Intratect® 50 g/l and 100 g/l

Human normal immunoglobulin for intravenous use1

Well tolerated IVIG therapy for use in

a wide range of immunodeficiency
and autoimmune diseases2

PM-UK-INT-0007 October 2018

 Intratect® | Table of contents

Table of contents

Intratect® - overview 4-5

The Intratect® - manufacturing process 6-11

Intratect® - key safety steps in manufacturing process 12-14

Clinical indications 15

Clinical efficacy 16-19

Intratect® - tolerability 20-23

List of abbreviations 24
References 25
Prescribing Information 28

3
 Intratect®
Intratect® is indicated for:1
Replacement therapy in adults and children (0-18 years) in:

• Primary immunodeficiency syndromes with impaired antibody production

• Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic
leukaemia, in whom prophylactic antibiotics have failed
• Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma
patients who have failed to respond to pneumococcal immunisation
• Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation
• Congenital AIDS with recurrent bacterial infections

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

• Primary immune thrombocytopenia, in patients at high risk of bleeding or prior to surgery to
correct the platelet count
• Guillain Barré syndrome
• Kawasaki disease

4
 Intratect®

High purity and natural structure

• The IgG content of Intratect® 50 g/L and 100 g/L is at least 96% IgG with no protein fragments1,3

• IgG subclass distribution is IgG1 57%, IgG2 37%, IgG3 3% and IgG4 3%1

• The products are a close match to normal serum1,4

Well tolerated IVIG therapy

• Repeated donor plasma tests and a four-stage procedure to eliminate or inactivate viruses, including
nanofiltration (20 nm), ensure a very high degree of protection against the transmission of human-
pathogenic viruses5

• Biotest has been certified in accordance with the QSEAL (Quality Standards of Excellence, Assurance and
Leadership) program6

• Intratect® is free from pro-coagulant activity3

• Intratect® 50 g/L and Intratect® 100 g/L are a close match to normal serum, sugar-free and isotonically
stabilised with glycine1,4

User-friendly
• Intratect® is a ready to use solution and can be kept for a period of three years at up to 25°C (room
temperature)1

• Each patient is different and the required IVIg amount must be individually calculated. This is facilitated
by four different package sizes: 1g, 2.5g, 5g, 10g, 20g1

Sugar-free improves tolerability

Sugars, other stabilisers, and sodium can contribute to differences between IVIG products with regard to
their tolerability.7
IN FOCUS
The major problem associated with the sugar content in IVIG preparations is the incidence of certain adverse
events, particularly acute renal failure or impairment; A disproportionate number of patients who showed
evidence of renal dysfunction or acute renal failure after receiving IVIG had received sucrose containing
preparation.7

Although very rare, treatment with some IVIG products may result in severe adverse events in individuals
with certain hereditary metabolic disorders. For instance, IVIG products that contain sorbitol as a stabilizer
should not be administered to patients with hereditary fructose intolerance, as there is the potential for
severe, and often fatal, hepatic failure.7

In addition, these formulations should not be administered to babies and young children, as hereditary
fructose intolerance may not yet be diagnosed in these patients and such treatment could be fatal.7

5
The Intratect® manufacturing process
aims to maximise quality
All process developments for the manufacture form with good tolerability. An important aspect
of intravenous immunoglobulin concentrates in this respect is the attainment of the highest
aim to conserve the natural structure of the IgG possible degree of safety with regard to the risk of
antibodies. Their efficacy and biological properties transmitting human-pathogenic viruses.
are preserved and available to the patient in a

Manufacturing begins with the right choice of donor

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

• For the UK, only plasma from officially licensed collecting centres is used to produce Intratect®. Plasma
comes from Belgium, Germany, Austria, Switzerland, Hungary, the Czech Republic, Canada and the USA8

• 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 virus antigens, as well as for antibodies against the
human immunodeficiency virus (HIV 1/2) and hepatitis C virus5,8

6
 Intratect® | manufacturing process aims to maximise quality and viral safety

• Biotest also maintains an inventory hold period of at least 60 days. If, during this time, the company were
to receive relevant safety-related information about the donor such as an illness that, was not evident at
the time of the donation, then these donations would be discarded6

• The plasma pools collected for processing are tested 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 containing a limited number of plasma donations and repeated later on
final production size plasma pool5

From the plasma pool to the final product

In the first step, cryoprecipitate and coagulation antibodies are then removed from the matrix and
factors are separated and ethanol precipitation collected as a pure eluate fraction.
is used to obtain the various fractions (I/II/III).
Fraction II is used for manufacturing Intratect®. Nanofiltration (20nm) ensures the removal of
This is followed by octanoic acid/calcium acetate virus particles (e.g. PPV, MEV, Reo, BVDV) on the
and solvent/detergent treatment which reduces principle of size exclusion traversing a three-
any potential viral load and removes thrombogenic dimensional void-capillary structure (Figure 1).
factors. Purification of immunoglobulin G (IgG) 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

The virus reduction procedure

The production process of Intratect employs
several steps, which contribute to the viral
safety of the final product. These steps include
removal of cryoprecipitate, 3 steps of the cold
ethanol fractionation process using filter aid for
separation of precipitated fractions, treatment
with caprylic acid, solvent/detergent treatment
and nanofiltration.

The results of validation studies and test series

(Table 1) show Intratect® virus and prion clearance.

7
 Intratect® | manufacturing process aims to maximise quality and viral safety

Fig. 1: Intratect® manufacturing steps5

Plasma from screened donors, serologically Plasma Separation of cryoprecipitate

tested donations pool and coagulation factors

Ethanol precipitation of plasma

fraction l/ll/lll and separation
of the fraction l/lll

ipitation/separation Step
Step
1: ethanol
1: ethanolprecipitation/separation
precipitation/separation Step 1: ethanol precipitation/separation
on I, III of fraction
of fractionI, IIII, III of fraction I, III
o, PPV, HIV, PRV) Virus
Virus
inactivation(Reo,
inactivation(Reo, PPV, PPV,HIV,HIV,
PRV)PRV) Virus inactivation(Reo, PPV, HIV, PRV)
ncreased the ethanol inactivation
inactivation
through
through
increased
increased the the
ethanol
ethanol
inactivation through increased the ethanol
nd decreased concentration
concentrationandand decreased
decreased concentration and decreased
mperature Tempo pH pHandand pH
temperature
temperature pHo and temperature
low
Temp
Temp Ethanol
o
pHlow
pHlow Tempo

Step 1: ethanol precipitation/separation

of fraction I, III
Step
Step1:1:ethanol
ethanol precipitation/separation
precipitation/separation
Virus inactivation(Reo, PPV, HIV, PRV)
ofoffraction
fraction
inactivation throughI,I,IIIincreased
III the ethanol
acid treatment
Virus
Virusinactivation(Reo,
inactivation(Reo,
concentration PPV,
PPV, and HIV,
HIV, PRV)
PRV)
decreased Ethanol precipitation of fraction ll
Step Step
2:and
octanoic
2: octanoic acidacid
treatment
treatment Step 2: octanoico acid treatment
V, EAV, BVDV, PRV)inactivation
inactivationthrough
through increased
pH increased the
temperature the ethanol
ethanol Temp pHlow
operties of caprylic
Virus
Virus
inactivation
inactivation
(HIV,(HIV,
EAV,
EAV,
BVDV,
BVDV,
PRV)
PRV)
Virus inactivation (HIV, EAV, BVDV, PRV)
non-ionised form
concentration
concentration
throughand
and
through decreased
decreased
virucidal
virucidal
properties
properties
of caprylic
of caprylic through virucidal properties of caprylic
ranes and crosslinks pH
pHand
andtemperature
acid temperature
acid
at low
at low
pH. pH.
TheThe
non-ionised
non-ionised
form
form acid at low pH.
Temp
Temp
The non-ionised form
o o
pH
pHlow
low
d proteins binds
binds
virus
virus
cellcell
membranes
membranesandand
crosslinks
crosslinks
binds virus cell membranes andacid
Octanoic crosslinks
(caprylic acid)/
virus
virus
capsid
capsid
proteins
proteins virus capsid proteins
calcium acetate treatment of
fraction ll (IgG crude fraction)

Step 2: octanoic acid treatment

tergent treatment Virus
Sterile inactivation
filling (HIV, EAV, BVDV, PRV)
in final containers
t of organic solvent through
Quality control
Stepvirucidal
and
Step properties
3:packaging
3: solvent
solvent
detergent oftreatment
detergent caprylic Step 3: solvent detergent treatment
treatment
activate viruses acidThe
atThe
combined
lowcombined
effect
pH. The effect
of organic
of organic
non-ionised solvent
solvent
form The combined effect of organic solvent
RV, WNV, EAV) Step
Step2: 2:octanoic
bindsoctanoic
andand
virus cellacid
acidtreatment
detergent
detergent
membranestreatment
inactivate
inactivateviruses
and viruses
crosslinks and detergent inactivate viruses
e lipid envelope (HIV,
(HIV,
BVDV,
BVDV,
PRV,PRV,WNV, WNV,
EAV)EAV) (HIV, BVDV, PRV, WNV, EAV)
Virus
Virusinactivation
inactivation(HIV, (HIV,
virus EAV,
EAV,
capsid
by destroying
by destroying BVDV,
BVDV,
proteins
the the
lipidlipid PRV)
PRV)
envelope
envelope by destroying the lipid envelope
through
throughvirucidal
virucidal properties
propertiesofofcaprylic
Dia- and ultrafiltration caprylic
acid
acidatatlow
lowpH.pH.TheThenon-ionised
non-ionisedform form
binds
bindsvirus
viruscell
cellmembranes
membranesand andcrosslinks
crosslinks
virus
viruscapsid
capsidproteins
proteins
nanofiltration
oval of even the Step
Step
4: 20
4: nm
20 nm
nanofiltration
nanofiltration Step 4: 20 nm nanofiltration
Dia- and ultrafiltration
es (HIV, EBV, HCV,
HAV and Parvo
HIV
(80–120 nm) Step(>42HBV
3:nm)solvent
Ensures
Ensures the thedetergent
removal
removal of evenoftreatment
even
the the Ensures the removal of even the
solution The smallest
smallest
combined virus virus
particles
effect particles
of(HIV, (HIV,
organic EBV,EBV,
HCV,HCV, smallestHIVvirus
solvent (80–120
HIV particles
(80–120
nm) nm)
HBV(HIV,
(>42 nm)
HBV
(>42 nm)
EBV, HCV, HIV
(80–120 nm)
HBV
(>42 nm)
HBV, HBV,
BVDV,BVDV,
Parvo Polio,
Polio,
HAV HAV andandParvo
Parvo HBV, BVDV, Polio, HAV and Parvo
and detergent (18–24 nm)
from from
inactivate
the3-dimensional
the
solution
solution
viruses from the solution
BVDV (HIV,
HAV BVDV, PRV,
Pore size
(20 nm)
WNV,
void-capillary
membrane
EAV) ParvoParvo
(18–24
(18–24
nm) nm)
Parvo
(18–24 nm
(50–70 nm) (22–30 nm)
by destroying the lipid envelope Solvent/detergent treatment
3-dimensional
3-dimensional
BVDVBVDV HAV HAV Pore size void-capillary
Pore size void-capillaryBVDV HAV Po
(50–70
(50–70
nm) nm) (22–30
(22–30
nm) nm) (20 nm)
(20 nm) membrane
membrane
(50–70 nm) (22–30 nm) (2

Step3:3:solvent
Step solventdetergent
detergenttreatment
treatment
Thecombined
The combinedeffect
effectofoforganic
organicsolvent
solvent
anddetergent
and detergent
20 nm virus inactivate
inactivate
filtration viruses
viruses
Cation exchange
chromatography
(HIV,BVDV,
(HIV, BVDV,PRV,PRV,WNV, WNV,EAV)
EAV)
bybydestroying
destroyingthe thelipidlipidenvelope
envelope
Step 4: 20 nm nanofiltration
virus elimination/inactivation
Ensures the removal of even the
elimination ofsmallest virus particles
thrombogenic factors (HIV, EBV, HCV, HIV HBV
(80–120 nm) (>42 nm)
HBV, BVDV, Polio, HAV and Parvo8
from the solution
Parvo
(18–24 nm)
 Intratect® | manufacturing process aims to maximise quality and viral safety

Table 1: Capacity of the Intratect® production process to eliminate viruses and prions5

Reduction factors (as log 10 value)

Production process HIV PRV BVDV Reo PPV MEV Prions

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

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

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

Nanofiltration (20 nm) n.a. n.a. > 4.49 > 4.72 3.82 > 6.33 > 4.07

Total reduction > 15.05 > 16.18 > 16.55 > 12.30 7.89 > 10.24 > 7.72

n.a. = not analysed

Table 2: Viruses used in validation studies5

HIV Human immunodeficiency virus RNA virus with envelope 80 – 110 nm

PRV Porcine pseudorabies virus DNA virus with envelope 120 – 200 nm
(model virus for herpes viruses and HBV)

BVDV Bovine viral diarrhea virus RNA virus with envelope 40 – 60 nm

(model virus for HCV)

Reo Reovirus RNA virus non-enveloped 60 – 80 nm

(model virus for non-enveloped viruses)

PPV Porcine parvovirus DNA virus non-enveloped 18 – 22 nm

(model virus for human parvovirus B19)

MEV Murine encephalomyelitis virus RNA virus non-enveloped 22 – 30 nm

(model virus for HAV)

Biotest complies with the strict standards of the Plasma Protein Therapeutic Association
(PPTA), including the International “Quality Plasma Program” or IQPP which applies to
the collection of plasma6

Biotest has been certified in accordance with the QSEAL programme6

9
Intratect® | manufacturing process aims to maximise quality and viral safety

Protein-chemical characterisation
Table 3: Protein-chemical characterisation of Intratect®3

Parameter Intratect® 100 g/l*

Monomers and dimers 99.8 %
Polymers 0.24 %
Fragments 0%
IgG 98.8 %
IgA 1.1 %
IgM 0.1 %
Albumin 0%
Alpha-1-globulin 0%
Alpha-2-globulin 0%
Betaglobulin 0%
Anti-A titre 1:18
Anti-B titre 1:12
Kallikrein 2.3 PEU
Prekallikrein 3 EU
Proteolytic activity 0.5 U/l
Fibrinogen 0%
Anticomplementary activity (ACA) 0.68 CH50/mg
Fc-part function 98 %

Other excipients9
Sodium 1.7 mmol/l
Chloride 10.27 mmol/l
* mean values from several batches, internal documentation
** below detection limit

10
 Intratect® | manufacturing process aims to maximise quality and viral safety

Spectrum of anti-viral and anti-bacterial antibodies9

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

Antigen Intratect® 100 g/l

Parvovirus B19 983 U/ml
Epstein-Barr virus (EBV, virus capsid) 837 U/ml
Hepatitis B virus 2.5 IU/ml
Measles virus 863 U/ml
Rubella virus 613 IU/ml
Influenza virus type B 1221U/ml
Enterococcus faecalis 855U/ml
Escherichia coli 912U/ml
Haemophilus influenzae type B 1037U/ml
Tetanus toxoid 900U/ml
Corynebacterium diphtheriae 932U/ml
Candida albicans 1100 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).1,4

Table 5: IgG subclass distribution and half-life range1,4

IgG1 IgG2 IgG3 IgG4 Serum

half-life
(days)
Normal Adult Range4 43-75% 16-48% 1.7-7.5% 0.8-11.7% 7-21

Intratect® 100 g/l 57% 37% 3% 3% ~34

(Mean)1

11
Intratect® | manufacturing process aims to maximise quality and viral safety

Intratect® removal of pro-coagulant

activity3
Residual coagulation factors in immunoglobulin preparations can compromise safety. 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 may include, deep vein
thrombosis, pulmonary embolism, myocardial infarction or stroke.10,11

Fig. 2: Activation of coagulation cascade

Adapted from Konig, 2011

12
 Intratect® | manufacturing process aims to maximise quality and viral safety

The elimination of thrombogenic factors to minimise risk of

thromboembolic events12
Three major production steps gradually remove thrombogenic substances and prevent the formation of
new activated factors:

• Ethanol precipitation of fraction I/II/III

• Ethanol precipitation of fraction II
• 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) 12

Amount compared with Cryo-poor plasma

(with DEAE Sephadex)

Cryo-poor plasma (CPP)

Fraction I/II/III

Fraction II

Octanoic (caprylic) acid treated

0% 20% 40% 60% 80% 100%

Factor II
Factor VII
Factor IX
Factor X
Factor XI
Factor XII

13
Intratect® | manufacturing process aims to maximise quality and viral safety

Confidence through optimal testing of the final product

Causes of thrombotic complications with IVIG
therapies includes increased blood viscosity,
certain specific antibodies and other contaminants,
including procoagulant factors such as kallikrein,
FXIa and FXIIa (prekallikrein).10,13
as benchmarks to correlate with the amount of
FXIa present. Changes in the kinetics occurring
after the addition of the IVIG to be tested will
show any residual coagulation activity in the final
product.15

In accordance with the European Pharmacopoeia, In addition to coagulation factors, the presence
maximum PKA activity in the final product may of kallikrein in the final product can also be
not exceed 35 IU/ml IVIG.14 The PKA activity of established by determining prothrombin complex
Intratect® is below direction limits (0 IU/ml).3 activity. Chromogenic tests are used.13

The thrombogenic activity of immunoglobulin

compounds can be determined with the aid of two
different global tests, NAPTT test (non-activated
partial thromboplastin time) and TGT (thrombin
generation test).13,15

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 has to
be above 150 seconds for NAPTT batch release.13

The thrombin generation test depicts the kinetics

involved in thrombin formation (FIIa) initiated by
FXIa. This involves mixing 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 of thrombin formation are measured

Summary
Intratect® has reduced pro-coagulant activity compared to cryo-poor plasma
and intermediary fractions in the production process. This has been confirmed
by determining the thrombogenic factors with optimised global tests and with
specific tests for individual coagulation factors in the final product.3,16

14
 Intratect® | Indications

Clinical Indications1
Indication Dose Frequency of infusions
Replacement therapy in primary starting dose:
immunodeficiency 0.4-0.8 g/kg
thereafter: every 3-4 weeks to obtain IgG trough
0.2-0.8 g/kg level of at least 5-6 g/l
Replacement therapy in secondary 0.2-0.4 g/kg every 3-4 weeks to obtain IgG trough
immunodeficiency level of at least 5-6 g/l
Congenital AIDS 0.2-0.4 g/kg every 3-4 weeks
Hypogammaglobulinaemia (< 4 g/l) in 0.2-0.4 g/kg every 3-4 weeks to obtain IgG trough
patients after allogeneic haematopoietic level above 5 g/l
stem cell transplantation
Immunomodulation:
Primary immune thrombocytopenia 0.8-1 g/kg on day 1, possibly repeated once
within 3 days
or
0.4 g/kg/d for 2-5 days
Guillain Barré syndrome 0.4 g/kg/d for 5 days
Kawasaki disease 1.6-2 g/kg in divided doses over 2-5 days in
or association with acetylsalicylic acid
2 g/kg in one dose in association with
acetylsalicylic acid

Intratect® 10% saves time and reduces healthcare costs

Intratect®: a ready to use IVIG solution has a flexible infusion speed

Intratect 5% and 10% - i.v. infusion rate initially 1.4 mg/kg BW/h for 30 minutes, then if well
tolerated may gradually increase up to 1.9 mg/kg BW/h for the remainder of infusion.
In replacement therapy:
Intratect 10% - may further increase infusion rate if 1.9 mg/kg B/h is well tolerated gradually to 6
mg/kg BW/h and then up to 8 mg/kg BW/h again if well tolerated1
For immunomodulation therapy please refer to Summary of Product Characteristics

15
 Intratect® | Clinical efficacy

Clinical efficacy
Building on the heritage of Intratect 5%

Safety monitoring of the intravenous immunoglobulin preparation

Intratect® in primary and secondary immunodeficiencies: a prospective
non-interventional study
Intratect® 5% therapy correlated with an improvement of clinical symptoms and a decline in the frequency
of infectious episodes2,18

• In 72.2% of patients who had not been treated with IVIG previously, infection frequency was
assessed to be reduced2,18
• In 43.9% of patients previously treated with IVIG, infection frequency was assessed to be reduced2,18

Frequency of infection episodes

Without IVIG pre-treatment (n=1,782) With IVIG pre-treatment (n=3,612)

8080 8080
72.2%
72.2%
Frequency of infection episodes (%)
Frequency of infection episodes (%)
Frequency of infection episodes (%)
Frequency of infection episodes (%)

7070 7070

6060 6060

5050 5050
43.9%
43.9% 45.4%
45.4%
4040 4040

3030 3030
22.6%
22.6%
2020 2020
9.8%
9.8%
1010 1010
4.6%
4.6% 1.0%
1.0%
0.7%
0.7%
00 00
Reduced Unchanged Increased
Reduced Unchanged Increased Not
Notspecified
specified Reduced Unchanged Increased
Reduced Unchanged Increased Not
Notspecified
specified

Note: The last evaluation was made after 328 days (mean).

Adapted from Biometric Report Interim Analysis, 2013

100
100
9090 87.4%
87.4%
Improvement in clinical symptoms (%)
Improvement in clinical symptoms (%)

8080
7070
6060
• 32.7% of all adverse events were drug related2
5050
• Serious
4040 adverse drug reactions (ADRs) were rare
2

• N30
o30patients experienced haemolysis
2020
• 1 10
TEE 11.1%
11.1%
(thromboembolic event) from 21,995 infusions was assessed as possibly related to
10
Intratect® 1.5%
1.5%
00
Good
Goodoror Moderate
Moderate Not
Notsatisfactory
satisfactory
• No incidence ofvery
renal
verygood
complication
good
assessed as being related to Intratect®
• No serious allergic reaction suggestive of a reaction to IgA could be identified

16
5050 5050
of
of
 Intratect® 10% | Clinical efficacy

Clinical study: Intratect® 10% for primary antibody

deficiency13
Intratect® 100g/l is a highly purified 10% human IVlg (10g human plasma protein per 100 mL of solution)
with a IgG subclass distribution similar to that in normal serum. Its manufacturing is identical to the
manufacturing process of Intratect® 5%. The higher concentration of the 10% offers the advantage of
reduced volume and shorter infusion time.

This study investigated the pharmacokinetics and tolerability of Intratect® 10% in PID patients (part A), as
well as the tolerability of higher infusion rates (Part B).

PART A PART B

Months 1 2 3 4 5 6

Infusion No. 1st 2nd 3rd 4th 5th 6th

Infusion Rate up to 2.0ml/kg/h Escalation Individual max.

infusion rate
PK

Tolerability of
Endpoints Safety & PK
escalating infusion rates

Adapted from Krivan, 2015

In the part A of the study three infusions with Intratect® 10% 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.
The infusion rate was increased to a maximum of 8 ml/ kg/h at the start of part B (4th to 6th infusions) to
ascertain the maximum tolerable rate for each patient. This individually determined maximum rate was
then used for the 5th and 6th infusions.17

Intratect® dosage was between 200 and 800 mg/kg BW and based on the individual doses dispensed in the
six months preceding the study.17

Well tolerated
• Well tolerated in a primary immune deficiency clinical study allowing a maximum infusion rate of
up to 8 ml/kg BW/h17
• The number of related AEs is comparable with other slower to infuse IVIG17
• No premedication to prevent AEs was administered in the study17

Reducing the burden of treatment

• Escalation of Intratect® infusion rates were well tolerated in most patients in the Krivan study17
• Shorter infusion times were achieved thus reducing the time that patients spend receiving their
IVIG treatment17
• reducing the burden of this condition for chronically ill patients
• lowering the demand on healthcare resources

17
Intratect® 10% | Clinical efficacy

Pharmacokinetics of Intratect® 10%17

With Intratect® 10%, most patients achieved an IgG trough level above 6 g/l.

Median IgG levels increased from 8g/l (pre-dose) to 17g/l (immediately after infusion). (Figure 4)

Overall Tolerability Profile of Intratect 10%17

Adverse events assessed as temporary associated were reported in 40 of 165 infusions (24.2%) for overall
study (Part A+B). No serious related adverse event was reported during the study.

Fig. 4: IgG serum levels and IgG subclass distribution after the 3rd infusion of Intratect® 10%17

Adapted from Krivan, 2015

18
 Intratect® 10% | Tolerability

Tolerability of increased infusion rate17

The duration of infusion decreased substantially
with increasing infusion rates, from a median of
around 2.5 h in Part A to around 1.6 h in Part B. Thus,
the identification of an individual’s maximum
tolerated infusion rate in Part B shortened the
duration of infusion, thereby optimising the
convenience of Intratect treatment.
The overall pattern of AEs in Parts A and B
combined was comparable with that in Part A only,
indicating that the escalation of infusion rates in
Part B was well tolerated. It should be noted that
no premedication to prevent AEs was administered
in this study.
Investigations in the second study phase (Part B)
showed that 17 from 25 patients (68%) tolerated
an infusion rate of 6 ml/kg/h. Eight patients (32
%) tolerated an infusion rate of 8 ml/kg/h. In 11
patients (48 %) the targeted infusion rate of 8 ml/
kg/h was not achieved, as the individual IVIG dose
was administered before the maximum infusion
rate was reached.
All patients could tolerate their individual
maximum tolerated infusion rate as determined
at their 4th infusion, Figure 5 shows the
proportion of patients at maximum tolerated
infusion rate.
These data demonstrate that escalating infusion
rates of Intratect 10% up to 8 ml/kg/h in patients
with PID can facilitate the identification of an
individual maximum tolerated infusion rate that
can then be applied at subsequent infusions.

100
Fig. 5: Maximum tolerated infusion rates at 5th and 6th infusions.

90

80

70
Percentage of patients [%]

60

50

40

30

20

10

0
3 4 5 6
8
Maximum infusion rate [ml/kg/h]
Adapted from Krivan, 2015

Summary17
During treatment with Intratect® 10% effective and reliable IgG serum levels are achieved which are
consistent with those of other IVIGs and are also comparable to those of Intratect 5%.

The tolerability profile of Intratect® 10% is comparable to that of other IVIGs.

Escalation of Intratect infusion rates was tolerated in most patients. Therefore, shorter infusion times were
achieved thus reducing the time that patients with PID spend receiving their Intratect® treatment, reducing
the burden of this condition on these chronically ill patients and lowering the demand for healthcare
resources.

19
Intratect® | Tolerability

Intratect® - Fully fractionated to reduce isoagglutinins19

Haemolysis is a known adverse effect following intravenous immunoglobulin infusion however, the impact
of the isoagglutinin content in different preparations had not been established.

To this end and following apparent increased reporting of haemolytic reactions, the Swiss and German
health authorities jointly launched an investigation to identify the potential risk.

Using the EudraVigilance database they examined haemolytic reactions reported between 2008 and 2013
for seven products. This yielded 466 reports which could be evaluated: approximately 20% were categorised
as mild/moderate and 80% as severe (Hb decline >2g/dl).

Intratect® has low risk of haemolytic reactions compared to other IVIG

products examined in this study 19

The manufacturing process and isoagglutinins

Fig 6: Intratect®Manufacturing Process.

The manufacturing process appears to
Adapted from Bellac, 2015.
have a profound effect on the isoagglutinin
levels.19
INTRATECT® MANUFACTURING PROCESS
Intratect® undergoes full fractionation.3,5,19

(Cryo-poor) Plasma

Optional:
Summary ≅ 8% EtOH
Fraction I
High cumulative doses of IVIG are associated
with an increased risk of haemolysis ≅ 20% EtOH

especially in patients with blood group A

Globulin Fraction
or AB. Harmonised batch release testing, (Crude Immunoglobulins)
modifications of the manufacturing process Cohn Fraction (I) + II + III /
KN Precipitate A
to achieve low isoagglutinin titres, and
individualised treatment regimens assuring ≅ 13% EtOH
Fraction (I) + III /
selection of the IVIG brand most suitable for KN Precipitate B
≅ 25% EtOH
the needs of each individual patient should
be considered as risk mitigation measures.
Gammaglobulin Fraction
Cohn Fraction II
KN Precipitate GG

Post-fractionation Purification
(e.g. Chromatography)

Immunoglobulin G
(Purified Fraction II /
Purified KN Precipitate GG)

Cases of haemolysis (% of total)

5%

20
 Intratect® | Tolerability

Intratect® 10% - IVIG designed for your complex patients7

Some properties of IVIG formulations are
associated with an increased risk of serious
adverse events (Table 6) in certain at-risk patient
populations. Such risks can be minimised by
selecting a product with properties that do
not exacerbate these risk factors and careful
management of the best applicable infusion rate
and concentration.
For instance, in patients at a risk of renal failure
(e.g. those with pre-existing renal insufficiency,
diabetes, age >65 years, volume depletion, sepsis,
or paraproteinemia, or those receiving nephrotoxic
drugs), products with high sugar (particularly
sucrose) and/or sodium content, high osmolality/
osmolarity, or high volume load should be avoided
and products should be administered at the lowest
dose and slowest infusion rate possible.
Products with a low pH are suitable for patients
who should avoid a sugar load, including those
at risks of renal dysfunction or failure (sucrose-
containing products), patients with diabetes
(glucose-containing products), and those with or
at risk of hereditary fructose intolerance (sorbitol-
containing products), hereditary hyperprolinemia
(L-proline-containing products) or maple syrup
urine disease (L-isoleucine-containing products).
Many IVIG products are commercially available;
however, formulations differ in composition and
preparation methods. While this appears to have
no significant effect on efficacy between IVIG
products, differences in tolerability profiles are
evident, and each product should be considered
unique. To achieve the optimal result in patients
requiring IVIG treatment, treatment should be
tailored to the patient’s needs. Patient risk factors
should be identified prior to treatment, and the
IVIG product should be chosen to optimise efficacy
and convenience, while minimising the risk of
adverse effects.

Table 6: Intravenous human normal immunoglobulin IVIG

formulation properties of concern in patients with various risk factors7

Formulation properties

high high sorbitol/

high sugar
osmolality/ sodium volume load IgA low pH fructose
Patient risk factors content
osmolarity content content

Renal impairment P P P P P
Cardiovascular disease P P P
Thromboembolic disorders P P P
Obesity
P
Immobility
P
Older age P P P P
Pre(diabetes) mellitus Pa
Pediatric age P P P P
IgA deficiency with anti-IgA antibodies P
Hereditary fructose intolerance P
a Glucose-containing solutions.

Adapted from Cherin, 2010

21
Intratect® | Tolerability

Intratect®5% - Summary of tolerability1

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 tolerability.
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.

The majority of these ADRs were mild to moderate and self-limiting.

No serious ADRs were observed during the studies.

Frequencies have been evaluated according to the following convention: very common (≥1/10); common
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000);
not known (cannot be estimated from the available data).

MedDRA Adverse reaction Frequency Frequency

System Organ Class (MedDRA preferred based on infusions based on patients
(SOC) term (PT)) administered (n=830) treated (n=92)

Blood and lymphatic Haemolysis (mild) Uncommon Common

system disorders

Nervous system Headache Common Very Common

disorders
Dysgeusia Uncommon Common

Vascular disorders Hypertension, throm- Uncommon Common

bophlebitis superficial

Gastrointestinal Nausea, vomiting, Uncommon Common

disorders gastrointestinal pain

Skin and subcutane- Papular rash Uncommon Common

ous tissue disorders

General disorders and Pyrexia Common Very common

administration site
conditions Chills, feeling hot Uncommon Common

Investigations Body temperature

increased, Coombs
test (indirect and
direct) positive

22
 Intratect® | Tolerability

Intratect®10% - Summary of tolerability1

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 tolerability

These 30 patients received a total of 165 infusions of Intratect 100 g/l, whereof a total of 19 infusions
(11.5%) were associated with adverse drug reactions (ADRs).

The majority of these ADRs were mild to moderate and self-limiting.

No serious ADRs were observed during the studies.

Frequencies have been evaluated according to the following convention: very common (≥1/10); common
(≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000);
not known (cannot be estimated from the available data).

MedDRA Adverse reaction Frequency Frequency

System Organ Class (MedDRA preferred based on infusions based on patients
(SOC) term (PT)) administered (n=165) treated (n=30)

Immune system Infusion related Common Common

disorders reaction
Hypersensitivity Uncommon Common

Nervous system Headache Common Common

disorders
Sensory disturbance Uncommon Common

Cardiac Disorders Palpitations Common Common

Vascular disorders Hyperaemia, Uncommon Common

hypertension

Gastrointestinal Diarrhoea, Uncommon Common

disorders abdominal pain
Skin and Pain of skin, rash Uncommon Common
subcutaneous tissue
disorders
Musculoskeletal and Arthralgia, back pain, Common Common
connective tissue bone pain
disorders
Myalgia Uncommon Common

General disorders and Discomfort Common Very Common

administration site
conditions Fatigue, chills, Uncommon Uncommon
hypothermia

Rarely normal human immunoglobulins;

• can result in sudden drop in blood pressure and in isolated cases may cause an anaphylactic shock
• may cause thromboembolic reactions, reversible aseptic meningitis or haemolytic reactions

23
Intratect® | List of abbreviations

List of abbreviations
BW Bodyweight

CVID Common variable immunodeficiency

EMA European Medicines Agency

HAV Hepatitis A virus

HBV Hepatitis B virus

HCV Hepatitis C virus

HIV Human immunodeficiency virus

IVIG Intravenous immunoglobulin G

CPP Cryo-poor (depleted) plasma

NAPTT non-activated partial thromboplastin time

NAT Nucleic acid amplification technique

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

PID Primary immunodeficiency disease

PKA Prekallikrein activator

TGT Thrombin generation test

vCJD Variant form of Creutzfeldt-Jakob disease

24
 Intratect® | Bibliography

References
1. Intratect® Summary of Product Characteristics

2. Bauhofer A. at al.: Safety monitoring of the intravenous immunoglobulin preparation Intratect® in

primary and secondary immunodefi ciencies: a prospective non-interventional study. International
Journal of Clinical Pharmacology and Therapeutics. 2015. 53: 21-31

3. UK Data on file 2.3.S Drug Substance REF 00207

4. Meulenbroek, A.J. Human IgG subclasses: useful diagnostic markers for immunocompetence, 2008
ISBN 90-5267-011-0

5. UK data on file 2.3.A Appendices. REF 00206

6. Quality Standards of Excellence, Assurance and Leadership (QSEAL).Available at www.pptaglobal.org/

safety-quality/standards/qseal Accessed July 2018

7. Cherin P, Cabane J: Relevant Criteria for Selecting an Intravenous Immunoglobulin Preparation for
Clinical Use. Biodrugs 2010; 24 (4): 211-223

8. Data on File Plasma master file REF 00210

9. Data on file 2.3.S Drug substance pages 61 & 65 REF 00238

10. Funk et al. Thromboembolic events associated with immunoglobulin treatment. Vox Sang. 2013; 105,
54-64

11. König H, Etscheid M: Untersuchungen zur Thrombogenität von therapeutischen immunglobulinen

BfArM/PEI Bull. Arzneimittelsicherheit (2011) 2: 22–25

12. UK Data on file Biotest summarising report 2012 REF00237

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 Human normal immunoglobulin for intravenous adminstration
monograph 01/2012:0918

15. Grundmann C et al.: Modified thrombin generation assay: application to the analysis of immunoglobulin
concentrates WebmedCentral Immunother. (2010): 1(11):WMC001116

16. Voges-Haas R et al. Manufacturing Process of Intratect efficaciously eliminates thrombogenic potential.
WebmedCentral Immunotherapy 2014; 5 (1): WMC004514

17. Krivan G et al: An open, prospective trial investigating the pharmacokinetics and safety, and the
tolerability of escalating infusion rates of a 10% human normal immunoglobulin for intravenous
infusion (IVIg), BT090, in patients with primary immunodeficiency disease. Vox Sang. (2015) doi:
10.1111/vox.12275

18. Immunoglobulin substitution for prevention and treatment of infections in patients with
immunodeficiency syndromes. Biometric Report Interim Analysis. November 2013

19. Bellac CL et al.:The role of isoagglutinins in intravenous immunoglobulin–related hemolysis. Transfusion

(2015) 55 (Suppl.): S13 -S22
25
Notes

26
Notes

27
Abbreviated Prescribing Information
Intratect® 50 g/l and 100 g/l Human normal immunoglobulin solution for intravenous infusion
Please consult full Summary of Product Characteristics (SmPC) before prescribing
Intratect is a solution containing either 50 g/l or 100 g/l human
normal immunoglobulin (IVIg), purity at least 96% IgG. Intratect
50 g/l 20 ml vial contains 1 g, 50 ml vial 2.5 g; 100 ml vial 5 g and
200 ml vial 10 g of IVIg. Intratect 100 g/l 10ml vial contains 1 g, 25
ml vial 2.5 g, 50 ml vial 5 g, 100 ml vial 10 g and 200 ml vial 20 g
of IVIg. Indications and dosing: Replacement therapy in adults and
children (0-18 years) in: Primary immunodeficiency syndromes with
impaired antibody production, starting dose 0.4-0.8 g/kg once,
thereafter 0.2-0.8 g/kg every 3-4 weeks; 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. The
recommended dose is 0.2-0.4 g/kg every three to four weeks. The
dose regimen should achieve a trough level of IgG of at least 5 -6 g/l.
Immunomodulation in adults and children (0-18 years) in: Primary
immune thrombocytopenia, in patients at high risk of bleeding or
prior to surgery to correct the platelet count, there are two alternative
treatment schedules: 0.8-1 g/kg given on day one, this dose may be
repeated once within 3 days or, 0.4 g/kg given daily for two to five
days. The treatment can be repeated if relapse occurs. Guillain Barré
syndrome: 0.4 g/kg/day over 5 days. Kawasaki disease: 1.6- 2.0 g/kg
should be administered in divided doses over two to five days or
2.0 g/kg as a single dose, concomitantly with acetylsalicylic acid.
The dose and infusion rate may need to be individualised for each
patient dependent on the pharmacokinetic and clinical response,
but initially infusion rate not more than 1.4 ml/kg/h for 30 minutes
which can be increased gradually up to 1.9 ml/kg/h for remainder
of infusion if well tolerated. In replacement therapy with Intractect
100 g/l, if patients have tolerated the infusion rate of 1.9 ml/kg/h
well, the rate may be gradually increased to 6 ml/kg/h and if still well
tolerated then further increased gradually to a maximum of 8 ml/
kg/h. Contraindications and precautions: Hypersensitivity to human
immunoglobulins especially in patient with antibodies against IgA,
or to any excipients. Certain adverse reactions occur more frequently
with high infusion rates, when a patient is IVIg naïve, or, in rare cases
when human normal immunoglobulin product is switched or after
Adverse events should be reported. Reporting forms and information can be found at www.mhra.gov.uk/yellowcard or
search MHRA Yellow Card in the Google Play or Apple App Store. Adverse events should also be reported to Biotest (UK)
Ltd. on 0121 733 3393 or medicinesinformation.uk@biotest.com.
Biotest (U.K.) Ltd.,
First Floor, Park Point, Phone: +44 (0) 121 733 3393
17 High Street, Longbridge, Fax: +44 (0) 121 7333 3066
Birmingham, email: sales.UK@biotest.com
West Midlands B31 2UQ website: www.biotestuk.com
long interval since previous infusion. These can often be avoided
by initially injecting slowly, to ensure patient is not sensitive and
carefully monitoring for symptoms during and for at least 20 minutes
after infusion (1 hour for those at risk of more frequent adverse
reactions as noted). In all patients adequate hydration, monitoring
of urine output and creatinine levels and avoidance of loop diuretics
is required. Caution in patients who are obese or with pre-existing
risk factors for thrombotic events, risk factors for acute renal failure,
aseptic meningitis syndrome (AMS) or haemolytic anaemia. Refer to
SmPC for all special warnings and precautions. Undesirable effects:
Frequency of adverse events varies with indication and strength and
include: pyrexia, infusion related reaction, palpitations, arthralgia,
back or bone pain, myalgia, discomfort, chills, feeling hot, raised body
temperature, headache, abdominal pain, dizziness, fever, nausea,
vomiting, allergic reactions, papular rash, skin pain, mild haemolysis,
low or high blood pressure, dysgeusia, thrombophlebitis superficial,
indirect and direct Coombs test positive, sensory disturbance,
hyperaemia, diarrhoea, fatigue, hypothermia. Rarely normal human
immunoglobulins can result in sudden drop in blood pressure and
in isolated cases may cause an anaphylactic shock. May also rarely
cause thromboembolic reactions, reversible aseptic meningitis or
haemolytic reactions. Please refer to SmPC for further details of
frequency of adverse events by indication and strength of product
used. Shelf life: 3 years. Do not store above 25°C. Do not freeze. NHS
list price: £45/g. Legal category: POM. MA number: Intratect® 50 g/l
PL 04500/0005; 100 g/l PL 04500/0013 MA holder: Biotest Pharma
GmbH. Landsteinerstrasse 5, 63303 Dreieich, Germany. Revision of
prescribing information: May 2018.
Further information can be obtained from
Biotest (UK) Ltd.
First Floor, Park Point,
17 High Street,
Longbridge,
Birmingham,
West Midlands B31 2UQ.
Phone: +44 (0) 121 733 3393
Fax: +44 (0) 121 7333 3066.
email: medicinesinformation.uk@biotest.com
website www.biotestuk.com