulation activity 

in the final product. 21 

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 

IVIG depicts changes in human 

plasma coagulation time after 

IVIG is added. Any remaining 

FXIa activity in the final product 

reduces coagulation time compared 

to the control plasma. A 

coagulation time below 200 

The thrombin generation test 

depicts the kinetics involved in 

thrombin formation (FII) initiated 

by FXIa. This involves mix- 

In addition to coagulation factors, 

the presence of kallikrein 

in the final product can also 

be established by determining 

prothrombin complex activity. 

Chromogene tests are used. 13 

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 

Intratect® 328 sec 368 sec 

Control plasma** 352 sec 367 sec 

*) Levels below 200 seconds are seen as critical 15 **) platelet-poor plasma 

Thrombin generation test (TGT) 

Maximum quantity of 

generated thrombin 

Time to achieve 

maximum quantity 

Thrombin 

generation rate 

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 activity, 

as could be confirmed by determining the thrombogenic factors 

with optimised global tests und with specific tests for individual factors 

in the final product. 

15

Multitalented immunoglobulin G – 

More than just infection protection 

Intravenous immunoglobulins can do more than 

simply neutralise pathogens. Knowledge of the 

immunoregulatory properties of IgG gained 

over the course of many years has made immunoglobulin 

therapy a valued therapeutic option 

throughout the world. Today, its range of applications 

includes the prophylaxis and treatment of 

bacterial and viral infections, as well as the treatment 

of acute and chronic autoimmune diseases 

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 10 18 

IgG molecules. The immense diversity of antibodies 

in the human body enables the identification 

of 10 7 to 10 9 different antigen structures. These 

include pathogens such as viruses, bacteria and 

their toxins, and inflammation mediators circulating 

in the blood. Identification of the pathogens 

takes place in the variable region F(ab) 2 

of 

the antibody molecule. Particularly patients with 

antibody deficiency syndromes require additional 

immunoglobulin for prophylaxis against infection 

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 immune 

complexes with antigens. These bind to 

Fcc receptors on immunocompetent cells (macrophages, 

dendritic cells, B and T cells, natural 

killer cells, endothelial cells) to trigger an immune 

response. 

The Fcc receptor-mediated phagocytosis of immune 

complexes is essential for the elimination 

of pathogens and strengthens, for example, the 

immune system by developing antibodies to 

combat invasive pathogens. 

Depending on receptor properties this binding 

of Fcc receptors triggers an immunostimulatory 

or inhibitory signal cascade. Stimulation is manifested 

by increasing phagocyte activity, antigen 

presentation, cytokine release and NK cell activity. 

Binding to inhibitory receptors (Fcc-IIB) prevents, 

for example, the autoantibody production 

in B cells. 

Blockade of Fcc receptors on macrophages and 

(autoreactive) B and T cells modulates autoimmune 

and uncontrolled inflammatory reactions. 

In addition, IgG is also able to modulate receptor 

expression in immunocompetent cells. In its 

function as transport molecule it also indirectly 

supports cell proliferation and maturation, contributing 

in this way to the regeneration of damaged 

tissue and the healing process. 3,19,20,26 

Interaction with the complement system 

The activation fragments of the complement system 

– C3b and C4b – act as opsonins and neutralise 

pathogens, as does IgG. They are an essential 

component of innate immunity. 

The immune complexes formed from complement 

and antigen bind to macrophages via Fcc 

receptors and cleaved off in the cell. The contact 

with T and B cells then results in the formation of 

antibodies against pathogens. 

Uncontrolled complement activity during severe 

bacterial infections or inflammatory autoimmune 

diseases is problematic. In the process, excess 

activation of complement causes non-specific 

damage to the body's own cells and tissue. The 

activated complement factors C3b and C4b, and 

the C3a and C5a anaphylatoxins circulating in the 

blood promote inflammatory processes and raise 

vascular permeability. 

Immunoglobulins such as IgG, IgM and IgA regulate 

complement activity by capturing activated 

factors (C3b, C4b) and reducing the formation of 

membranolytic complexes (C5a-C9) to protect 

healthy cells from destruction. Binding with anaphylatoxins 

inhibits inflammatory processes and 

the bacterial function of neutrophil granulocytes 

is maintained. 4,9 

Regulation of autoimmune and inflammatory processes 

Immunoglobulins regulate the release of antiand 

pro-inflammatory mediators (for example, 

IFNc, TNFa, interleukins, growth factors), thereby 

contributing to the maintenance of immune 

balance. This occurs through direct Fcc receptor 

blockade and Fcc-mediated binding of immune 

complexes on immune cells, as well as in interaction 

with the complement, coagulation and nervous 

systems. Autoimmune processes are modulated 

by the neutralisation of autoantigens and 

antibodies (idiotype-anti-idiotype interaction). 

In addition, the IgG-mediated normalisation of 

the receptor repertoires of immune cells results 

in partial restoration of a normal immune system. 

This process is particularly important for the treatment 

of chronic autoimmune diseases and the 

restoration of therapeutic ability with resistance 

to long-term immunosuppressive therapies. 19,20,26 

17

Safety through clinical efficacy – 

Studies with Intratect® 

The clinical efficacy and tolerability of Intratect® 

(50 g/l) and Intratect® 100 g/l were investigated 

on patients with a primary antibody deficiency 

(PID) in three open clinical trials. 22,23,33 The efficacy 

of Intratect® (50 g/l) was also tested on patients 

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 

48, were substituted with 8 ml (400 mg) per kilogram 

BW Intratect® at intervals of 3 weeks (3 

patients) or 4 weeks (48 patients). The 12-month 

period of treatment was chosen to compensate, 

as far as possible, any seasonal influences on 

the health of the participating patients. A total 

of 642 infusions were dispensed. The maximum 

infusion rate averaged 2.1 to 2.4 ml/kg/h (range 

1.0 to 5.9 ml/kg/h). 

Table 6: Distribution of PID diagnoses 

Diagnosis 

Number of patients 

Common variable immunodeficiency (CVID) 20 

Congenital agammaglobulinaemia 12 

Congenital hypogammaglobulinaemia 5 

Ataxia teleangiectasia 5 

Hyper-IgM syndrome 5 

Hyper-IgE syndrome 1 

Severe combined immunodeficiency disease (SCID) 1 

Selective IgG subclass deficiency 2 

All patients had already substituted with various 

immunoglobulins before taking part in the trial 

and had been diagnosed for at least 10 years. 

occurred in only 6 of 642 (0,9 %) infusions. In no 

single case was it necessary to discontinue participation 

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 %) determinations 

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 connective 

tissue of the knee. The success criteria described 

by the European Guideline for IVIG, which 

specify that the frequency of severe bacterial infections 

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


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

This study investigated the pharmacokinetics and 

tolerability of a ten-percent IVIG compound with 

PID patients who regularly substituted (part A), 

as well as the tolerability of higher infusion rates 

(Part B). 23 

A total of 30 PID patients aged between 10 and 63 

(median 34.5) took part in the open prospective 

study. 26 of the patients suffered from CVID and 

4 from congenital agammaglobulinaemia (XLA). 

Prior to the study, all patients had been finely 

tuned to regular intravenous immunoglobulin. 

The average amount dispensed in the three preceding 

infusions was 397.4 mg/kg BW (range: 56 

to 727 mg/kg). IgG trough levels in the six months 

prior to beginning the study were between 4.9 

and 11 g/l (median: 7.68 g/l). 

In the first phase of the study (Part A) three infusions 

with Intratect® 100 g/l were dispensed at 

intervals of three to four weeks. The infusion rate 

was increased at 30-minute intervals from 0.3 to 

1.4 to a maximum of 2.0 ml/kg/h BW. The infusion 

rate was increased to a maximum of 8 ml/ 

kg/h at the start of phase two (Part B, 4 th to 6 th 

infusions) to ascertain the maximum tolerable 

rate for each patient. The initial interval between 

increments was 30 minutes; this could then be 

individually reduced. This individually determined 

maximum rate was then used for the 5 th and 6 th 

infusions. 

IVIG dosage was between 200 and 800 mg/kg BW 

and based on the individual doses dispensed in 

the six months preceding the study. 

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

20


Results 

All 30 patients completed the first part (Part A) 

of the study to investigate the pharmacokinetics, 

25 patients also completed the second phase of 

treatment (Part B). 

With Intratect® 100 g/l, most patients also 

achieved a IgG trough level above 6 g/l. Only 2 

patients had trough levels below 5 g/l, which corresponded 

to their previous values. 

Investigations in the second study phase (Part B) 

showed that 17 from 25 patients (68 %) tolerated 

an infusion rate of 6 ml/kg BW. Eight patients 

(32 %) tolerated an infusion rate of 8 ml/kg/h. In 

12 patients (48 %) the targeted infusion rate of 

8 ml/kg/h was not achieved, as the individual IVIG 

dose was reached before the maximum infusion 

rate. 

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 adverse 

events of IVIG 10 , resp. typical events for PID 

patients undergoing IVIG therapy, such as headaches, 

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 medication 

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


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

Typical for primary immune thrombocytopenia 

(ITP) is a significantly reduced thrombocyte lifecycle. 

The resulting thrombocyte loss can give 

rise to complications in connection with bleeding; 

this condition requires treatment. 

The only patients treated are those with acute 

haemorrhages and thrombocyte levels below 50/ 

nl, and patients with chronic ITP and an increased 

risk of haemorrhage prior to an operation or before 

giving birth. 

In a prospective clinical study, 24 adults with 

chronic ITP and thrombocyte levels ranging from 

3/nl to 27/nl received Intratect® therapy. 6 

Fifteen patients were each given 1.0 g/kg BW 

Intratect® on two days; nine patients were each 

given 0.4 g/kg on five days. Test criteria were a 

thrombocyte increase to M 50/nl and a drop in 

the number of haemorrhages within 28 days. 

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 

Mean 

Number of days 

Median 

Time to rise to M 50/nl 

total (n=24) 3.9 ± 2.4 3.0 

at 1.0 g/kg/d for 2 days (n=15) 4.4 ± 2.8 2.5 


Duration of response M 50/nl 

total (n=24) 19.8 ± 7.8 22.5 



Duration of response over starting count 

total (n=24) 24.4 ± 3.6 25.5 



22


Results 

22 of the 24 (91.7 %) patients responded to Intratect® 

treatment. Significant thrombocyte increases 

were found after an average of 3 days. On 

average, the maximum increase of 224 ± 144/nl 

thrombocytes was reached after 7.5 days. Average 

response time to treatment was 25.5 days. 

Bleeding tendency decreased significantly just a 

few days after administering Intratect®. After 7 

days, 72.2 % of patients experienced less haemorrhaging. 

Not until three weeks later did some 

patients find they tended to bleed again. 

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

unchanged 

80 

70 

72.2 

72.2 

72.2 

improved 

worse 

Changes in bleeding tendency (%) 

60 

50 

40 

30 

20 

27.8 

27.8 

22.2 

33.3 

55.6 

10 

5.6 

11.1 

0 

d 7 d 14 d 21 d 28 

After start of treatment 

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


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

secondary antibody deficiency syndromes 

In a non-interventional study (NIS) between 

2004 and 2010 a total of 21,995 Intratect® infusions 

were documented. A total of 95 centres 

participated in the study of 1,313 patients with 

primary and secondary antibody deficiency syndromes 

who received immunoglobulin substitution 

treatment on a regular basis. 

Intratect® therapy proved beneficial for patients 

that had not yet received IVIG treatment, as well 

as for patients who had already been fine-tuned 

to this therapy. 

Intratect® significantly raised the IgG trough 

level. The trough IgG serum level of patients who 

had never been treated with IVIG increased to 

6.62 g/l. Patients with previous IVIG treatment 

showed an increase of 4 %. 

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

The increase in the IgG trough level was accompanied 

by a significant improvement in the clinical 

symptoms and a reduced incidence of infection. 

This effect was particularly evident among 

patients with no previous IVIG treatment. The 

infection incidence decreased among 72.7 % of 

these patients. 

This investigation reaffirmed the excellent Intratect® 

tolerability that had already been established. 

The absolute number of adverse events 

brought about by therapy was 225, i.e. just 1 % 

of 21,995 infusions. In 97.1 % of cases, physicians' 

assessment of Intratect® tolerability was ‘very 

good’ or ‘good’. 

24


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 

significantly improved the chances particularly of 

chronically ill patients, intravenous immunoglobulin 

remains a valuable and indispensable therapy 

option. 

Immunoglobulins play a vital role in maintaining 

cellular and humoral immune responses. They 

control inflammatory activity, help regenerate 

damaged tissue and contribute toward maintaining 

important organ function. 

The spectrum of diseases for which they can be 

used is extensive. It includes primary and secondary 

antibody deficiency diseases, as well as acute 

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 

patients with a primary antibody deficiency syndrome 

is the finely tuned IgG substitution. 

Congenital antibody deficiency syndromes include 

common variable immunodeficiencies 

(CVID), severe combined immune deficiencies 

(SCID), the DiGeorge syndrome, the X-linked agammaglobulinaemia 

(Morbus Bruton), the Wiskott-Aldrich 

syndrome and the selective IgA or 

IgG subclass deficiencies. 

the patient protection from life-threatening infections, 

prevents the recurrence of severe bacterial 

infections, reduces the need for antibiotics, 

aids healing and improves the quality of life. 7,20 

The severely impaired antibody production is due 

to genetic defects in the lymphocytes, granulocytes, 

monocytes or thrombocytes and / or maturity 

and functional disorders of immune cells. 

Antibody deficiency can affect the entire immunoglobulin 

spectrum of individual immunoglobulin 

classes (IgG, IgM, IgA) or IgG subclasses. Vulnerability 

to severe bacterial infections increases 

with the severity of the condition. As inflammatory 

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


Secondary antibody deficiency syndromes 

Secondary (adaptive) antibody deficiencies often 

occur as a result of malignant lymphomas 

or during long-term administration of strong 

immunosuppressants. The associated dysfunctions 

of immune cells in the blood and inadequate 

cell-to-cell communication result in the 

inhibition of antibody production. The risk of 

infection increases with persistent hypogammaglobulinaemia 

and the ability to regenerate 

tissue and control inflammation is reduced. 

The European Guidelines recommend using IVIG 

for hypogammaglobulinaemia and recurrent 

bacterial infections in connection with chronic 

leukaemia or multiple myeloma, following haematopoietic 

stem cell transplantation (HSCT), 

as well as for children and juveniles with congenital 

AIDS and recurrent bacterial infections. 10 

Recommended therapy for secondary antibody deficiency 

Administration of an initial dose of 0.4 – 0.8 g/kg BW, followed by individually adapted maintenance 

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 misdirected 

immunological reactions to the body's 

own structures. They present with organ-specific 

or systemic symptoms as acute or chronic illnesses. 

Typical is the involvement of pathological antibodies 

and autoaggressive T and B cell clones 

that cause destruction of body cells and tissues 

by apoptotic or lytic mechanisms. 24,35 

The success story of intravenous immunoglobulin 

therapy for the treatment of autoimmune 

diseases goes back more than 25 years, when 

successful treatment of primary immune thrombocytopenia 

(ITP) was described for the first time. 

Subsequently, clinically controlled studies have 

confirmed the efficacy of IVIG therapy in a variety 

of autoimmune and inflammatory diseases 

worldwide. 2,3,12,17,19,27,30 

Immunoglobulins represent not only an antiinfectious 

and anti-toxic component of the immune 

defence, but above all, they also display 

immunoregulatory and anti-inflammatory 

properties. Their broad spectrum of actions also 

allows the therapeutic correction of immunological 

dysfunctions of assorted aetiologies. 

Immunoglobulins help restore the immune system's 

equilibrium. 2,9,24,26,35 

As the treatment of autoimmune diseases requires 

high doses of IVIG to be effective, 1 – 2 g/ 

kg BW IVIG must be given per treatment cycle. 

Acute autoimmune diseases, such as primary 

immune thrombocytopenia (ITP), Guillain-Barré 

syndrome and Kawasaki syndrome usually only 

require one single dose of IVIG. 

28


Patients with relapsing-remitting forms and 

chronic autoimmune diseases can usually be 

successfully treated with corticosteroids or immunosuppressants. 

In cases that do not respond 

to this therapy or to a combination therapy, or if 

treatment induces adverse effects, most patients 

(50 to 70 %) will show clinical improvement and 

therapeutic ability will be restored if treatment 

is supplemented with IVIG. 

Several cycles of IVIG therapy are required to 

achieve significant clinical improvement. Regeneration 

processes, including the regulation 

of receptor expression following long-term suppression, 

require several weeks. The partial restoration 

of immune equilibrium means that, in 

most cases, immunosuppressive medication can 

be considerably reduced, which also reduces the 

incidence of its adverse effects. The increased risk 

of infection associated with long-term suppression 

also diminishes after a certain time. 

Depending on the course of the illness, initially 

three to six cycles of 2 g/kg BW are given at intervals 

of 4 weeks. With clinical improvement 

or stability the dosage can be reduced (0.2 to 

1.1 g/kg) and/or the interval extended. Treatment 

can be discontinued with sufficient clinical 

improvement or when the patient is symptomfree. 

If a relapse occurs, it is advisable to give 

IVIG at an early stage to stop the course of the 

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) 

1, 2, 12, 17, 27, 30, 34, 36 

*) With the exception of GBS, CIDP, MMN, ITP and Kawasaki syndrome, use is off-label 

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 

subcutaneous or intramuscular 

injection, intravenously given 

immunoglobulins are immediately 

bioavailable. This means, 

with entry into the blood, IgG 

antibodies immediately neutralise 

pathogens and inflammation 

factors and activate 

the unspecific immune system. 

Through the Fcc-mediated 

binding to vascular endothelium 

and the immune cells 

circulating in the blood, these 

change their communication 

behaviour within just a few 

hours. 

The more pure and concentrated 

the IVIG compound, the 

quicker the desired effect. This 

is ideal for the neutralisation 

and elimination of pathogens 

and inflammation mediators. 

The effects at cell level (immunomodulation, 

receptor expression) 

depend on a number of 

factors. 

The type and severity of the disease 

to be treated, accompanying 

or previous illnesses, organ 

dysfunctions or the properties 

of blood influence cellular responses 

to immune therapies 

and also affect the tolerability 

of IVIG. 

Intravenous immunoglobulin 

compounds are usually well tolerated 

and, if properly applied, 

produce few adverse events. 

All compounds have a similar 

range of adverse events and included 

reactions such as headaches, 

influenza-like symptoms, 

raised temperature, hypotension, 

nausea and joint or back 

pains. 

Some of the complications observed 

are in connection with 

the infusion rate or changes in 

the viscosity of the blood following 

administration of immunoglobulins. 

Infusion rates and IVIG concentration form an alliance 

Clinics and physicians' surgeries 

typically suffer from high workloads 

and time pressure. They 

aim to treat each patient well, 

but also efficiently. When seeking 

to optimise work processes, 

IVIG therapy infusion rates are 

often a point of discussion. 

A number of opportunities have 

now arisen in connection with 

the introduction of 10 percent 

IVIG compounds. Whereas the 

infusion volume and time have 

decreased, the potential risk of 

adverse events for high dose 

therapy has, however, increased. 

Only an individual risk assessment 

before beginning therapy 

can help avoid unnecessary 

complications. 

30

To be determined: Inpatient or stationary treatment? 

considerably higher doses of up 

to 2 g/kg BW. To facilitate tolerability, 

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 

secondary antibody deficiency, 

no further individual risk factors 

and whose daily dose does not 

exceed 0.2 to 0.4 g/kg BW IVIG 

usually tolerate a ten percent 

IVIG compound that can be 

infused relatively quickly. This 

saves time for both medical 

staff and patient. 

Acute and/or seriously chronically 

ill patients require stationary 

treatment, as they need 

Sufficient liquid intake is necessary 

to avoid a rapid increase in 

blood viscosity. In such cases, a 

patient could benefit from a five 

percent IVIG solution. 

The question of whether inpatient 

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 

kidney dysfunctions or known 

thromboembolic complications 

should take the lowest possible 

daily dose rather slowly. Too rapid 

an increase in blood protein 

content could result in adverse 

reactions. 

Risk factors for thromboembolic 

complications with IVIG 

administration are hypertonia, 

vascular diseases, premature 

cardiac infarct, stroke, deep 

venous thrombosis, severe hypovolaemia 

or increased blood 

viscosity due to other medication, 

hyperlipidaemia, hypercoagulopathy, 

diabetes mellitus, 

oral contraceptives or longer 

periods of immobility. 

These are rare occurrences 

(l 0.01 %), the causes of which 

are as yet largely unknown. Arterial 

complications are most 

likely to occur during administration 

of IVIG or within the first 

24 hours, whereas venous complications 

do not usually arise 

before day two or later. 25,29,32 

IVIG compounds can contain 

blood group antibodies (anti-A, 

anti-B), which act as haemolysins 

(isoagglutinin) and bind 

with red blood cells. Clinically 

significant haemolysis can occur 

if the complement cascade 

is activated and there is significant 

inflammatory activity of 

the reticular endothelial system 

(RES). Haemolytic reactions are 

extremely rare. 

The proportion of anti-A or anti-B 

isoagglutinins in IVIG compounds 

depends on the crude 

plasma and is somewhat higher 

in 10 percent than in 5 percent 

compounds, which is due to the 

production process. 

Haemolysis-promoting factors 

are daily IVIG doses above 

100 g or more than 2 g/kg BW, 

a higher anti-A and anti-B IgG 

titer (L 1:32) in the compound, 

significant inflammatory activity 

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 factors 

involved, the lower the infusion 

rate and daily IVIG dose 

should be. 

Opting for a 5 % instead of a 

10 % immunoglobulin compound 

often helps avoid complications. 

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/ 

kg BW are usually well tolerated 

and can be given to patients 

who are neither acutely ill nor 

display additional risk factors 

in an ambulatory setting. The 

decisive factor is, however, the 

actual condition of the patient 

on the day of infusion. Sufficient 

liquid intake (drinking) 

reduces the risk of headache 

and nausea. 

If high-dose therapy (1 to 2 g/kg 

BW) is required, the daily dose 

must be adjusted to the patient's 

state of health and the 

severity of the illness. It must 

be ensured that temporary protein 

load increases do not cause 

organ dysfunctions, headaches, 

nausea or other adverse events. 

The total dose should be spread 

over several days (0.4 to 0.5 g/ 

kg per day). Opting for a 5 % 

instead of a 10 % infusion solution 

is also a means of reducing 

the risk of adverse reactions. 

The weight of the patient must 

also be taken into consideration. 

Heavy patients sometimes 

tolerate higher daily IVIG 

doses (more than 30 – 50 g/d) 

less well. In such cases, it is advisable 

to reduce the infusion 

rate to prevent the occurrence 

of complications. 

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 

Intratect 50 g/l, solution for infusion 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Human normal immunoglobulin (IVIg) 

One ml contains: 

Human normal immunoglobulin 50 mg (purity of at least 96 % IgG) 

Each vial of 20 ml contains: 1 g 

Each vial of 50 ml contains: 2.5 g 



Distribution of the IgG subclasses (approx. values): 

IgG1 57 % 

IgG2 37 % 

IgG3 3 % 

IgG4 3 % 

The maximum IgA content is 2000 micrograms/ml. 

Produced from the plasma of human donors. 

For a full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM 

Solution for infusion. 

The solution is clear to slightly opalescent and colourless to pale yellow. 

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

Replacement therapy in adults, and children and adolescents 

(0 – 18 years) in: 

• Primary immunodeficiency syndromes with impaired antibody production 

(see section 4.4). 

• Hypogammaglobulinaemia and recurrent bacterial infections in patients 

with chronic lymphocytic leukaemia, in whom prophylactic antibiotics 

have failed. 

• Hypogammaglobulinaemia and recurrent bacterial infections in plateau 

phase multiple myeloma patients who have failed to respond to 

pneumococcal immunisation. 

• Hypogammaglobulinaemia in patients after allogeneic haematopoietic 

stem cell transplantation (HSCT). 

• Congenital AIDS with recurrent bacterial infections. 

Immunomodulation in adults, and children and adolescents 

(0 – 18 years) in: 

• Primary immune thrombocytopenia (ITP), in patients at high risk of 

bleeding or prior to surgery to correct the platelet count. 

• Guillain Barré syndrome. 

• Kawasaki disease. 

4.2 Posology and method of administration 

Replacement therapy should be initiated and monitored under the supervision 

of a physician experienced in the treatment of immunodeficiency. 

Posology 

The dose and dose regimen is dependent on the indication. 

In replacement therapy the dose may need to be individualised for each 

patient dependent on the pharmacokinetic and clinical response. The 

following dose regimens are given as a guideline: 

Replacement therapy in primary immunodeficiency syndromes 

The dose regimen should achieve a trough level of IgG (measured before 

the next infusion) of at least 5 to 6 g/l. Three to six months are required 

after the initiation of therapy for equilibration to occur. The recommended 

starting dose is 8 – 16 ml (0.4 – 0.8 g)/kg given once, followed by at 

least 4 ml (0.2 g)/kg given every three to four weeks. 

The dose required to achieve a trough level of 5 – 6 g/l is of the order of 

4 – 16 ml (0.2 – 0.8 g)/kg/month. The dosage interval when steady state 

has been reached varies from 3 – 4 weeks. 

Trough levels should be measured and assessed in conjunction with the 

incidence of infection. To reduce the rate of infection, it may be necessary 

to increase the dosage and aim for higher trough levels. 

Hypogammaglobulinaemia and recurrent bacterial infections in patients 


have failed; hypogammaglobulinaemia and recurrent bacterial infections 

in plateau phase multiple myeloma patients who have failed to respond 

to pneumococcal immunisation; congenital AIDS with recurrent bacterial 

infections. 

The recommended dose is 4 – 8 ml (0.2 – 0.4 g)/kg every three to four weeks. 

Hypogammaglobulinaemia in patients after allogeneic haematopoietic 

stem cell transplantation 

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 

thereafter: 

0.2 – 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 0.2 – 0.4 g/kg every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/l 

Congenital AIDS 0.2 – 0.4 g/kg every 3 – 4 weeks 

Hypogammaglobulinaemia (l 4 g/l) in patients after 

allogeneic haematopoietic stem cell transplantation 

0.2 – 0.4 g/kg every 3 – 4 weeks to obtain IgG trough level above 5 g/l 

Immunomodulation: 

Primary immune thrombocytopenia 

0.8 – 1 g/kg 

or 

0.4 g/kg/d 

on day 1, 

possibly repeated once within 3 days 

for 2 – 5 days 

Guillain Barré syndrome 0.4 g/kg/d for 5 days 

Kawasaki disease 

1.6 – 2 g/kg 

or 

2 g/kg 

in divided doses over 2 – 5 days in association with acetylsalicylic acid 

in one dose in association with acetylsalicylic acid 

34



There are two alternative treatment schedules: 

• 16 – 20 ml (0.8 – 1 g)/kg given on day one, this dose may be repeated 

once within 3 days 

• 8 ml (0.4 g)/kg given daily for two to five days. The treatment can be 

repeated if relapse occurs. 

Guillain Barré syndrome 

8 ml (0.4 g)/kg/day over 5 days. 


32 – 40 ml (1.6 – 2.0 g)/kg should be administered in divided doses over 

two to five days or 40 ml (2.0 g)/kg as a single dose. Patients should receive 

concomitant treatment with acetylsalicylic acid. 

The dosage recommendations are summarised in the table. 

Paediatric population 

The posology in children and adolescents (0 – 18 years) is not different to 

that of adults as the posology for each indication is given by body weight 

and adjusted to the clinical outcome of the above mentioned conditions. 

Method of administration 

For intravenous use. 

Intratect should be infused intravenously at an initial rate of not more 

than 1.4 ml/kg/hr for 30 minutes. 

If well tolerated (see section 4.4), the rate of administration may gradually 

be increased to a maximum of 1.9 ml/kg/hr for the remainder of 

the infusion. 

4.3 Contraindications 

Hypersensitivity to the active substance or to any of the excipients (see 

section 4.4). 

Hypersensitivity to human immunoglobulins, especially in patients with 

antibodies against IgA. 

4.4 Special warnings and precautions for use 

Certain severe adverse reactions may be related to the rate of infusion. 

The recommended infusion rate given under section 4.2 must be closely 

followed. Patients must be closely monitored and carefully observed for 

any symptoms throughout the infusion period. 

Certain adverse reactions may occur more frequently 

• in case of high rate of infusion, 

• in patients who receive human normal immunoglobulin for the first 

time or, in rare cases, when the human normal immunoglobulin product 

is switched or when there has been a long interval since the previous 

infusion. 

Potential complications can often be avoided by ensuring that patients 

• are not sensitive to human normal immunoglobulin by initially injecting 

the product slowly (1.4 ml/kg/h corresponding to 0.023 ml/kg/min). 

• are carefully monitored for any symptoms throughout the infusion 

period. In particular, patients naive to human normal immunoglobulin, 

patients switched from an alternative IVIg product or when there has 

been a long interval since the previous infusion should be monitored 

during the first infusion and for the first hour after the first infusion, 

in order to detect potential adverse signs. All other patients should be 

observed for at least 20 minutes after administration. 

In case of adverse reaction, either the rate of administration must be 

reduced or the infusion stopped. The treatment required depends on 

the nature and severity of the adverse reaction. 

In case of shock, standard medical treatment for shock should be implemented. 

In all patients, IVIg administration requires: 

• 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 

Hypersensitivity 

True hypersensitivity reactions are rare. They can occur in patients with 

anti-IgA antibodies. 

IVIg is not indicated in patients with selective IgA deficiency where the 

IgA deficiency is the only abnormality of concern. 

Rarely, human normal immunoglobulin can induce a fall in blood pressure 

with anaphylactic reaction, even in patients who had tolerated previous 

treatment with human normal immunoglobulin. 

Thromboembolism 

There is clinical evidence of an association between IVIg administration 

and thromboembolic events such as myocardial infarction, cerebral vascular 

accident (including stroke), pulmonary embolism and deep vein 

thromboses which is assumed to be related to a relative increase in blood 

viscosity through the high influx of immunoglobulin in at-risk patients. 

Caution should be exercised in prescribing and infusing IVIg in obese 

patients and in patients with pre-existing risk factors for thrombotic 

events (such as advanced age, hypertension, diabetes mellitus and a history 

of vascular disease or thrombotic episodes, patients with acquired 

or inherited thrombophilic disorders, patients with prolonged periods of 

immobilisation, severely hypovolaemic patients, patients with diseases 

which increase blood viscosity). 

In patients at risk for thromboembolic adverse reactions, IVIg products 

should be administered at the minimum rate of infusion and dose practicable. 

Acute renal failure 

Cases of acute renal failure have been reported in patients receiving IVIg 

therapy. In most cases, risk factors have been identified, such as preexisting 

renal insufficiency, diabetes mellitus, hypovolaemia, overweight, 

concomitant nephrotoxic medicinal products or age over 65 years. 

In case of renal impairment, IVIg discontinuation should be considered. 

While these reports of renal dysfunction and acute renal failure have 

been associated with the use of many of the licensed IVIg products containing 

various excipients such as sucrose, glucose and maltose, those 

containing sucrose as a stabiliser accounted for a disproportionate share 

of the total number. In patients at risk, the use of IVIg products that 

do not contain these excipients may be considered. Intratect does not 

contain sucrose, maltose or glucose. 

In patients at risk for acute renal failure, IVIg products should be administered 

at the minimum rate of infusion and dose practicable. 

Aseptic meningitis syndrome (AMS) 

Aseptic meningitis syndrome has been reported to occur in association 

with IVIg treatment. 

Discontinuation of IVIg treatment has resulted in remission of AMS 

within several days without sequelae. 

The syndrome usually begins within several hours to 2 days following 

IVIg treatment. Cerebrospinal fluid studies are frequently positive with 

pleocytosis up to several thousand cells per mm3, predominantly from 

the granulocytic series, and elevated protein levels up to several hundred 

mg/dl. 

AMS may occur more frequently in association with high-dose (2 g/kg) 

IVIg treatment. 

Haemolytic anaemia 

IVIg products can contain blood group antibodies which may act as 

haemolysins and induce in vivo coating of red blood cells with immunoglobulin, 

causing a positive direct antiglobulin reaction (Coombs' test) 

and, rarely, haemolysis. Haemolytic anaemia can develop subsequent 

to IVIg therapy due to enhanced red blood cells (RBC) sequestration. 

IVIg recipients should be monitored for clinical signs and symptoms of 

haemolysis. (See section 4.8.) 

35


Interference with serological testing 

After injection of immunoglobulin the transitory rise of the various passively 

transferred antibodies in the patient's blood may result in misleading 

positive results in serological testing. 

Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D 

may interfere with some serological tests for red cell antibodies for example 

the direct antiglobulin test (DAT, direct Coombs' test). 

Transmissible agents 

Standard measures to prevent infections resulting from the use of medicinal 

products prepared from human blood or plasma include selection 

of donors, screening of individual donations and plasma pools for specific 

markers of infection and the inclusion of effective manufacturing steps 

for the inactivation/removal of viruses. Despite this, when medicinal 

products prepared from human blood or plasma are administered, the 

possibility of transmitting infective agents cannot be totally excluded. 

This also applies to unknown or emerging viruses and other pathogens. 

The measures taken are considered effective for enveloped viruses such 

as HIV, HBV and HCV. The measures taken may be of limited value against 

non-enveloped viruses such as HAV and parvovirus B19. 

There is reassuring clinical experience regarding the lack of hepatitis 

A or parvovirus B19 transmission with immunoglobulins and it is also 

assumed that the antibody content makes an important contribution 

to the viral safety. 

It is strongly recommended that every time that Intratect is administered 

to a patient, the name and batch number of the product are recorded 

in order to maintain a link between the patient and the batch of the 

product. 

4.5 Interactions with other medicinal products and other forms of interaction 

Live attenuated virus vaccines: 

Immunoglobulin administration may impair for a period of at least 6 

weeks and up to 3 months the efficacy of live attenuated virus vaccines 

such as measles, rubella, mumps and varicella. After administration of 

this medicinal product, an interval of 3 months should elapse before 

vaccination with live attenuated virus vaccines. In the case of measles, 

this impairment may persist for up to 1 year. Therefore patients receiving 

measles vaccine should have their antibody status checked. 

4.6 Fertility, pregnancy and lactation 

Pregnancy 

The safety of this medicinal product for use in human pregnancy has not 

been established in controlled clinical trials and therefore should only 

be given with caution to pregnant women and breast-feeding mothers. 

IVIg products have been shown to cross the placenta, increasingly after 

the third trimester. Clinical experience with immunoglobulins suggests 

that no harmful effects on the course of pregnancy, or on the foetus and 

the neonate are to be expected. 

Breast-feeding 

Immunoglobulins are excreted into the milk and may contribute to 

protecting the neonate from pathogens which have a mucosal portal 

of entry. 

Fertility 

Clinical experience with immunoglobulins suggests that no harmful 

effects on fertility are to be expected. 

4.7 Effects on ability to drive and use machines 

The ability to drive and operate machines may be impaired by some 

adverse reactions associated with Intratect. Patients who experience 

adverse reactions during treatment should wait for these to resolve before 

driving or operating machines. 

4.8 Undesirable effects 

Summary of the safety profile 

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic 

reactions, nausea, arthralgia, low blood pressure and moderate low 

back pain may occur occasionally. 

Rarely human normal immunoglobulins may cause a sudden fall in blood 

pressure and, in isolated cases, anaphylactic shock, even when the patient 

has shown no hypersensitivity to previous administration. 

Cases of reversible aseptic meningitis and rare cases of transient cutaneous 

reactions have been observed with human normal immunoglobulin. 

Reversible haemolytic reactions have been observed in patients, especially 

those with blood groups A, B, and AB. Rarely, haemolytic anaemia 

requiring transfusion may develop after high dose IVIg treatment (see 

also Section 4.4). 

Increase in serum creatinine level and/or acute renal failure have been 

observed. 

Very rarely: Thromboembolic reactions such as myocardial infarction, 

stroke, pulmonary embolism, deep vein thromboses. 

For safety with respect to transmissible agents, see 4.4. 

Details of further spontaneously reported adverse reactions: 

Cardiac disorders: Angina pectoris (very rare) 

General disorders and administrations site conditions: Rigors (very rare) 

Immune system disorders: Anaphylactic shock (very rare), allergic reaction 

(very rare) 

Investigations: Blood pressure decreased (very rare) 

Musculoskeletal and connective tissue disorders: Back pain (very rare) 

Respiratory, thoracic and mediastinal disorders: Dyspnoe NOS (very rare) 

Vascular disorders: Shock (very rare) 

Occasionally, hypersensitivity reactions have been observed including 

various symptoms, such as: 

chills, headache, dizziness, fever, vomiting, cutaneous reactions, nausea, 

arthralgia, low blood pressure and back pain. 

Three clinical studies have been performed with Intratect: two in patients 

with primary immunodeficiencies (PID) and one in patients with immune 

thrombocytopenic purpura (ITP). In the two PID studies overall 68 

patients were treated with Intratect and evaluated for safety. Treatment 

period was 6 and 12 months respectively. The ITP study was performed 

in 24 patients. 

These 92 patients received a total of 830 infusions of Intratect, whereby 

a total of 51 suspected adverse drug reactions (ADRs) were recorded. 

The majority of these ADRs was mild to moderate and self-limiting. No 

serious ADRs were observed during the studies. 

The ADRs reported in the three studies are summarised and categorised 

according to the MedDRA System organ class and frequency below. 

Tabulated list of adverse reactions 

The table presented below is according to the MedDRA system organ 

classification (SOC and Preferred Term Level). 

Frequencies have been evaluated according to the following convention: 

very common (M 1/10); common (M 1/100 to l 1/10); uncommon 

(M 1/1,000 to


Description of selected adverse reactions 

Product specific adverse reactions have not been reported. The reported 

adverse reactions for Intratect are in the expected profile for human 

normal immunoglobulins. 


Frequency, type and severity of adverse reactions in children are expected 

to be the same as in adults. 

4.9 Overdose 

Overdose may lead to fluid overload and hyperviscosity, particularly in 

patients at risk, including elderly patients or patients with cardiac or 

renal impairment. 

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, 

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 immunoglobulin 

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. 

6.6 Special precautions for disposal and other handling 

The product should be brought to room or body temperature before use. 

The solution should be clear or slightly opalescent and colourless or pale 

yellow. Solutions that are cloudy or have deposits should not be used. 

Any unused product or waste material should be disposed of in accordance 

with local requirements. 

7. MARKETING AUTHORISATION HOLDER 

Biotest Pharma GmbH 

Landsteinerstraße 5 

63303 Dreieich 

Germany 

Tel.: (+49) 06103 801 0 

Fax: (+49) 06103 801 150 

8. MARKETING AUTHORISATION NUMBER(S) 

– 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

– 

10. DATE OF REVISION OF THE TEXT 

July 2011 

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 bioavailable 

in the recipient's circulation after intravenous administration. It is 

distributed relatively rapidly between plasma and extravascular fluid, 

after approximately 3 – 5 days equilibrium is reached between the intraand 

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 reticuloendothelial 

system. 

5.3 Preclinical safety data 

Immunoglobulins are normal constituents of the human body. In animals, 

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 heterologous 

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 

Intratect® 100 g/l 

solution for infusion 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 

Human normal immunoglobulin (IVIg) 

One ml contains: 

Human normal immunoglobulin 100 mg (purity of at least 96 % IgG) 





Distribution of the IgG subclasses (approx. values): 

IgG1 57 % 

IgG2 37 % 

IgG3 3 % 

IgG4 3 % 

The maximum IgA content is 1800 micrograms/ml. 

Produced from the plasma of human donors. 

For a full list of excipients, see section 6.1. 

3. PHARMACEUTICAL FORM 

Solution for infusion. 

The solution is clear to slightly opalescent and colourless to pale yellow. 

4. CLINICAL PARTICULARS 

4.1 Therapeutic indications 

Replacement therapy in adults, and children and adolescents 

(0 – 18 years) in: 

• Primary immunodeficiency syndromes with impaired antibody production 

(see section 4.4). 

• Hypogammaglobulinaemia and recurrent bacterial infections in patients 


have failed. 

• Hypogammaglobulinaemia and recurrent bacterial infections in plateau 

phase multiple myeloma patients who have failed to respond to 

pneumococcal immunisation. 

• Hypogammaglobulinaemia in patients after allogeneic haematopoietic 

stem cell transplantation (HSCT). 

• Congenital AIDS with recurrent bacterial infections. 

Immunomodulation in adults, and children and adolescents 

(0 – 18 years) in: 

• Primary immune thrombocytopenia (ITP), in patients at high risk of 

bleeding or prior to surgery to correct the platelet count. 

• Guillain Barré syndrome. 

• Kawasaki disease. 

4.2 Posology and method of administration 

Replacement therapy should be initiated and monitored under the supervision 

of a physician experienced in the treatment of immunodeficiency. 

Posology 

The dose and dose regimen is dependent on the indication. 

In replacement therapy the dose may need to be individualised for each 

patient dependent on the pharmacokinetic and clinical response. The 

following dose regimens are given as a guideline: 

Replacement therapy in primary immunodeficiency syndromes 

The dose regimen should achieve a trough level of IgG (measured before 

the next infusion) of at least 5 to 6 g/l. Three to six months are required 

after the initiation of therapy for equilibration to occur. The recommended 

starting dose is 4 – 8 ml (0.4 – 0.8 g)/kg given once, followed by at least 

2 ml (0.2 g)/kg given every three to four weeks. 

The dose required to achieve a trough level of 5 – 6 g/l is of the order of 

2 – 8 ml (0.2 – 0.8 g)/kg/month. The dosage interval when steady state 

has been reached varies from 3 – 4 weeks. 

Trough levels should be measured and assessed in conjunction with the 

incidence of infection. To reduce the rate of infection, it may be necessary 

to increase the dosage and aim for higher trough levels.. 

Hypogammaglobulinaemia and recurrent bacterial infections in patients 


have failed; hypogammaglobulinaemia and recurrent bacterial infections 

in plateau phase multiple myeloma patients who have failed to respond 

to pneumococcal immunisation; congenital AIDS with recurrent bacterial 

infections. 


weeks. 

Hypogammaglobulinaemia in patients after allogeneic haematopoietic 

stem cell transplantation 


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 

thereafter: 

0.2 – 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 0.2 – 0.4 g/kg every 3 – 4 weeks to obtain IgG trough level of at least 5 – 6 g/l 

Congenital AIDS 0.2 – 0.4 g/kg every 3 – 4 weeks 

Hypogammaglobulinaemia (l 4 g/l) in patients after 

allogeneic haematopoietic stem cell transplantation 

0.2 – 0.4 g/kg every 3 – 4 weeks to obtain IgG trough level above 5 g/l 

Immunomodulation: 


0.8 – 1 g/kg 

or 

0.4 g/kg/d 

on day 1, 

possibly repeated once within 3 days 

for 2 – 5 days 

Guillain Barré syndrome 0.4 g/kg/d for 5 days 


1.6 – 2 g/kg 

or 

2 g/kg 

in divided doses over 2 – 5 days in association with acetylsalicylic acid 

in one dose in association with acetylsalicylic acid 

38



There are two alternative treatment schedules: 

• 8 – 10 ml (0.8 – 1 g)/kg given on day one, this dose may be repeated once 

within 3 days 

• 4 ml (0.4 g)/kg given daily for two to five days. 

The treatment can be repeated if relapse occurs. 

Guillain Barré syndrome 

4 ml (0.4 g)/kg/day over 5 days. 


16 – 20 ml (1.6 – 2.0 g)/kg should be administered in divided doses over 

two to five days or 20 ml (2.0 g)/kg as a single dose. Patients should receive 

concomitant treatment with acetylsalicylic acid. 

The dosage recommendations are summarised in the following table: 


The posology in children and adolescents (0 – 18 years) is not different to 

that of adults as the posology for each indication is given by body weight 

and adjusted to the clinical outcome of the above mentioned conditions. 

Method of administration 

For intravenous use. 

Intratect 100 g/l should be infused intravenously at an initial rate of not 

more than 1.4 ml/kg/hr for 30 minutes. 

If well tolerated (see section 4.4), the rate of administration may gradually 

be increased to a maximum of 1.9 ml/kg/hr for the remainder of 

the infusion. 

4.3 Contraindications 

Hypersensitivity to the active substance or to any of the excipients (see 

section 6.1). 

Hypersensitivity to human immunoglobulins, especially in patients with 

antibodies against IgA. 

4.4 Special warnings and precautions for use 

Certain severe adverse reactions may be related to the rate of infusion. 

The recommended infusion rate given under section 4.2 must be closely 

followed. Patients must be closely monitored and carefully observed for 

any symptoms throughout the infusion period. 

Certain adverse reactions may occur more frequently 

• in case of high rate of infusion, 

• in patients who receive human normal immunoglobulin for the first 

time or, in rare cases, when the human normal immunoglobulin product 

is switched or when there has been a long interval since the previous 

infusion. 

Potential complications can often be avoided by ensuring that patients 

• are not sensitive to human normal immunoglobulin by initially injecting 

the product slowly (1.4 ml/kg/h corresponding to 0.023 ml/kg/min), 

• are carefully monitored for any symptoms throughout the infusion 

period. In particular, patients naive to human normal immunoglobulin, 

patients switched from an alternative IVIg product or when there has 

been a long interval since the previous infusion should be monitored 

during the first infusion and for the first hour after the first infusion, 

in order to detect potential adverse signs. All other patients should be 

observed for at least 20 minutes after administration. 

In case of adverse reaction, either the rate of administration must be 

reduced or the infusion stopped. The treatment required depends on 

the nature and severity of the adverse reaction. 

In case of shock, standard medical treatment for shock should be implemented. 

In all patients, IVIg administration requires 

• 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 

Hypersensitivity 

True hypersensitivity reactions are rare. They can occur in patients with 

anti-IgA antibodies. 

IVIg is not indicated in patients with selective IgA deficiency where the 

IgA deficiency is the only abnormality of concern. 

Rarely, human normal immunoglobulin can induce a fall in blood pressure 

with anaphylactic reaction, even in patients who had tolerated previous 

treatment with human normal immunoglobulin. 

Thromboembolism 

There is clinical evidence of an association between IVIg administration 

and thromboembolic events such as myocardial infarction, cerebral vascular 

accident (including stroke), pulmonary embolism and deep vein 

thromboses which is assumed to be related to a relative increase in blood 

viscosity through the high influx of immunoglobulin in at-risk patients. 

Caution should be exercised in prescribing and infusing IVIg in obese 

patients and in patients with pre-existing risk factors for thrombotic 

events (such as advanced age, hypertension, diabetes mellitus and a history 

of vascular disease or thrombotic episodes, patients with acquired 

or inherited thrombophilic disorders, patients with prolonged periods of 

immobilisation, severely hypovolaemic patients, patients with diseases 

which increase blood viscosity). 

In patients at risk for thromboembolic adverse reactions, IVIg products 

should be administered at the minimum rate of infusion and dose practicable. 

Acute renal failure 

Cases of acute renal failure have been reported in patients receiving IVIg 

therapy. In most cases, risk factors have been identified, such as preexisting 

renal insufficiency, diabetes mellitus, hypovolaemia, overweight, 

concomitant nephrotoxic medicinal products or age over 65 years. 

In case of renal impairment, IVIg discontinuation should be considered. 

While these reports of renal dysfunction and acute renal failure have 

been associated with the use of many of the licensed IVIg products containing 

various excipients such as sucrose, glucose and maltose, those 

containing sucrose as a stabiliser accounted for a disproportionate share 

of the total number. In patients at risk, the use of IVIg products that do 

not contain these excipients may be considered. Intratect 100 g/l does 

not contain sucrose, maltose or glucose. 

In patients at risk for acute renal failure, IVIg products should be administered 

at the minimum rate of infusion and dose practicable. 

Aseptic meningitis syndrome (AMS) 

Aseptic meningitis syndrome has been reported to occur in association 

with IVIg treatment. 

Discontinuation of IVIg treatment has resulted in remission of AMS 

within several days without sequelae. 

The syndrome usually begins within several hours to 2 days following 

IVIg treatment. Cerebrospinal fluid studies are frequently positive with 

pleocytosis up to several thousand cells per mm3, predominantly from the 

granulocytic series, and elevated protein levels up to several hundred mg/dl. 

AMS may occur more frequently in association with high-dose (2 g/kg) 

IVIg treatment. 

Haemolytic anaemia 

IVIg products can contain blood group antibodies which may act as 

haemolysins and induce in vivo coating of red blood cells with immunoglobulin, 

causing a positive direct antiglobulin reaction (Coombs' test) 

and, rarely, haemolysis. Haemolytic anaemia can develop subsequent 

to IVIg therapy due to enhanced red blood cells (RBC) sequestration. 

IVIg recipients should be monitored for clinical signs and symptoms of 

haemolysis. (See section 4.8.) 

Interference with serological testing 

After injection of immunoglobulin the transitory rise of the various passively 

transferred antibodies in the patient's blood may result in misleading 

positive results in serological testing. 

39


Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D 

may interfere with some serological tests for red cell antibodies for example 

the direct antiglobulin test (DAT, direct Coombs' test). 

Transmissible agents 

Standard measures to prevent infections resulting from the use of 

medicinal products prepared from human blood or plasma include selection 

of donors, screening of individual donations and plasma pools 

for specific markers of infection and the inclusion of effective manufacturing 

steps for the inactivation/removal of viruses. Despite this, 

when medicinal products prepared from human blood or plasma are 

administered, the possibility of transmitting infective agents cannot 

be totally excluded. This also applies to unknown or emerging viruses 

and other pathogens. 

The measures taken are considered effective for enveloped viruses such 

as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and 

hepatitis C virus (HCV). The measures taken may be of limited value 

against non-enveloped viruses such as hepatitis A virus and parvovirus 

B19. 

There is reassuring clinical experience regarding the lack of hepatitis 

A or parvovirus B19 transmission with immunoglobulins and it is also 

assumed that the antibody content makes an important contribution 

to the viral safety. 

It is strongly recommended that every time that Intratect 100 g/l is 

administered to a patient, the name and batch number of the product 

are recorded in order to maintain a link between the patient and the 

batch of the product. 


The special warnings and precautions for use mentioned for the adults 

should also be considered for the paediatric population. 

4.5 Interactions with other medicinal products and other forms of interaction 

Live attenuated virus vaccines: 

Immunoglobulin administration may impair for a period of at least 6 

weeks and up to 3 months the efficacy of live attenuated virus vaccines 

such as measles, rubella, mumps and varicella. After administration of 

this medicinal product, an interval of 3 months should elapse before 

vaccination with live attenuated virus vaccines. In the case of measles, 

this impairment may persist for up to 1 year. Therefore patients receiving 

measles vaccine should have their antibody status checked. 


It is expected that the same interaction mentioned for the adults may 

also occur in the paediatric population. 

4.6 Fertility, pregnancy and lactation 

Pregnancy 

The safety of this medicinal product for use in human pregnancy has not 

been established in controlled clinical trials and therefore should only 

be given with caution to pregnant women and breast-feeding mothers. 

IVIg products have been shown to cross the placenta, increasingly during 

the third trimester. Clinical experience with immunoglobulins suggests 

that no harmful effects on the course of pregnancy, or on the foetus and 

the neonate are to be expected. 

Breast-feeding 

Immunoglobulins are excreted into the milk and may contribute to 

protecting the neonate from pathogens which have a mucosal portal 

of entry. 

Fertility 

Clinical experience with immunoglobulins suggests that no harmful 

effects on fertility are to be expected. 

4.7 Effects on ability to drive and use machines 

The ability to drive and operate machines may be impaired by some 

adverse reactions associated with Intratect 100 g/l. Patients who experience 

adverse reactions during treatment should wait for these to resolve 

before driving or operating machines. 

4.8 Undesirable effects 

Summary of the safety profile 

Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic 

reactions, nausea, arthralgia, low blood pressure and moderate low 

back pain may occur occasionally. 

Rarely human normal immunoglobulins may cause a sudden fall in blood 

pressure and, in isolated cases, anaphylactic shock, even when the patient 

has shown no hypersensitivity to previous administration. 

Cases of reversible aseptic meningitis and rare cases of transient cutaneous 

reactions have been observed with human normal immunoglobulin. 

Reversible haemolytic reactions have been observed in patients, especially 

those with blood groups A, B, and AB. Rarely, haemolytic anaemia 

requiring transfusion may develop after high dose IVIg treatment (see 

also Section 4.4). 

Increase in serum creatinine level and/or acute renal failure have been 

observed. 

Very rarely: Thromboembolic reactions such as myocardial infarction, 

stroke, pulmonary embolism, deep vein thromboses. 

For safety information with respect to transmissible agents, see section 

4.4. 

Details of further spontaneously reported adverse reactions: 

Cardiac disorders: Angina pectoris (very rare) 

General disorders and administrations site conditions: Rigors (very rare) 

Immune system disorders: Anaphylactic shock (very rare), allergic reaction 

(very rare) 

Investigations: Blood pressure decreased (very rare) 

Musculoskeletal and connective tissue disorders: Back pain (very rare) 

Respiratory, thoracic and mediastinal disorders: Dyspnoe NOS (very rare) 

Vascular disorders: Shock (very rare) 

Occasionally, hypersensitivity reactions have been observed including 

various symptoms, such as: 

chills, headache, dizziness, fever, vomiting, cutaneous reactions, nausea, 

arthralgia, low blood pressure and back pain. 

Suspected Adverse Drug Reactions reported in completed clinical trials: 

Three clinical studies have been performed with Intratect 50 g/l: two in 

patients with primary immunodeficiencies (PID) and one in patients with 

immune thrombocytopenic purpura (ITP). In the two PID studies overall 

68 patients were treated with Intratect 50 g/l and evaluated for safety. 

Treatment period was 6 and 12 months respectively. The ITP study was 

performed in 24 patients. 

These 92 patients received a total of 830 infusions of Intratect 50 g/l, 

whereby a total of 51 adverse drug reactions (ADRs) were recorded. 

With Intratect 100 g/l one clinical study has been performed in patients 

with PID. 30 patients were treated with Intratect 100 g/l over 3 to 6 

months and evaluated for safety. These 30 patients received a total of 

90 infusions of Intratect 100 g/l, whereof a total of 13 infusions (14.4 %) 

were associated with adverse drug reactions (ADRs). 

The majority of these ADRs was mild to moderate and self-limiting. No 

serious ADRs were observed during the studies. 

Tabulated list of adverse reactions 

The table presented below is according to the MedDRA system organ 

classification (SOC and Preferred Term Level). 

Frequencies have been evaluated according to the following convention: 

very common (M 1/10); common (M 1/100 to l 1/10); uncommon 

(M 1/1,000 to


Nervous system disorders Headache Common 

Skin and subcutaneous 

tissue disorders 

Vascular disorders 

Frequency of Adverse Drug Reactions (ADRs) in a clinical study with 

Intratect 100 g/l 

MedDRA 

System Organ Class (SOC) 

Adverse reaction 

Frequency 

Cardiac Disorders Palpitations Common 

Gastrointestinal disorders Diarrhoea, abdominal pain Common 

General disorders and 

administration site conditions 

Immune system disorders 

Nervous system disorders 

Musculosketal and connective 

tissue disorders 

Skin and subcutaneous tissue 

disorders 

Dysgeusia 

Papular rash 

Hypertension, thrombophlebitis 

superficial 

Discomfort, fatigue, chills 

Infusion related reaction, 

hypersensitivity 

Headache, sensory 

disturbance 

Arthralgia, back pain, 

bone pain, myalgia 

Pain of skin 

Uncommon 

Uncommon 

Uncommon 

Common 

Common 

Common 

Common 

Common 

Vascular disorders Hyperaemia, hypertension Common 

Description of selected adverse reactions 

Product specific adverse reactions have not been reported. The reported 

adverse reactions for Intratect are in the expected profile for human 

normal immunoglobulins. 


Frequency, type and severity of adverse reactions in children are expected 


4.9 Overdose 

Overdose may lead to fluid overload and hyperviscosity, particularly in 

patients at risk, including elderly patients or patients with cardiac or 

renal impairment. 


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 

intravenous immunoglobulins. 

5. PHARMACOLOGICAL PROPERTIES 

5.1 Pharmacodynamic properties 

Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, 

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 immunoglobulin 

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. 

distributed relatively rapidly between plasma and extravascular fluid, 

after approximately 3 – 5 days equilibrium is reached between the intraand 

extravascular compartments. 

Intratect 100 g/l has a half-life of about 34 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 reticuloendothelial 

system. 

5.3 Preclinical safety data 

Immunoglobulins are normal constituents of the human body. 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 heterologous 

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 

10 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. Not 

all pack sizes may be marketed. 

6.6 Special precautions for disposal and other handling 

The product should be brought to room or body temperature before use. 

The solution should be clear or slightly opalescent and colourless or pale 

yellow. Solutions that are cloudy or have deposits should not be used. 

Any unused product or waste material should be disposed of in accordance 

with local requirements. 

7. MARKETING AUTHORISATION HOLDER 


Landsteinerstraße 5 


Germany 

Tel.: (+49) 06103 801 0 

Fax: (+49) 06103 801 150 

8. MARKETING AUTHORISATION NUMBER(S) 

– 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

– 

10. DATE OF REVISION OF THE TEXT 

September 2012 

The mechanism of action in indications other than replacement therapy 

is not fully elucidated, but includes immunomodulatory effects. 


The pharmacokinetic properties in the paediatric population are expected 


5.2 Pharmacokinetic properties 

Human normal immunoglobulin is immediately and completely bioavailable 

in the recipient's circulation after intravenous administration. It is 

41

Intratect® I Bibliography 

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mode of action for treatment of pemphigus 

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2) Arnson Y et al.: Intravenous immunoglobulin therapy for 

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Autoimmunity: (2009) 42: 1–8 

3) Ballow M: The IgG molecule as a biological immune response 

modifier: mechanisms of action of intravenous immune 

serum globulin in autoimmune and inflammatory disorders 

J. Allergy Clin. Immunol. (2011) 127: 315–323 

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complement system: activation versus inhibition 

Mol. Immunol. (2008) 45: 4073–4079 

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Clin. Exp. Immunol. (2011) 164 (Suppl.2): 16–19 

8) Dalakas MC: Immunotherapy of myositis: issues, concerns 

and future prospects 

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9) Durandy A et al.: Intravenous immunoglobulins – understanding 

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EMA/CHMP/BPWP/94038/2007 rev. 3 (effective since May 2011) 

11) EMA Guideline on the clinical investigation of human normal 

immunoglobulin for intravenous administration (IVIg) 

EMA/CHMP/BPWP/94033/2007 rev. 2 (effective since Feb. 2011) 

12) Enk A and the Guideline Subcommittee “Immunoglobulin” 

of the European Dermatology Forum: Guideline on the use 

of high-dose intravenous immunoglobulin in dermatology - 

update 2011 

www.euroderm.org/index.php/edf-guidelines 

13) Etscheid M et al.: Identification of kallikrein and FIX as impurities 

in therapeutic immunoglobulins: implications for the 

safety and control of intravenous blood products. 

Vox Sang. (2012) 102: 40-46 

14) European Pharmacopoeia 7.5, 01/2012: 0918, pp. 4645–4646 

15) Funk MB et al.: Thromboembolic events associated with immunoglobulin 

treatment 

Publication in preparation (2012) 

16) Funk, M.: Erhöhte Melderate von schweren hämolytischen 

Reaktionen nach der intravenösen Gabe von Immunglobulinen 

BfArM / PEI – Bulletin zur Arzneimittelsicherheit (2012) 2: 15–17 

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42

Intratect® I List of abreviations 

List of abbreviations 

AIHA 

BW 

CIDP 

CVID 

EMA 

FDA 

GBS 

HAV 

HBC 

HCV 

HIV 

ITP 

IVIG 

CPP 

MMN 

NAPTT 

NAT 

PEI 

PID 

PKA 

TGT 

vCJD 

Autoimmune haemolytic anaemia 

Bodyweight 

Chronic inflammatory demyelinating polyneuropathy 

Common variable immunodeficiency 

European Medicines Agency 

Food and Drug Administration (US) 

Guillain-Barré syndrome 

Hepatitis A virus 

Hepatitis B virus 

Hepatitis C virus 

Human immunodeficiency virus 

Primary immune thrombocytopenia (idiopathic thrombocytopenic purpura) 

Intravenous immunoglobulin G 

Cryo-poor (depleted) plasma 

Multifocal motor neuropathy 

non-activated partial thromboplastin time 

Nucleic acid amplification technique 

Paul-Ehrlich Institute (German federal institute of vaccines and biomedical drugs) 

Primary immunodeficiency disease 

Prekallikrein activator 

Thrombin generation test 

Variant form of Creutzfeldt-Jakob disease 

43


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Germany 

Tel. +49 (0) 6103 801-0 

Fax +49 (0) 6103 801-125 

ivig@biotest.de 

www.biotest.com 

698 604 101 

2013

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