ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Privigen 100 mg/ml solution for infusion
2.
Human normal immunoglobulin (IVIg).
One ml contains:
human plasma protein ................................................................................................................. 100 mg
(purity of at least 98% IgG)
One vial of 25 ml contains: 2.5 g
One vial of 50 ml contains: 5 g
One vial of 100 ml contains: 10 g
One vial of 200 ml contains: 20 g
Distribution of the IgG subclasses (average values):
IgG
1
.................... 67.8%
IgG
2
.................... 28.7%
IgG
3
...................... 2.3%
IgG
4
...................... 1.2%
The maximum IgA content is 0.025 mg/ml.
For a full list of excipients, see section 6.1.
3.
Solution for infusion.
The solution is clear or slightly opalescent and colourless to pale yellow.
Privigen is isotonic, with an osmolality of 320 mOsmol/kg.
4.
Replacement therapy in
•
Primary immunodeficiency (PID) syndromes such as:
–
–
congenital agammaglobulinaemia and hypogammaglobulinaemia
–
severe combined immunodeficiency
–
Wiskott Aldrich syndrome
•
Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia
and recurrent infections.
•
Children with congenital AIDS and recurrent infections.
Immunomodulation
•
Immune thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior
to surgery to correct the platelet count.
•
Guillain-Barré syndrome.
•
Kawasaki disease.
2
common variable immunodeficiency
Allogeneic bone marrow transplantation
Posology
The dose and dosage regimen is dependent on the indication.
In replacement therapy the dosage may need to be individualised for each patient depending on the
pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.
Replacement therapy in primary immunodeficiency syndromes
The dosage regimen should achieve a trough IgG level (measured before the next infusion) of at least
4 to 6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur.
The recommended starting dose is 0.4 to 0.8 g/kg body weight (bw) followed by at least 0.2 g/kg bw
every three weeks.
The dose required to achieve a trough level of 6 g/l is of the order of 0.2 to 0.8 g/kg bw/month. The
dosage interval when steady state has been reached varies from two to four weeks.
Trough levels should be measured in order to adjust the dose and dosage interval.
Replacement therapy in myeloma or chronic lymphocytic leukaemia with severe secondary
hypogammaglobulinaemia and recurrent infections; replacement therapy in children with AIDS and
recurrent infections
The recommended dose is 0.2 to 0.4 g/kg bw every three to four weeks.
Immune thrombocytopenic purpura
For the treatment of an acute episode, 0.8 to 1 g/kg bw on day one, which may be repeated once within
three days, or 0.4 g/kg bw daily for two to five days. The treatment can be repeated if relapse occurs.
Guillain-Barré syndrome
0.4 g/kg bw/day for three to seven days.
Experience in children is limited.
Kawasaki disease
1.6 to 2.0 g/kg bw should be administered in divided doses over two to five days or 2.0 g/kg bw as a
single dose.
Patients should receive concomitant treatment with acetylsalicylic acid.
Allogeneic bone marrow transplantation:
Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after
the transplantation.
For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually
tailored. The starting dose is normally 0.5 g/kg bw/week, starting seven days before transplantation
and continued for up to three months after the transplantation.
In case of persistent lack of antibody production, a dose of 0.5 g/kg bw/month is recommended until
antibody levels return to normal.
The dosage recommendations are summarised in the following table:
3
Indication
Dose
Frequency of injections
Replacement therapy
–
in primary immunodeficiency
starting dose:
0.4–0.8 g/kg bw
thereafter:
0.2–0.8 g/kg bw
0.2–0.4 g/kg bw
every two to four weeks to obtain
IgG trough levels of at least 4–6 g/l
–
in secondary immunodeficiency
every three to four weeks to obtain
IgG trough levels of at least 4–6 g/l
0.2–0.4 g/kg bw
–
Children with AIDS
every three to four weeks
Immunomodulation
0.8–1 g/kg bw
or
0.4 g/kg bw/d
0.4 g/kg bw/d
1.6–2 g/kg bw
–
Immune thrombocytopenic purpura
on day one, possibly repeated once
within three days
for two to five days
–
Guillain-Barré syndrome
for three to seven days
–
Kawasaki disease
in divided doses over two to
five days in association with
acetylsalicylic acid
or
2 g/kg bw
in one dose in association with
acetylsalicylic acid
Allogeneic bone marrow transplantation
0.5 g/kg bw
–
treatment of infections and prophylaxis
of graft versus host disease
every week from seven days before
up to three months after
transplantation
–
persistent lack of antibody production
0.5 g/kg bw
every month until antibody levels
return to normal
Method of administration
Human normal immunoglobulin should be infused intravenously. The initial infusion rate is 0.3 ml/kg
bw/hr. If well tolerated, the rate of administration may gradually be increased to 4.8 ml/kg bw/hr.
In PID patients who have tolerated the infusion rate of 4.8 ml/kg bw/hr well, the rate may be further
increased gradually to a maximum of 7.2 ml/kg bw/hr.
If dilution prior to infusion is desired, Privigen may be diluted with 5% glucose solution to a final
concentration of 50 mg/ml (5%). For instruction, see section 6.6.
Hypersensitivity to the active substance or to any of the excipients.
Hypersensitivity to homologous immunoglobulins, especially in the very rare cases of IgA deficiency
when the patient has antibodies against IgA.
4
Patients with hyperprolinaemia.
Certain severe adverse drug reactions may be related to the rate of infusion. The recommended
infusion rate given under section 4.2 "Method of administration" must be followed closely. 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 with hypo- or agammaglobulinaemia with or without IgA deficiency,
–
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.
True hypersensitivity reactions are rare. They can occur in the very rare cases of IgA deficiency with
anti-IgA antibodies.
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.
Potential complications can often be avoided by ensuring that patients:
–
are not sensitive to human normal immunoglobulin by initially infusing the product slowly
(0.3 ml/kg bw/hr);
–
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 one hour after, in order to detect potential adverse signs. All other patients
should be observed for at least twenty minutes after administration.
Haemolytic anaemia
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo
coating of red blood cells (RBC) with immunoglobulin, causing a positive direct antiglobulin reaction
(Coomb’s test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy
due to enhanced RBC sequestration. IVIg recipients should be monitored for clinical signs and
symptoms of haemolysis (see also Section 4.8).
There is clinical evidence of an association between IVIg administration and thromboembolic events
such as myocardial infarction, 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 and patients with diseases which increase blood viscosity).
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk
factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia,
being overweight, concomitant nephrotoxic medicinal products or age over 65.
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, 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 sucrose may be considered. Privigen does not contain sucrose or other sugars.
5
In patients at risk of acute renal failure or thromboembolic adverse reactions, IVIg products should be
administered at the minimum rate of infusion and dose practicable.
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.
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 side effect.
In case of shock, standard medical treatment for shock should be implemented.
For patients suffering from diabetes mellitus and requiring dilution of Privigen to lower
concentrations, the presence of glucose in the recommended diluent should be taken into account.
Information on safety with respect to 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, and
for the non-enveloped viruses HAV and B19V.
There is reassuring clinical experience regarding the lack of hepatitis A or B19V 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 Privigen 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.
6
Live attenuated virus vaccines
Immunoglobulin administration may impair the efficacy of live attenuated virus vaccines such as
measles, mumps, rubella and varicella for a period of at least six weeks and up to three months. After
administration of this product, an interval of three months should elapse before vaccination with live
attenuated virus vaccines. In the case of measles, this impairment may persist for up to one year.
Therefore patients receiving measles vaccine should have their antibody status checked.
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 allo-antibodies (e.g. Coombs test).
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. 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.
Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies
to the neonate.
No effects on ability to drive and use machines have been observed.
With human normal immunoglobulin for intravenous administration, adverse reactions such as chills,
headache, 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
and deep vein thromboses.
Three clinical studies with Privigen were performed, two in patients with primary immunodeficiency
(PID) and one in patients with immune thrombocytopenic purpura (ITP). In the pivotal PID study 80
subjects were enrolled and treated with Privigen. Of these, 72 completed the twelve months of
treatment. In the PID extension study 55 subjects were enrolled and treated with Privigen. The ITP
study was performed in 57 patients.
7
Most adverse drug reactions (ADRs) observed in the three clinical studies were mild to moderate in
nature.
The ADRs reported in the three studies are summarised and categorised according to the MedDRA
System organ class and frequency below. Frequency per infusion has been evaluated using the
following criteria: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1 000 to
<1/100).
Within each frequency grouping, undesirable effects are presented in order of decreasing severity.
Frequency of Adverse Drug Reactions (ADRs) in clinical studies with Privigen
MedDRA System Organ
Class
MedDRA preferred term
ADR
frequency
category
Investigations
Bilirubin conjugated increased, blood bilirubin
unconjugated increased, Coombs direct test
positive, Coombs test positive, blood lactate
dehydrogenase increased, haematocrit decreased,
alanine aminotransferase increased, aspartate
aminotransferase increased, blood creatinine
increased, blood pressure decreased, blood
pressure increased, body temperature increased,
haemoglobin decreased
Uncommon
Cardiac disorders
Palpitations
Uncommon
Blood and lymphatic
system disorders
Anaemia, anisocytosis
Uncommon
Nervous system disorders Headache
Very common
Dizziness, head discomfort, somnolence, tremor,
sinus headache
Uncommon
Respiratory, thoracic and
mediastinal disorders
Dyspnoea, oropharyngeal blistering, painful
respiration, throat tightness
Uncommon
Gastrointestinal disorders Vomiting, nausea
Common
Diarrhoea, abdominal pain upper
Uncommon
Renal and urinary
disorders
Proteinuria
Uncommon
Skin and subcutaneous
tissue disorders
Pruritus, skin disorder, night sweats, urticaria
Uncommon
Musculoskeletal and
connective tissue
disorders
Back pain
Common
Neck pain, pain in extremity, musculoskeletal
stiffness, muscle spasms, musculoskeletal pain,
myalgia
Uncommon
Vascular disorders
Flushing, hypertension, hypotension
Uncommon
General disorders and
administration site
conditions
Chills, fatigue, pyrexia
Common
Chest pain, general symptom, asthenia, influenza
like illness, hyperthermia, pain, injection site pain
Uncommon
Hepatobiliary disorders
Hyperbilirubinaemia
Uncommon
For safety with respect to transmissible agents, see section 4.4.
8
elderly patients or patients with renal impairment.
5.
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 1,000 donors. 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.
The mechanism of action in indications other than replacement therapy is not fully elucidated, but
includes immunomodulatory effects.
The safety and efficacy of Privigen was evaluated in three prospective, open-label, single-arm,
multicenter studies performed in Europe (ITP and PID studies) and the USA (PID study).
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, equilibrium between the intra- and extravascular compartments is reached after
approximately three to five days.
The pharmacokinetic parameters for Privigen were determined in a clinical study in PID patients (see
section 5.1). Twenty-five patients (aged 13 to 69 years) participated in the pharmacokinetic (PK)
assessment. In this study, the median half-life of Privigen in primary immunodeficiency patients was
36.6 days. In an extension of this study, thirteen PID patients (aged 3 to 65 years) participated in a PK
sub-study. The results of this study show the median half-life of Privigen to be 31.1 days (see table
below). The half-life may vary from patient to patient, particularly in primary immunodeficiency.
Pharmacokinetic parameters of Privigen in PID patients
Extension Study (N=13)
ZLB05_006CR
Median (Range)
C
max
(peak, g/l) 23.4 (10.4-34.6) 26.3 (20.9-32.9)
C
min
(trough, g/l) 10.2 (5.8-14.7) 12.3 (10.4-18.8) (3-week schedule)
9.4 (7.3-13.2) (4-week schedule)
t
½
(days) 36.6 (20.6-96.6) 31.1 (14.6-43.6)
C
max
, maximum serum concentration; C
min,
trough (minimum level) serum concentration; t
½
,
elimination half-life
Pivotal Study (N= 25)
ZLB03_002CR
Median (Range)
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
5.3 Preclinical safety data
9
Parameter
Immunoglobulins are a normal constituent of the human body. L-proline is a physiological, non-
essential amino acid.
The safety of Privigen has been assessed in several preclinical studies, with particular reference to the
excipient L-proline. Some published studies pertaining to hyperprolinaemia have shown that long-
term, high doses of L-proline have effects on brain development in very young rats. However, in
studies where the dosing was designed to reflect the clinical indications for Privigen, no effects on
brain development were observed.
Non-clinical data reveal no special risk for humans based on safety
pharmacology and toxicity studies.
6.
6.1 List of excipients
L-proline
Water for injections
6.2 Incompatibilities
This medicinal product must not be mixed with other medicinal products except those mentioned in
section 6.6.
6.3 Shelf life
3 years
If the product is diluted to lower concentrations (see section 6.6), immediate use after dilution is
recommended. The in-use stability of Privigen after dilution with a 5% glucose solution to a final
concentration of 50 mg/ml (5%) has been demonstrated for 10 days at 30°C; however, the microbial
contamination aspect was not studied.
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
25 ml of solution in a single vial (type I glass), with a stopper (elastomeric), a cap (aluminium crimp),
a flip off disc (plastic), label with integrated hanger.
50 or 100 ml of solution in a single vial (type I or II glass), with a stopper (elastomeric), a cap
(aluminium crimp), a flip off disc (plastic), label with integrated hanger.
200 ml of solution in a single vial (type II glass), with a stopper (elastomeric), a cap (aluminium
crimp), a flip off disc (plastic), label with integrated hanger.
Pack sizes:
1 vial (2.5 g/25 ml, 5 g/50 ml, 10 g/100 ml or 20 g/200 ml),
3 vials (10 g/100 ml or 20 g/200 ml).
Not all pack sizes may be marketed.
10
6.6 Special precautions for disposal and other handling
Privigen comes as a ready-for-use solution in single-use vials. The product should be at room or body
temperature before use. A vented infusion line should be used for the administration of Privigen.
Always pierce the stopper at its centre, within the marked area.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have
particulate matter.
If dilution is desired, 5 % glucose solution should be used. For obtaining an immunoglobulin solution
of 50 mg/ml (5%), Privigen 100 mg/ml (10%) should be diluted with an equal volume of the 5%
glucose solution. Aseptic technique must be strictly observed during the dilution of Privigen.
Once the vial has been entered under aseptic conditions, its contents should be used promptly. Because
the solution contains no preservative, Privigen should be infused as soon as possible.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
CSL Behring GmbH
Emil-von-Behring-Strasse 76
D-35041 Marburg
Germany
8.
EU/1/08/446/001
EU/1/08/446/002
EU/1/08/446/003
EU/1/08/446/004
EU/1/08/446/005
EU/1/08/446/006
9.
25 April 2008
Detailed information on this product is available on the website of the European Medicines Agency:
http://www.ema.europa.eu/
11
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDERS RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
12
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDERS RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer(s) of the biological active substance(s)
CSL Behring AG
Wankdorfstrasse 10, 3000 Bern 22
Switzerland
Name and address of the manufacturer(s) responsible for batch release
CSL Behring GmbH
Emil-von-Behring-Strasse 76
D-35041 Marburg
Germany
The printed package leaflet of the medicinal product must state the name and address of the
manufacturer responsible for the release of the concerned batch.
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to medical prescription.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 1.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and
whilst the product is on the market.
Risk Management Plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in
the Pharmacovigilance Plan, as agreed in version 1.3 of the Risk Management Plan (RMP) presented
in Module 1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP
agreed by the CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report
(PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being
reached
•
At the request of the European Medicines Agency
Official batch release: in accordance with Article 114 Directive 2001/83/EC as amended, the official
batch release will be undertaken by a state laboratory or a laboratory designated for that purpose.
13
14
ANNEX III
LABELLING AND PACKAGE LEAFLET
15
A. LABELLING
16
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER BOX
1.
Privigen 100 mg/ml solution for infusion
Human normal immunoglobulin (IVIg)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains:
Human plasma protein.............100 mg
IgG purity ................................. ≥ 98%
IgA ..................................... ≤ 0.025 mg
2.5 g/25 ml
5 g/50 ml
10 g/100 ml
20 g/200 ml
Will be placed in the upper right corner of the main face of the box to give total content and volume of
the container
3.
LIST OF EXCIPIENTS
Excipients: L-proline, water for injections.
4.
Solution for infusion (10%)
Contains 1 vial.
Contains 3 vials.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
17
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
Do not store above 25 °C.
Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Marketing authorisation holder:
CSL Behring GmbH
D-35041 Marburg
Germany
EU/1/08/446/001 5 g/50 ml
EU/1/08/446/002 10 g/100 ml
EU/1/08/446/003 20 g/200 ml
EU/1/08/446/004 2.5 g/25 ml
EU/1/08/446/005 10 g/100 ml (3 vial pack size)
EU/1/08/446/006 20 g/200 ml (3 vial pack size)
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
18
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL
1.
Privigen 100 mg/ml solution for infusion
Human normal immunoglobulin (IVIg)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains:
Human plasma protein 100 mg. IgG purity ≥ 98%. IgA ≤ 0.025 mg.
2.5 g/25 ml
5 g/50 ml
10 g/100 ml
20 g/200 ml
Will be placed in the upper right corner of the label to give total content and volume of the container
3.
LIST OF EXCIPIENTS
L-proline, water for injections.
4.
Solution for infusion (10%)
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use only.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
19
Do not store above 25 °C. Do not freeze.
Keep the vial in the outer carton in order to protect from light.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
CSL Behring GmbH, D-35041 Marburg, Germany
EU/1/08/446/001 5 g/50 ml
EU/1/08/446/002 10 g/100 ml
EU/1/08/446/003 20 g/200 ml
EU/1/08/446/004 2.5 g/25 ml
EU/1/08/446/005 10 g/100 ml (3 vial pack size)
EU/1/08/446/006 20 g/200 ml (3 vial pack size)
13. BATCH NUMBER
LOT
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Justification for not including Braille accepted.
20
B. PACKAGE LEAFLET
21
PACKAGE LEAFLET: INFORMATION FOR THE USER
Privigen 100 mg/ml (10%) solution for infusion
Human normal immunoglobulin (IVIg)
Read all of this leaflet carefully before you start using this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or health care professional.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or health care professional.
In this leaflet:
1. What Privigen is and what it is used for
2. Before you receive Privigen
3. How to use Privigen
4. Possible side effects
5. How to store Privigen
6. Furtherinformation
1. WHAT PRIVIGEN IS AND WHAT IT IS USED FOR
What Privigen is
Privigen is a ready-to-use solution for infusion. The solution contains special proteins, isolated from
human blood plasma. These proteins belong to the class of "immunoglobulins", also called antibodies.
How Privigen works
Antibodies are usually produced by our immune system and help the body to fight infections. Certain
diseases can cause severe disturbance of the immune system. Because of this, you may not have
enough of your own antibodies or you may need additional antibodies. The antibodies which are given
to you by Privigen can complement your own antibodies or substitute missing antibodies. The
antibodies in Privigen are isolated from human blood plasma. Therefore they work exactly as if they
were your own antibodies.
Privigen can also reduce the symptoms in certain inflammatory disorders. In these cases Privigen is
regulating the malfunctioning immune system. However, these effects are not fully understood.
What Privigen is used for
Privigen is used in three different situations:
A) Treatment of patients with too few antibodies (replacement therapy). There are three groups:
1.
Patients with an inborn lack of antibodies (primary immunodeficiency syndromes (PID))
such as:
●
●
congenital agammaglobulinaemia or hypogammaglobulinaemia,
●
severe combined immunodeficiency,
●
Wiskott Aldrich syndrome.
2.
Patients with certain kinds of blood cancer which lead to a lack of antibody production
and recurrent infections such as:
●
myeloma,
●
chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia.
22
common variable immunodeficiency,
3.
Children who suffer from inborn AIDS (Acquired Immunodeficiency Syndrome) and
recurrent infections.
B)
Treatment of patients with certain inflammatory disorders (immunomodulation). There are three
groups:
1.
Patients who do not have enough blood platelets (immune thrombocytopenic purpura
(ITP)) and
●
who are at high risk of bleeding,
2.
Patients with Guillain-Barré syndrome. This is an acute disease that is characterised by
inflammation of the peripheral nerves that causes severe muscle weakness mainly in the
legs and upper limbs.
will have a surgery in the near future.
3.
Patients with Kawasaki disease. This is an acute disease of primarily young children
characterised by an inflammation of the blood vessels throughout the body.
C)
Treatment or prevention of infections after a bone marrow transplantation (allogeneic bone
marrow transplantation).
2. BEFORE YOU RECEIVE PRIVIGEN
Î
Please read this section carefully. The information given should be taken into consideration by
you and your doctor before you receive Privigen.
Privigen must not be used
► If you are allergic (hypersensitive)
● to human immunoglobulins,
● to any other ingredient of Privigen (for a complete list of ingredients see section 6 of this
leaflet).
Î
Please tell your doctor or health care professional prior to treatment about any medicine
or food which you have not well tolerated earlier.
► If you have antibodies against immunoglobulins of the type IgA in your blood.
This is very rare and may occur if you do not have enough immunoglobulins of the type IgA in
your blood.
Î
Please tell your doctor or health care professional prior to treatment if you have an
immunoglobulin type IgA deficiency.
► If you have too much of the amino acid proline in your blood (hyperprolinaemia). This is an
extremely rare disorder. Only a few families with this disease are known worldwide.
Î
Please tell your doctor or health care professional prior to treatment if you have too much
proline in your blood.
Take special care with Privigen
►
The risk of having certain side effects
may be increased in the following circumstances:
●
you are overweight,
●
you have diabetes,
●
you have been bedridden for a longer time,
●
you have or have already had problems with your blood vessels (vascular diseases or
blockage of a vessel),
●
you have or have already had kidney problems,
●
you have a high blood pressure,
●
you suffer from a disease which causes your blood to thicken,
●
you suffer from an increased tendency for blood clotting (thrombophilia),
23
●
●
you are elderly,
●
you blood volume is too low (hypovolaemia),
● you suffer from a condition that causes low antibody levels in your blood
(hypogammaglobulinaemia or agammaglobulinaemia),
● you suffer from a kidney disease,
● you are taking medicines that can damage your kidneys (nephrotoxic medicines),
● you are receiving Privigen for the first time or after a long break in treatment (e.g. several
months).
Î
Please tell your doctor or health care professional prior to treatment if at least one of these
circumstances applies to you. Your doctor will then choose the right intravenous
immunoglobulin for you and will take special precautions.
Î
Although Privigen does not contain sugar, it may be diluted with a special sugar solution
(5% glucose), which could affect your blood sugar level.
► You may be
allergic (hypersensitive) to immunoglobulins (antibodies) without knowing it
.
This may occur even if you have previously received human immunoglobulins and had tolerated
them well. It may happen particularly if you do not have enough immunoglobulins of the type
IgA in your blood. In these rare cases
allergic reactions
such as a
sudden fall in blood
pressure
or
shock
may occur.
Î
If you
notice such reactions
during the infusion of Privigen,
please tell your doctor
immediately
. He will decide whether to slow down the infusion rate or whether to abort
the infusion completely.
For your personal safety the treatment with Privigen will take place under the supervision of your
doctor or health care professional. You will usually be observed during the whole infusion and for at
least 20 minutes thereafter. In certain circumstances, special precautions may be necessary. Examples
of such circumstances are:
● you are receiving Privigen at a high infusion rate
or
● you are receiving Privigen for the first time or after a long break in treatment (e.g. several
months).
In these cases you will be closely observed during the whole infusion and for at least 1 hour thereafter.
Information on the starting material of Privigen
Privigen is made from human blood plasma (this is the liquid part of the blood).
When medicines are made from human blood or plasma, certain measures are put in place to prevent
infections being passed on to patients. These include
● careful selection of blood and plasma donors to make sure those at risk of carrying infections
are excluded,
and
● the testing of each donation and pools of plasma for signs of virus/infections.
Manufacturers of these products also include steps in the processing of the blood or plasma that can
inactivate or remove viruses. Despite these measures, when medicines prepared from human blood or
plasma are administered, the possibility of passing on infection cannot be totally excluded. This also
applies to any unknown or emerging viruses and other types of infections.
The measures taken are considered effective for enveloped viruses such as human immunodeficiency
virus (HIV), hepatitis B virus and hepatitis C virus, and for the non-enveloped hepatitis A and B19
viruses.
Immunoglobulins like Privigen have not been associated with hepatitis A or B19 infections. This is
possibly because antibodies against these infections are also present in immunoglobulins. These
antibodies may help prevent hepatitis A or B19 infections.
► It is strongly recommended that every time you receive a dose of Privigen
the name and batch
number of the product are recorded
in order to maintain a record of the batches used.
Taking Privigen with other medicines
Î
Please tell your doctor or health care professional prior to treatment
●
24
if you are currently taking any other medicines or
● if you have recently taken any other medicines.
This also includes non-prescription medicines.
Vaccinations
After receiving Privigen, the efficacy of certain vaccinations may be impaired. Affected are
vaccinations with live attenuated virus vaccines such as vaccinations against measles, mumps, rubella
and varicella. Such vaccinations should be postponed for at least 3 months after the last infusion of
Privigen. In the case of measles vaccinations the impairment may persist for up to one year. Therefore
your vaccinating doctor should check the efficacy of the measles vaccination.
Î
Please tell your vaccinating doctor prior to a vaccination about your treatment with Privigen.
Blood tests
After receiving Privigen, the results of certain blood tests (serological tests) may be impaired for a
certain time.
Î
Please tell your doctor about your treatment with Privigen prior to any blood test.
Pregnancy and breast-feeding
Î
Please tell your doctor or health care professional if you are pregnant or breast-feeding. Your
doctor will decide whether you can receive Privigen during your pregnancy or while you are
breast-feeding.
The use of Privigen in pregnant or breast-feeding women has not been studied separately.
Nevertheless, medicines containing antibodies have been used in pregnant or breast-feeding women.
The long-time experience showed that no harmful effects on the course of the pregnancy or the
newborn are to be expected.
If you receive Privigen while you are breast-feeding the antibodies in this medicine will also be found
in the breast milk. Thus also your baby can receive the protecting antibodies.
Driving and using machines
No effects of Privigen on the ability to drive and use machines are expected.
3.
HOW TO USE PRIVIGEN
► Privigen is usually administered by your doctor or health care professional.
► Privigen is intended solely for the infusion into a vein (intravenous infusion).
► Your doctor decides how much Privigen you will receive. The amount depends on your illness,
your present condition and your body weight.
► At the beginning of the infusion you will receive Privigen at a slow infusion rate. If you tolerate
this well your doctor can gradually increase the infusion rate.
If you receive more Privigen than you should
Privigen is usually administered under medical supervision only. Overdose is therefore very unlikely
to occur. If, in spite of this, you receive more Privigen than you should, your blood may become too
thick (hyperviscous). This may happen particularly if you are a patient at risk, for example if you are
elderly or if you suffer from a kidney disease.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Privigen can cause side effects, although not everybody gets them.
25
► You may be allergic (hypersensitive) to immunoglobulins (antibodies) and
allergic reactions
such as a
sudden fall in blood pressure
or
shock
may occur.
Î
If you
notice such reactions
during the infusion of Privigen,
please tell your doctor
immediately
.
Please see also section 2 of this leaflet about the risk of allergic reactions.
► Possible side effects may be reduced or even avoided by infusing Privigen at a slow infusion
rate.
The general experience with immunoglobulin preparations showed that the following side effects may
occur:
●
headache,
●
chills,
●
vomiting,
●
mild hypersensitivity reactions (allergic reactions),
●
nausea,
●
pain in the joints (arthralgia),
●
low blood pressure,
●
moderate low back pain.
In rare and isolated cases, the following side effects have also been reported with immunoglobulin
preparations:
●
temporary non-infectious meningitis (reversible aseptic meningitis),
●
transient skin reactions,
●
increase in blood creatinine level,
●
sudden fall in blood pressure,
●
severe hypersensitivity reactions (anaphylactic shock), even when you have shown no
hypersensitivity on previous infusions,
●
formation of blood clots which may be carried off in the blood circulation (thromboembolic
reactions) and which may result e.g. in:
–
myocardial infarction,
–
lung vein blockage (pulmonary embolism),
–
deep vein thrombosis,
●
transient decrease of red blood cells (reversible haemolytic anaemia/haemolysis).
Three clinical studies with Privigen were conducted. In these studies the following side effects have
been observed.
The following side effects were
common
(in more than
1 in 100
, but less than
1 in 10
infusions):
●
headache,
●
vomiting,
●
upset stomach (nausea),
●
back pain,
●
chills,
●
tiredness (fatigue),
●
fever.
The following side effects were
uncommon
(in more than
1 in 1000
, but less than
1 in 100
infusions):
●
abnormal awareness of heartbeat,
●
temporary lowering of red blood cell count,
●
irregularity of red blood cell shape (microscopic finding),
26
●
fever,
●
acute renal failure,
–
stroke,
●
dizziness,
●
head discomfort,
●
sleepiness,
●
shiver (tremor),
●
breathlessness,
●
blisters in mouth and throat,
●
painful breathing,
●
throat tightness,
●
diarrhoea,
●
upper stomach pain,
●
protein in the urine (on testing),
●
itching,
●
skin disorder,
●
night sweats,
●
hives / rash,
●
pain (including neck pain, pain in extremity, chest pain, muscle pain, pain and stiffness of
muscles and bones)
●
muscle spasms,
●
flushing,
●
high or low blood pressure,
●
weakness,
●
flu-like illness,
●
injection site pain,
●
mild jaundice.
Routine laboratory tests may uncommonly reveal changes to liver or kidney functions as well as
changes in blood count.
Such side effects may occur even when you have previously received human immunoglobulins
(antibodies) and had tolerated them well.
Î
Please tell your doctor or health care professional
●
if any of the side effects gets serious or
●
if you notice any side effects not listed in this leaflet.
5.
HOW TO STORE PRIVIGEN
► Keep out of the reach and sight of children.
Do not use Privigen after the expiry date which is stated on the outer carton and the vial label after
EXP. The expiry date refers to the last day of that month.
► Do not store above 25 °C.
► Do not freeze.
► Keep the vial in the outer carton in order to protect from light.
Do not use Privigen if you notice that the solution is cloudy or has particles.
6.
FURTHER INFORMATION
What Privigen contains
27
●
The
active substance
is human normal immunoglobulin (antibodies of the type IgG). Privigen
contains 100 mg/ml (10%) human protein of which at least 98% is IgG.
●
The
other ingredients
are the amino acid L-proline and water for injections.
What Privigen looks like and contents of the pack
Privigen is presented as a solution for infusion.
The solution is clear or slightly opalescent and colourless to pale-yellow.
Pack sizes:
1 vial (2.5 g/25 ml, 5 g/50 ml, 10 g/100 ml or 20 g/200 ml),
3 vials (10 g/100 ml or 20 g/200 ml).
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
CSL Behring GmbH
Emil-von-Behring-Strasse 76
D-35041 Marburg
Germany
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
CSL Behring NV
Technologielaan 13
B-3001 Leuven
Tél/Tel: +32 16 38 80 80
Luxembourg/Luxemburg
CSL Behring NV
Technologielaan 13
B-3001 Leuven, Belgique/Belgien
Tél/Tel: +32 16 38 80 80
България
Новимед ООД
Манастирски ливади 114, Евроцентър
1404, София, България
Тел: +359 2 958 84 68
Magyarország
Plazmed Kft.
Fő u. 200
H-2193 Galgahévíz
Tel.: +36 28 59 10 00
Česká republika
IBP medica s.r.o.
Pod Karlovem 8/1670
CZ 120 00 Praha 2
Tel: +42 02 22 56 07 23
Malta
AM Mangion Ltd.
Mangion Buildings
New Street in Valletta Road
MT-LQA 6000 Luqa
Tel: +356 2397 6333
Danmark
CSL Behring ApS
Lyngby Hovedgade 70B, 1.tv
DK-2800 Kgs. Lyngby
Tlf: +45 4520 1420
Nederland
CSL Behring BV
Claudius Prinsenlaan 128
NL-4818 CP Breda
Tel: + 31 76 523 6045
28
Deutschland
CSL Behring GmbH
Philipp-Reis-Strasse 2
D-65795 Hattersheim
Tel: +49 69 30584437
Norge
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd, Sverige
Tlf: +46 8 544 966 70
Eesti
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd, Rootsi
Tel: +46 8 544 966 70
Österreich
CSL Behring GmbH
Altmannsdorfer Strasse 104
A-1121 Wien
Tel: +43 1 80101 2463
Ελλάδα
CSL Behring ΜΕΠΕ
Χατζηγιάννη Μέξη 5
GR-115 28 Αθήνα
Τηλ: +30 210 7255 660
Polska
Imed Poland sp. z.o.o.
Ul. Puławska 314
PL-02-819 Warszawa
Tel.: +48 22 663 43 10
España
CSL Behring S.A.
Av. Països Catalans, 34, 3
a
E-08950 Esplugues de Llobregat (Barcelona)
Tel: +34 933 67 1870
Portugal
CSL Behring Lda
Av. 5 de Outubro, 198 – 3º Esq.
P-1050-064 Lisboa
Tel: +351 21 782 62 30
France
CSL Behring SA
30 rue Cambronne
F-75015 Paris
Tél: + 33 1 53 58 54 00
România
Nicofarma DCI SRL
Strada Tepeş Voda 79
Sector 2
Bucureşti 021522-RO
Tel: +40 21 327 2614
Ireland
CSL Behring UK Ltd.
Hayworth House, Market Place
Haywards Heath,
West Sussex RH16 1DB – UK
Tel: +44 1444 447400
Slovenija
MediSanus d.o.o.
Vagajeva ulica 4
SI-1000 Ljubljana
Tel: +386 1 25 71 496
Ísland
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd, Svíþjóð
Sími: +46 8 544 966 70
Slovenská republika
TIMED, s.r.o.
Trnavská cesta 112
SK-821 01 Bratislava
Tel: +421 2 4820 95 11
Italia
CSL Behring S.p.A.
Viale Del Ghisallo, 20
I-20151 Milano
Tel: +39 02 34964 200
Suomi/Finland
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd, Ruotsi/Sverige
Puh/Tel: +46 8 544 966 70
Κύπρος
ΑΚΗΣ ΠΑΝΑΓΙΩΤΟΥ & ΥΙΟΣ ΛΤΔ
Γ. Κρανιδιώτη 4
CY-1522 Λευκωσία
Τηλ: +357 22677038
Sverige
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd
Tel: +46 8 544 966 70
29
Latvija
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd, Zviedrija
Tel: +46 8 544 966 70
United Kingdom
CSL Behring UK Ltd.
Hayworth House, Market Place
Haywards Heath,
West Sussex RH16 1DB – UK
Tel: +44 1444 447400
Lietuva
CSL Behring AB
P.O.Box 712
S-182 17 Danderyd, Švedija
Tel: +46 8 544 966 70
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu/.
--------------------------------------------------------------------------------------------------------------------------
The following information is intended for healthcare professionals only:
The dosage recommendations are summarised in the following table:
30
Indication
Dose
Frequency of injections
Replacement therapy
–
in primary immunodeficiency
starting dose:
0.4–0.8 g/kg bw
thereafter:
0.2–0.8 g/kg bw
0.2–0.4 g/kg bw
every two to four weeks to obtain
IgG trough levels of at least 4–6 g/l
–
in secondary immunodeficiency
every three to four weeks to obtain
IgG trough levels of at least 4–6 g/l
0.2–0.4 g/kg bw
–
Children with AIDS
every three to four weeks
Immunomodulation
0.8–1 g/kg bw
or
0.4 g/kg bw/d
0.4 g/kg bw/d
1.6–2 g/kg bw
–
Immune thrombocytopenic purpura
on day one, possibly repeated once
within three days
for two to five days
–
Guillain-Barré syndrome
for three to seven days
–
Kawasaki disease
in divided doses over two to
five days in association with
acetylsalicylic acid
or
2 g/kg bw
in one dose in association with
acetylsalicylic acid
Allogeneic bone marrow transplantation
0.5 g/kg bw
–
treatment of infections and prophylaxis
of graft versus host disease
every week from seven days before
up to three months after
transplantation
–
persistent lack of antibody production
0.5 g/kg bw
every month until antibody levels
return to normal
Method of administration
•
Human normal immunoglobulin should be infused intravenously. The initial infusion rate is
0.3 ml/kg bw/hr. If well tolerated, the rate of administration may gradually be increased to
4.8 ml/kg bw/hr.
•
In PID patients who have tolerated the infusion rate of 4.8 ml/kg bw/hr well, the rate may be
further increased gradually to a maximum of 7.2 ml/kg bw/hr.
•
If dilution prior to infusion is desired, Privigen may be diluted with 5% glucose solution to a final
concentration of 50 mg/ml (5%).
Special precautions
•
In case of adverse reaction, either the rate of administration must be reduced or the infusion
stopped.
•
It is strongly recommended that every time Privigen 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.
Incompatibilities
31
This medicinal product must not be mixed with other medicinal products
Special precautions for disposal and other handling
•
The product should be at room or body temperature before use. A vented infusion line should be
used for the administration of Privigen. Always pierce the stopper at its centre, within the marked
area.
•
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have
particulate matter.
•
If dilution is desired, 5% glucose solution is recommended. For obtaining an immunoglobulin
solution of 50 mg/ml (5%), Privigen 100mg/ml (10%) should be diluted with an equal volume of
the glucose solution. Aseptic technique must be strictly observed during the dilution of Privigen.
•
Once the vial has been entered under aseptic conditions, its contents should be used promptly.
Because the solution contains no preservative, Privigen should be infused as soon as possible.
•
Any unused product or waste material should be disposed of in accordance with local
requirements.
32
Source: European Medicines Agency
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