ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Flebogamma DIF 50 mg/ml solution for infusion
2.
One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG.
The percentage of IgG subclasses is approximately 66.6% IgG
1
, 28.5% IgG
2
, 2.7% IgG
3
and
2.2% IgG
4
. It contains trace amounts of IgA (lower than 0.05 mg/ml).
Excipient:
One ml contains 50 mg of D-sorbitol.
For a full list of excipients, see section 6.1.
3.
Solution for infusion.
The solution is clear or slightly opalescent and colourless or pale yellow.
4.
4.1. Therapeuticindications
Flebogamma DIF is indicated for:
Replacement therapy in:
Primary immunodeficiency syndromes such as:
-
congenital agammaglobulinaemia and hypogammaglobulinaemia
-
common variable immunodeficiency
-
severe combined immunodeficiency
Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and
recurrent infections.
Children with congenital AIDS and recurrent infections.
Immunomodulation
Idiopathic 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.
Allogeneic bone marrow transplantation.
- 2 -
-
Wiskott Aldrich syndrome
Posology
The dose and dosage regimen is dependent on the indication.
In replacement therapy the dosage may need to be individualised for each patient dependent 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 level of IgG (measured before the next infusion) of at
least 4 - 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 - 0.8 g/kg followed by at least 0.2 g/kg every three weeks.
The dose required to achieve a trough level of 6 g/l is of the order of 0.2 - 0.8 g/kg/month. The dosage
interval when steady state has been reached varies from 2 - 4 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 - 0.4 g/kg every three to four weeks.
Idiopathic thrombocytopenic purpura
For the treatment of an acute episode, 0.8 - 1 g/kg on day one, which may be repeated once within
3 days, or 0.4 g/kg daily for two to five days. The treatment can be repeated if relapse occurs.
Guillain Barré syndrome
0.4 g/kg/day for 3 to 7 days.
Experience in children is limited.
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.
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 transplant.
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/week, starting seven days before transplantation and
for up to 3 months after transplantation.
In case of persistent lack of antibody production, dosage of 0.5 g/kg/month is recommended until
antibody level returns to normal.
- 3 -
The dosage recommendations are summarised in the following table:
Indication
Dose
Frequency
Replacement therapy in primary
immunodeficiency
- starting dose:
0.4 - 0.8 g/kg
- thereafter:
0.2 - 0.8 g/kg
0.2 - 0.4 g/kg
every 2 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
Replacement therapy in secondary
immunodeficiency
every 3 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
0.2 - 0.4 g/kg
Children with AIDS
every 3 - 4 weeks
Immunomodulation:
0.8 - 1 g/kg
or
0.4 g/kg/d
0.4
g/kg/d
1.6 - 2 g/kg
or
2 g/kg
Idiopathic thrombocytopenic purpura
on day 1, possibly repeated once
within 3 days
for 2 - 5 days
Guillain Barré syndrome
for 3 - 7 days
Kawasaki disease
in several doses for 2 - 5 days in
association with acetylsalicylic acid
in one dose in association with
acetylsalicylic acid
Allogeneic bone marrow transplantation:
0.5 g/kg
-
treatment of infections and prophylaxis
of graft versus host disease
every week from day -7 up to 3
months after transplantation
0.5 g/kg
-
persistent lack of antibody production
every month until antibody levels
return to normal
Method of administration
Flebogamma DIF should be infused intravenously at an initial rate of 0.01 - 0.02 ml/kg/min for the
first thirty minutes. If well tolerated, the rate of administration may gradually be increased to a
maximum of 0.1 ml/kg/min.
Hypersensitivity to any of the components (see section 4.4).
Hypersensitivity to homologous immunoglobulins, especially in very rare cases of IgA deficiency,
when the patient has antibodies against IgA.
Fructose intolerance (see section 4.4).
Certain severe adverse drug reactions may be related to the rate of infusion. The recommended
Patients must be closely monitored and carefully observed for any symptoms throughout the infusion
period.
- 4 -
Certain adverse reactions may occur more frequently
-
in case of high rate of infusion,
-
in patients who receive human normal immunoglobulin for the first time, or in rare cases, when
the human normal immunoglobulin product is switched or when there has been a long interval
since the previous infusion.
True hypersensitivity reactions are rare. They can occur in the very seldom 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 first injecting the product
slowly at an initial rate of 0.01 - 0.02 ml/kg/min;
-
that patients are carefully monitored for any symptoms throughout the infusion period. In
particular, patients naive to human normal immunoglobulin, patients switched from an
alternative IVIg product or when there has been a long interval since the previous infusion
should be monitored during the first infusion and for the first hour after the first infusion, in
order to detect potential adverse signs. All other patients should be observed for at least
20 minutes after administration.
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 hypovolemic 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, hypovolemia,
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.
In patients at risk for 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
-
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.
- 5 -
-
in patients with hypo- or agammaglobulinaemia with or without IgA deficiency,
-
monitoring of serum creatinine levels
In case of shock, standard medical treatment for shock should be implemented.
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 parvovirus B19.
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19
transmission with immunoglobulins and it is also assumed that the antibody content makes an
important contribution to viral safety.
It is strongly recommended that every time Flebogamma DIF 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.
Special warnings about excipients: This medicinal product contains 50 mg of sorbitol per ml as
excipient. Patients with rare hereditary problems of fructose intolerance should not take this medicine.
In babies and young children hereditary fructose intolerance may not yet be diagnosed and may
be fatal, thus, they should not receive sorbitol-containing solutions
.
In other patients in case of inadvertent application and suspicion of fructose intolerance the infusion
has to be stopped immediately, normal glycemia has to be re-established and organ function has to be
stabilized by means of intensive care.
Interferences with determination of blood glucose levels are not expected.
Live attenuated virus vaccines
Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the
efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After
administration of this product, an interval of 3 months should elapse before vaccination with live
attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year.
Therefore patients receiving measles vaccine should have their antibody status checked.
Interference with serological testing
After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in
the patients blood may result in misleading positive results in serological testing.
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some
serological tests for red cell antibodies, for example the antiglobulin test (Coomb’s 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.
- 6 -
Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies
to the neonate.
No studies on the effects on the ability to drive and use machines have been performed.
Since Flebogamma DIF might induce dizziness, patients should be cautioned when driving or
operating machines.
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, isolated cases of reversible haemolytic anaemia/haemolysis and
rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin.
Increase in serum creatinine level and/or acute renal failure have been observed.
Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism,
deep vein thromboses.
Two multicenter clinical trials were performed, one of them in children and adults with primary
immune deficiency and the second one in patients with chronic immune thrombocytopenic purpura in
acute phase. Forty-six patients were included in the first trial and 41 completed the study. They were
followed during 1 year of treatment at a dose of 300-600 mg/kg every 3 to 4 weeks. A total of
20 patients were included in the second study. Patients received a total dose of 400 mg/kg body weight
for 5 consecutive days and were followed for 3 months. Therefore, a total of 66 patients have been
exposed to Flebogamma DIF and they have received 806 infusions. Data from both studies indicate a
good tolerability of the product as incidence of adverse events was low and most of them were mild to
moderate in intensity
.
Of the 806 infusions administered in patients enrolled in both studies 10.8% (1-sided 95% CI upper
bound =
12.9%) were associated with an adverse event suspected to be related to the product. No
patients died, only 6 patients withdrew from the studies but none of them because of potentially
related adverse events. Four patients experienced 8 serious adverse events that were considered not
related to the study medicinal product. Pyrexia and headache were the most frequently reported
adverse events potentially related to the medicinal product in both studies.
The adverse drug reactions reported in the 2 trials by at least the 5% of the patients are summarised
and categorised according to the MedDRA system organ class in the table below:
Frequency has been determined using the following criteria:
-
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.)
Within each frequency grouping, undesirable effects are presented in order of decreasing of
seriousness.
- 7 -
System Organ Class
Body System Preferred Term
ADR frequency
evaluation
Investigations
Coombs test positive, blood pressure
systolic decreased, blood pressure
systolic increased, body temperature
increased
Uncommon
Nervous system disorder
Headache
Common
Dizziness
Uncommon
Respiratory, thoracic and
mediastinal disorder
Bronchitis, cough, wheezing
Uncommon
Gastrointestinal disorders
Diarrhoea, nausea, vomiting, abdominal
pain, abdominal pain upper
Uncommon
Skin and subcutaneous tissue
disorders
Urticaria, rash pruritic, dermatitis
contact
Uncommon
Musculoskeletal and
connective tissue disorder
Back pain, arthralgia, myalgia, muscle
cramp
Uncommon
Vascular disorders
Hypotension, hypertension, diastolic
hypertension, blood pressure
fluctuations
Uncommon
General disorders &
administration site conditions
Pyrexia, injection site reaction
Common
Rigors, asthenia, pain, infusion site
inflammation, injection site oedema,
injection site pain, injection site
pruritus, injection site swelling,
migration of implant
Uncommon
For safety with respect to transmissible agents, see section 4.4.
Overdose may lead to fluid overload and hyper viscosity, particularly in patients at risk, including
elderly patients or patients with renal impairment.
5.1. Pharmacodynamicproperties
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for
intravascular administration, ATC code: J06BA02.
Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of
antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is
usually prepared from pooled plasma from not fewer than 1000 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.
- 8 -
The mechanism of action in indications other than replacement therapy is not fully elucidated, but
includes immunomodulatory effects. A significant increase in median platelet levels was achieved in a
clinical trial in chronic ITP patients (64,000/µl) although it did not reach normal levels.
Two clinical trials were performed with Flebogamma DIF, one for replacement therapy in patients
with primary immunodeficiency (both in adults and in children above 10 years) and another for
immunomodulation in adults patients with immune thrombocytopenic purpura.
5.2. Pharmacokineticproperties
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s
circulation after intravenous administration. It is distributed relatively rapidly between plasma and
extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and
extravascular compartments.
Flebogamma DIF has a half-life of about 30-32 days. This half-life may vary from patient to patient,
in particular in primary immunodeficiency.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
5.3. Preclinical safety data
Single dose toxicity studies were carried out in rats and mice. The absence of mortality in the
non-clinical studies performed with Flebogamma DIF with dosages up to 2500 mg/kg, and the lack of
any confirmed relevant adverse sign affecting respiratory, circulatory and central nervous system, of
the treated animals supports the safety of Flebogamma DIF.
Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to induction of,
and interference with antibodies. Effects of the product on the immune system of the newborn have
not been studied.
6.
6.1. List of excipients
D-sorbitol
Water for injections
6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products or intravenous fluids. It
should be administered by a separate intravenous line.
6.3. Shelflife
2 years.
6.4. Special precautions for storage
Do not store above 30 ºC.
Do not freeze.
- 9 -
6.5. Nature and contents of container
10 ml, 50 ml, 100 ml, 200 ml or 400 ml solution in a vial (type II glass) with stopper (chloro-butyl-
rubber).
Pack size: 1 vial
Not all pack sizes may be marketed.
6.6. Specialprecautions
for disposal and other handling
The product should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have
deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
EU/1/07/404/001-005
23/08/2007
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu
.
- 10 -
1.
Flebogamma DIF 100 mg/ml solution for infusion
2.
Human normal immunoglobulin (IVIg)
One ml contains:
Human normal immunoglobulin …………..100 mg
(purity of at least 97% IgG)
One vial of 50 ml contains: 5 g of human normal immunoglobulin
One vial of 100 ml contains: 10 g of human normal immunoglobulin
One vial of 200 ml contains: 20 g of human normal immunoglobulin
Distribution of the IgG subclasses (approx. values):
IgG
1
66.6%
IgG
2
27.9%
IgG
3
3.0%
IgG
4
2.5%
The maximum IgA content is 100 micrograms/ml.
Produced from the plasma of human donors.
Excipients:
One ml contains 50 mg of D-Sorbitol.
For a full list of excipients, see section 6.1.
3.
Solution for infusion
The solution is clear or slightly opalescent and colourless or pale yellow.
Flebogamma DIF is isotonic, with an osmolality from 240 to 370 mOsm/kg.
4.
4.1. Therapeuticindications
Replacement therapy in adults, children and adolescents (0-18 years) in:
-
Primary immunodeficiency syndromes with impaired antibody production.
-
Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic
lymphocytic luekaemia, in whom prophylactic antibiotics have failed.
-
Hypogammaglobulinemia and recurrent bacterial infections in plateau phase multiple myeloma
patients who failed to respond to pneumococcal immunisation.
-
Hypogammaglobulinaemia in patients after allogenic haematopoietic stem cell transplantation
(HSCT).
- 11 -
Replacement therapy in children and adolescents (0-18 years) in:
-
Congenital AIDS with recurrent bacterial infections.
Immunomodulation in adults, children and adolescents (0-18 years) in:
-
Idiopathic Thrombocytopenic Purpura (ITP), in patients at high risk of bleeding or prior to
surgery to correct the platelet count.
-
Guillain Barré syndrome.
-
Kawasaki disease.
Posology
The dose and posology is dependent on the indication.
In replacement therapy the dose may need to be individualised for each patient dependent on the
pharmacokinetic and clinical response. The following dose regimens are given as a guideline.
Replacement therapy in primary immunodeficiency syndromes
The dose should achieve a trough level of IgG (measured before the next infusion) of at least 4 - 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 - 0.8 g/kg followed by at least 0.2 g/kg/month given in divided
doses every three to four weeks.
The dose required to achieve a trough level of 6 g/l is of the order of 0.2 - 0.8 g/kg/month. The dose
interval when steady state has been reached varies from 3 - 4 weeks.
Trough levels should be measured and assessed in conjuction with the incidence of infection. To
reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough
levels (>6-9 g/l).
Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic
lekaemia, in whom prophylactic antibiotics have falied; hypogammaglobulinaemia and recurrent
bacterial infections in plateau phase multiple myeloma patients who have failed to respond to
pneumococcal immunisation; children and adolescents with congenital AIDS and recurrent bacterial
infections
The recommended dose is 0.2 - 0.4 g/kg every three to four weeks.
Hypogammaglobulinaemia in patients after allogenic haematopoietic stem cell transplantation
The recommended dose is 0.2-0.4 g/kg every three to four weeks. The trough levels should be
maintained above 5 g/l.
Idiopathic Thrombocytopenic Purpura
For the treatment of an acute episode, 0.8 - 1 g/kg on day one, which may be repeated once within
3 days, or 0.4 g/kg daily for two to five days. The treatment can be repeated if relapse occurs.
- 12 -
Guillain Barré syndrome
0.4 g/kg/day for 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. Patients should receive concomitant treatment with acetylsalicylic acid.
The dose recommendations are summarised in the following table:
Indication
Dose
Frequency
Replacement therapy in primary
immunodeficiency
- starting dose:
0.4 - 0.8 g/kg
- thereafter:
0.2 - 0.8 g/kg
0.2 - 0.4 g/kg
every 3 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
Replacement therapy in secondary
immunodeficiency
every 3 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
0.2 - 0.4 g/kg
0.2-0.4 g/kg
Children and adolescents with AIDS
every 3 - 4 weeks
Hypogammaglobulinaemia (< 4 g/l) in
patients after allogeneic haematopoietic stem
cell transplantation
every 3 - 4 weeks
Immunomodulation:
0.8 - 1 g/kg
or
0.4 g/kg/d
0.4
g/kg/d
1.6 - 2 g/kg
or
2 g/kg
Idiopathic Thrombocytopenic Purpura
on day 1, possibly repeated once
within 3 days
for 2 - 5 days
Guillain Barré syndrome
for 5 days
Kawasaki disease
in several doses for 2 - 5 days in
association with acetylsalicylic acid
in one dose in association with
acetylsalicylic acid
Paediatric population
See above
See above
Paediatric population
The safety and efficacy of Flebogamma DIF in children and adolescents aged 3 to 16
years have been
established in 3 primary immunodeficient patients and in 9 patients with immune thrombocytopenic
purpura.
The safety and efficacy of Flebogamma DIF in children aged 0 to 2 years have not been established in
clinical trials.
As the posology for each indication is given by body weight and adjusted to the clinical outcome of
the above mentioned conditions, the posology in children is not considered to be different to that of
adults.
- 13 -
Method of administration
Flebogamma DIF should be infused intravenously at an initial rate of 0.01 ml/kg/min for the first
thirty minutes. If tolerated, advance to 0.02 ml/kg/min for the second 30 minutes. Again, if tolerated,
advance to 0.04 ml/kg/min for the third 30 minutes. If the patient tolerates the infusion well, additional
increments of 0.02 ml/kg/min may be made at 30-minute intervals up to a maximum of
0.08 ml/kg/min.
It has been reported that the frequency of adverse reactions to IVIg increases with the infusion rate.
Infusion rates during the initial infusions should be slow. If there are no adverse reactions, the infusion
rate for subsequent infusions can be slowly increased to the maximum rate. For patients experiencing
adverse reactions, it is advisable to reduce the infusion rate in subsequent infusions and limit the
maximum rate to 0.04 ml/kg/min or administer IVIg at a 5% concentration (see section 4.4).
Hypersensitivity to the active substance or to any of the excipients (see section 4.4).
Hypersensitivity to human immunoglobulins, especially in very rare cases of IgA deficiency, when the
patient has antibodies against IgA.
Hereditary fructose intolerance (see section 4.4).
Sorbitol
Each ml of this medicinal product contains 50 mg of sorbitol. Patients with rare hereditary
problems of fructose intolerance must not take this medicine.
In case of inadvertent application and suspicion of hereditary fructose intolerance the infusion
has to be stopped immediately, normal glycaemia has to be re-established and organ function
has to be stabilized by means of intensive care.
Interferences with determination of blood glucose levels are not expected.
Paediatric population
In babies and young children hereditary fructose intolerance may not yet be diagnosed and may
be fatal, thus, they should not receive this medicinal product.
Infusion rate
Certain severe adverse reactions to the medicinal product may be related to the rate of infusion. The
recommended infusion rate given under section 4.2 must be closely followed. Patients must be closely
monitored and carefully observed for any symptoms throughout the infusion period.
Certain adverse reactions may occur more frequently
-
in case of high rate of infusion
-
in patients who receive human normal immunoglobulin for the first time, or in rare cases, when
the human normal immunoglobulin product is switched or when there has been a long interval
since the previous infusion.
Potential complications can often be avoided by ensuring that patients:
-
are not sensitive to human normal immunoglobulin by first injecting the product slowly at an
initial rate of 0.01 ml/kg/min;
- 14 -
-
in patients with hypo- or agammaglobulinaemia with or without IgA deficiency
-
are carefully monitored for any symptoms throughout the infusion period. In particular, patients
naive to human normal immunoglobulin, patients switched from an alternative IVIg product or
when there has been a long interval since the previous infusion should be monitored during the
first infusion and for the first hour after the first infusion, in order to detect potential adverse
signs. All other patients should be observed for at least 20 minutes after administration.
In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped.
The treatment required depends on the nature and severity of the adverse reactions.
In case of shock, standard medical treatment for shock should be implemented.
In all patients, IVIg administration requires:
-
adequate hydration prior to the initiation of the infusion of IVIg
-
monitoring of urine output
-
monitoring of serum creatinine levels
-
avoidance of concomitant use of loop diuretics
Hypersensitivity
True hypersensitivity reactions are rare. They can occur in the very seldom 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.
Thromboembolism
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 hypovolemic patients, and patients with diseases which increase blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the
minimum rate of infusion and dose practicable.
Acute renal failure
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk
factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolemia,
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 an excipient 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. Flebogamma DIF does not contain sucrose.
In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of
infusion and dose practicable.
- 15 -
Haemolytic anaemia
IVIg products can contain blood group antibodies which may act as haemolysins and induce
in vivo
coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction
(Coomb’s test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy
due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical
signs and symptoms of haemolysis.
Interference with serological testing
After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in
the patient’s blood may result in misleading positive results in serological testing.
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D, may interfere with some
serological tests for red cell antibodies, for example the antiglobulin test (Coomb’s test).
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from
human blood or plasma include selection of donors, screening of individual donations and plasma
pools for specific markers of infection and the inclusion of effective manufacturing steps for the
inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or
plasma are administered, the possibility of transmitting infective agents cannot be totally excluded.
This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV, and
for the non-enveloped viruses HAV and parvovirus B19.
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19
transmission with immunoglobulins and it is also assumed that the antibody content makes an
important contribution to viral safety.
It is strongly recommended that every time Flebogamma DIF 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.
Live attenuated virus vaccines
Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the
efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After
administration of this product, an interval of 3 months should elapse before vaccination with live
attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year.
Therefore patients receiving measles vaccine should have their antibody status checked.
Paediatric population
It is expected that the same interactions than those mentioned for the adults may be presented by the
paediatric population.
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been established in controlled
clinical trials and therefore should only be given with caution to pregnant women and breast-feeding
- 16 -
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.
Breast-feeding
Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies
to the neonate.
Fertility
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be
expected.
The ability to drive and operate machines may be impaired by some adverse reactions, such as
dizziness, associated with Flebogamma DIF. Patients who experience adverse reactions during
treatment should wait for these to resolve before driving or operating machines.
Summary of the safety profile
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, isolated cases of reversible haemolytic anaemia/haemolysis and
rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin.
Increase in serum creatinine level and/or acute renal failure have been observed.
Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism,
deep vein thromboses.
For safety with respect to transmissible agents, see section 4.4.
Tabulated summary of adverse reactions
Increase in the frequency of adverse reactions through the clinical trials likely related to the increased
infusion rate has been observed (see section 4.2).
The adverse reactions categorised according to the MedDRA system organ class reported in any
patient in the 3 trials are summarised in the table below. Frequency of each adverse reaction has been
determined using the following criteria:
-
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)
Within each frequency grouping, adverse reactions are presented in order of decreasing of seriousness.
- 17 -
System Organ Class
Body System Preferred Term
ADR frequency
evaluation
Infections and infestations
Influenza, urinary tract infection
Uncommon
Blood and lymphatic system
disorders
Bicytopenia, leukopenia
Uncommon
Metabolism and nutrition
disorders
Anorexia
Uncommon
Nervous system disorders
Headache
Very common
Dizziness, radicular syndrome, syncope
vasovagal, tremor
Uncommon
Eye disorders
Conjunctivitis, maculopathy,
photophobia
Uncommon
Ear and labyrinth disorders
Ear pain, vertigo
Uncommon
Cardiac disorders
Tachycardia
Common
Vascular disorders
Hypotension
Common
Diastolyc hypertension, flushing,
hematoma, hypertension, systolic
hypertension, thrombosis
Uncommon
Respiratory, thoracic and
mediastinal disorders
Postnasal drip, sinus pain, wheezing
Uncommon
Gastrointestinal disorders
Nausea
Common
Abdominal distension, abdominal pain,
abdominal pain upper, diarrhoea,
flatulence, vomiting
Uncommon
Skin and subcutaneous tissue
disorders
Acne, ecchymosis, erythema, pruritus,
rash
Uncommon
Musculoskeletal and
connective tissue disorders
Back pain, myalgia,
Common
Arthralgia, muscle spasms, muscle
tightness, neck pain, pain in extremity
Uncommon
General disorders and
administration site conditions
Pain, pyrexia, rigors
Common
Chest discomfort, chest pain, chills,
fatigue, feeling cold, feeling jittery,
influenza like illness, infusion related
reaction, infusion site erythema,
infusion site pain, infusion site reaction,
malaise, peripheral oedema
Uncommon
Investigations
Body temperature increased
Common
Blood pressure diastolic decreased,
blood pressure increased, blood
pressure systolic increased,
haemoglobin decreased, heart rate
increased
Uncommon
Paediatric population
The safety results for 3 paediatric patients (those 16 years old) included in the PID study and the
results for the 9 children (aged 3 to 15) included in the ITP study appeared to be generally similar to
those for the overall patient population.
Overdose may lead to fluid overload and hyper viscosity, particularly in patients at risk, including
elderly patients or patients with renal impairment.
- 18 -
Paediatric population
Information on overdose in children has not been established with Flebogamma DIF. However, as in
adult population, overdose may lead to fluid overload and hyperviscosity as with any other
intravenous immunoglobulins.
5.1. Pharmacodynamicproperties
Pharmacotherapeutic group: Immune Sera and Immunoglobulins: immunoglobulins, normal human,
for intravascular administration; ATC code: J06BA02
Human normal immunoglobulin contains mainly immunoglobulin G (IgG) with a broad spectrum of
antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is
usually prepared from pooled plasma from not fewer than 1000 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.
5.2. Pharmacokineticproperties
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s
circulation after intravenous administration. It is distributed relatively rapidly between plasma and
extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and
extravascular compartments.
Flebogamma DIF has a half-life of about 34-37 days. This half-life may vary from patient to patient,
in particular in primary immunodeficiency.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
Paediatric population
No differences of the pharmacokinetic properties are expected in the paediatric population.
5.3. Preclinical safety data
Single dose toxicity studies were carried out in rats and mice. The absence of mortality in the
non-clinical studies performed with Flebogamma DIF with doses up to 2,500 mg/kg, and the lack of
any confirmed relevant adverse sign affecting respiratory, circulatory and central nervous system, of
the treated animals supports the safety of Flebogamma DIF.
Repeated dose toxicity testing and embryo-foetal toxicity studies are impracticable due to induction of,
and interference with antibodies. Effects of the product on the immune system of the newborn have
not been studied.
- 19 -
6.
6.1. List of excipients
D-sorbitol
Water for injections
6.2. Incompatibilities
This medicinal product must not be mixed with other medicinal products or intravenous fluids. It
should be administered by a separate intravenous line.
6.3. Shelflife
2 years.
6.4. Special precautions for storage
Do not store above 30 ºC.
Do not freeze.
6.5. Nature and contents of container
50 ml, 100 ml or 200 ml solution in a vial (type II glass) with stopper (chloro-butyl-rubber).
Pack size: 1 vial
Not all pack sizes may be marketed.
6.6. Specialprecautions
for disposal and other handling
The product should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent. Do not use solutions that are cloudy or have
deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
7.
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
Detailed information on this product is available on the website of the European Medicines Agency
- 20 -
ANNEX II
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
- 21 -
A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND
MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
Instituto Grifols, S.A.
Polígono Levante
Can Guasch, 2,
E-08150 Parets del Vallès
Barcelona, Spain
Name and address of the manufacturer responsible for batch release
Instituto Grifols, S.A.
Polígono Levante
Can Guasch, 2
E-08150 Parets del Vallès
Barcelona, Spain
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 3.0 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 pharmacovigilance activities detailed in the Pharmacovigilance
Plan, as agreed in version 4.3 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, an
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.
- 22 -
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.
- 23 -
ANNEX III
LABELLING AND PACKAGE LEAFLET
- 24 -
A. LABELLING
- 25 -
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
(0.5 g, 2.5 g, 5 g, 10 g and 20 g)
1.
Flebogamma DIF 50 mg/ml solution for infusion
Human normal immunoglobulin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG.
3.
LIST OF EXCIPIENTS
D-sorbitol, water for injections.
4.
Solution for infusion.
0.5 g / 10 ml
2.5 g / 50 ml
5 g / 100 ml
10 g / 200 ml
20 g / 400 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use.
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
- 26 -
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30 ºC. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
EU/1/07/404/001
EU/1/07/404/002
EU/1/07/404/003
EU/1/07/404/004
EU/1/07/404/005
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
- 27 -
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL LABEL
(2.5 g, 5 g, 10 g and 20 g)
1.
Flebogamma DIF 50 mg/ml solution for infusion
Human normal immunoglobulin
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 50 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG.
3.
LIST OF EXCIPIENTS
D-
s
orbitol
, water for injections.
4.
Solution for infusion
2.5 g / 50 ml
5 g / 100 ml
10 g / 200 ml
20 g / 400 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use
Read the package leaflet before use.
To hang pull here
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
- 28 -
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30 ºC. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
EU/1/07/404/002
EU/1/07/404/003
EU/1/07/404/004
EU/1/07/404/005
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
- 29 -
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL LABEL
(0.5 g)
1.
Flebogamma DIF 50 mg/ml solution for infusion
Human normal immunoglobulin
For intravenous use
2.
METHOD OF ADMINISTRATION
Read the package leaflet before use.
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
0.5 g / 10 ml
6.
OTHER
- 30 -
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON
(5 g, 10 g and 20 g)
1.
Flebogamma DIF 100 mg/ml solution for infusion
Human normal immunoglobulin (IVIg)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 100 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG.
The maximum IgA content is 100 micrograms/ml.
3.
LIST OF EXCIPIENTS
D-sorbitol, water for injections. See leaflet for further information.
4.
Solution for infusion
5 g / 50 ml
10 g / 100 ml
20 g / 200 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For intravenous use
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
- 31 -
9.
SPECIAL STORAGE CONDITIONS
Do not store above 30 ºC. Do not freeze.
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused product or waste material should be disposed of in accordance with local requirements.
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
EU/1/XX/XXX/XXX
EU/1/XX/XXX/XXX
EU/1/XX/XXX/XXX
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
- 32 -
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL LABEL
(5 g)
1.
Flebogamma DIF 100 mg/ml solution for infusion
Human normal immunoglobulin (IVIg)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
3.
LIST OF EXCIPIENTS
4.
Solution for infusion
5 g / 50 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
To hang pull here
For intravenous use
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT
OF THE REACH AND SIGHT OF CHILDREN
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
- 33 -
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
- 34 -
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING
VIAL LABEL
(10 g and 20 g)
1.
Flebogamma DIF 100 mg/ml solution for infusion
Human normal immunoglobulin (IVIg)
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One ml contains 100 mg of human normal immunoglobulin (IVIg) of which at least 97% is IgG.
3.
LIST OF EXCIPIENTS
D-
s
orbitol, water for injections.
4.
Solution for infusion
10 g / 100 ml
20 g / 200 ml
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
To hang pull here
For intravenous use
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
Do not store above 30 ºC. Do not freeze.
- 35 -
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
- 36 -
B. PACKAGE LEAFLET
- 37 -
PACKAGE LEAFLET: INFORMATION FOR THE USER
Flebogamma DIF 50 mg/ml 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 pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
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 pharmacist.
In this leaflet
:
1.
What Flebogamma DIF is and what it is used for
2.
Before you use Flebogamma DIF
3.
How to use Flebogamma DIF
5.
How to store Flebogamma DIF
6.
Further information
1.
WHAT FLEBOGAMMA DIF IS AND WHAT IT IS USED FOR
Flebogamma DIF is one of the group of medicines called intravenous immunoglobulins. These are
used to treat conditions where the body’s defence system against disease is not working properly.
It is used to raise antibody levels in your blood. A lower than normal level of antibodies in your blood
results in the incorrect functioning of your body’s defence (immune) system. The low levels of
antibodies may be inherited or may have developed as you have grown older. Other medical
conditions such as myeloma or chronic lymphocytic leukaemia can also reduce the level of antibodies
in your blood. Raising antibody levels by regular injections of Flebogamma DIF will help your body
fight off infections.
It is used to treat Guillain Barré syndrome, where the immune system damages the nerves and hinders
them from working properly.
It is used to treat Kawasaki disease, an illness in children where the blood vessels (arteries) in the body
become enlarged.
It is used in bone marrow transplantation, when you are given bone narrow cells from another person.
The antibodies in Flebogamma DIF help to stop infections and help to stop your body rejecting the
new cells.
It is used to treat a condition called idiopathic thrombocytopenic purpura (ITP), where the number of
platelets in your blood stream is greatly reduced. Platelets form an important part of the clotting
process and a reduction in their numbers may cause unwanted bleeding and bruising. Injection of
Flebogamma DIF results in an increase in the number of platelets, and an improvement in your
condition.
In children with the acquired immune deficiency syndrome (AIDS), it can be used to prevent
troublesome infections.
If you have any question about use of Flebogamma DIF please ask your doctor.
- 38 -
4.
Possible side effects
2.
BEFORE YOU USE FLEBOGAMMA DIF
Do not use Flebogamma DIF
-
if you are allergic (hypersensitive) to human normal immunoglobulin or any of the other
ingredients of Flebogamma DIF (see special warnings about excipients at the end of this
section).
-
if you have immunoglobulin A (IgA) deficiency with anti-IgA antibodies.
-
fructose intolerance.
Take special care with Flebogamma DIF
Certain adverse reactions may occur more frequently:
in case of high rate of infusion.
if you have hypo- or agammaglobulinaemia (a condition implying low immunoglobulin levels
in your blood) with or without IgA deficiency.
if you are having Flebogamma DIF for the first time, or it is a long time since your last infusion
(e.g. several weeks). You will be watched carefully until an hour after the infusion to detect
potential adverse signs.
True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency
with anti-IgA antibodies.
Rarely, human normal immunoglobulin can induce a fall in blood pressure with allergic reaction, even
if you had tolerated previous treatment with human normal immunoglobulin.
Patient with pre-existing risk factors
Please tell your doctor if you have any other condition and/or illness, as caution is required.
In particular, tell your doctor if you have:
diabetes
high blood pressure
history of vascular disease or thrombosis
overweight
blood volume decrease
diseases which increase blood viscosity
advanced age
Patients with a kidney problem
If you have a kidney problem, your doctor should consider whether to stop treatment since cases of
acute renal failure have been reported in patients receiving IVIg therapy, generally in patients with risk
factors.
Tell your doctor, even when any of the above-mentioned circumstances had happened to you in the
past.
Special safety warning
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
- 39 -
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 applies to any unknown or emerging viruses or 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
parvovirus B19 viruses.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly
because the antibodies against these infections, which are contained in the product, are protective.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Effects on vaccines: Flebogamma DIF may reduce the effectiveness of certain type of vaccines
such as measles, rubella, mumps and varicella.
Effects on blood tests
If you are having a blood test after receiving Flebogamma DIF, please tell the analyst or your doctor
that you have been given this medicine. The level of certain antibodies can rise.
Pregnancy and breast feeding
Ask your doctor or pharmacist for advice before taking any medicine.
If you are pregnant or breast-feeding you must tell your doctor. Your doctor will decide if
Flebogamma DIF can be used during pregnancy and lactation.
Driving and using machines
Dizziness can sometimes occur and might affect the ability to drive and use machines.
Important information about some of the ingredients of Flebogamma DIF
Special warnings about ingredients: This medicine contains 50 mg of sorbitol per ml as excipient. If
you have been told by your doctor that you have an intolerance to some sugars, contact your doctor
before taking this medicine.
In babies and young children hereditary fructose intolerance may not yet be diagnosed and may
be fatal, thus, they should not receive sorbitol-containing solutions.
3.
HOW TO USE FLEBOGAMMA DIF
Flebogamma DIF is given by injection into your veins (intravenous administration). It may be self
administered if you have been fully trained by hospital staff. You must make up the infusion in
exactly the way you have been shown in order to stop germs getting in. You must never self
administer it alone; a responsible adult must be always present
.
The dose that you will be given will depend on your weight and will be worked out by your doctor.
At the beginning of your infusion you will receive Flebogamma DIF at a slow rate
(0.01-0.02 ml/kg/min). Depending on how comfortable you feel, your doctor may then gradually
increase the infusion rate (up to 0.1 ml/kg/min).
- 40 -
The solution should be clear or slightly opalescent. Do not use Flebogamma DIF if you notice that the
solution is cloudy or has deposits.
If you use more Flebogamma DIF than you should
If you get more Flebogamma DIF than you should, your body may take on too much fluid. Tell your
doctor immediately.
If you forget to use Flebogamma DIF
Tell your doctor or pharmacist immediately and follow his/her instructions.
You must not be given a double dose to make up for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Flebogamma DIF can cause side effects, although not everybody gets them.
Tell your doctor if any of the following side effects happen during or after the infusion:
Chills
Headache
Fever
Nausea
Vomiting
Allergic reaction
Joint pain
Low blood pressure
Moderate low back pain
Rare side effects, which are likely to occur in fewer than 1 in 1,000 patients
,
are
:
A sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even if you have
shown no hypersensitivity to previous administration.
Cases of temporary meningitis (reversible aseptic meningitis).
Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic
anaemia/haemolysis).
Cases of transient cutaneous reactions.
Increase in serum creatinine level and/or acute renal failure.
Very rare side effects, which are likely to occur in fewer than 1 in 10,000 patients or which cannot be
estimated from the available data, are:
Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep
vein thromboses.
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 pharmacist.
5.
HOW TO STORE FLEBOGAMMA DIF
Keep out of the reach and sight of children.
Do not use Flebogamma DIF after the expiry date which is stated on the label and carton after EXP.
The expiry date refers to the last day of that month.
- 41 -
Do not store above 30 ºC. Do not freeze.
Any unused product or waste material should be disposed of in accordance with local requirements.
Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Flebogamma DIF contains
-
The active substance is human normal immunoglobulin (IVIg). One ml contains 50 mg of
human normal immunoglobulin, of which at least 97% is IgG.
The percentage of IgG subclasses is approximately 66.6% IgG
1
, 28.5% IgG
2
, 2.7% IgG
3
and
2.2% IgG
4
. It contains trace amounts of IgA (lower than 0.05 mg/ml).
-
The other ingredients are sorbitol and water for injections (see section 2. ‘Before you use
Flebogamma DIF’ for further information about ingredients).
What Flebogamma DIF looks like and contents of the pack
Flebogamma DIF is a solution for infusion. The solution is clear or slightly opalescent and colourless
or pale yellow.
Flebogamma DIF is supplied as 0.5 g/10 ml, 2.5 g/50 ml, 5 g/100 ml, 10 g/200 ml and 20 g/400 ml
vials.
Pack size of 1 vial.
Not all sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tél/Tel: +34 93 571 01 00
Luxembourg/Luxemburg
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tél/Tel: +34 93 571 01 00
България
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Magyarország
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
- 42 -
Česká republika
Grifols S.R.O.
Zitná 2
CZ-120 00 Praha 2
Tel: +4202 2223 1415
Malta
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Danmark
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tél/Tel: +34 93 571 01 00
Nederland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Deutschland
Grifols Deutschland GmbH
Siemensstraße 32
D-63225 Langen
Tél/Tel: +49 6103 750215
Norge
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tél/Tel: +34 93 571 01 00
Eesti
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Österreich
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Ελλάδα
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Polska
Grifols Polska
Sp. z o. o.
UL. Nowogrodzka 68
PL-02-014 Warsaw
Tel: +48 22 504 06 41
España
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Portugal
Grifols Portugal, Lda.
Rua de São Sebastião, nº 2
Zona Industrial de Cabra Figa
P-2635-448 Río de Mouro
Tel: +351 219 255 200
France
Grifols France, SARL
Parc Technologique Sainte Victoire
Bâtiment 10, 1er étage
F-13590 Meyreuil
Tél/Tel: +33 442 54 44 00
România
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Ireland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Slovenija
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Ísland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Slovenská republika
Grifols Internacional, S.A.
Trnavská cesta 50
821 02, Bratislava
Tel: +421 2 44 63 82 01
- 43 -
Italia
Grifols Italia S.p.A.
Via Carducci, 62 d
I-56010 Ghezzano (Pisa)
Tel: +39 050 8755 113
Suomi/Finland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Κύπρος
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Sverige
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Latvija
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
United Kingdom
Grifols UK Ltd.
Byron House
Cambridge Business Park
Cambridge, CB4 0WZ
Tel: +44 01223 395700
Lietuva
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
This leaflet was last approved in 09/2010
Detailed information on this medicine is available on the European Medicines Agency (EMEA)
website:
http://www.emea.europa.eu
The following information is intended for medical or healthcare professionals only:
The dose and dosage regimen is dependent on the indication.
In replacement therapy the dosage will be adapted dependent on your pharmacokinetic and clinical
response. The following dosage regimens are given as a guideline:
The dosage recommendations are summarised in the following table:
Indication
Dose
Frequency
Replacement therapy in primary
immunodeficiency
- starting dose:
0.4 - 0.8 g/kg
- thereafter:
0.2 - 0.8 g/kg
0.2 - 0.4 g/kg
every 2 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
Replacement therapy in secondary
immunodeficiency
every 3 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
0.2 - 0.4 g/kg
Children with AIDS
every 3 - 4 weeks
- 44 -
Indication
Dose
Frequency
Immunomodulation:
Idiopathic thrombocytopenic purpura
0.8 - 1 g/kg
or
0.4 g/kg/d
0.4 g/kg/d
1.6 - 2 g/kg
or
2 g/kg
on day 1, possibly repeated once
within 3 days
for 2 - 5 days
Guillain Barré syndrome
for 3 - 7 days
Kawasaki disease
in several doses for 2 - 5 days in
association with acetylsalicylic acid
in one dose in association with
acetylsalicylic acid
Allogeneic bone marrow transplantation:
0.5 g/kg
-
treatment of infections and
prophylaxis of graft versus host
disease
every week from day -7 up to 3
months after transplantation
0.5 g/kg
-
persistent lack of antibody
production
every month until antibody levels
return to normal
Flebogamma DIF should be infused intravenously at an initial rate of 0.01-0.02 ml/Kg/min for the first
thirty minutes. If well tolerated, the rate of administration may gradually be increased to a maximum
of 0.1 ml/kg/min
.
A significant increase in median platelet levels was achieved in a clinical trial in chronic ITP patients
(64,000/µl) although it did not reach normal levels.
Incompatibilities
Flebogamma DIF should not be mixed with other medicines or intravenous solutions and it should be
administered by a separate intravenous line.
Special precautions
It is strongly recommended that every time Flebogamma DIF is administered, the name and batch
number of the product is recorded in order to maintain a record of the batches used.
Instructions for handling and disposal
The product should be brought at room temperature (no more than 30 ºC) before use.
The solution should be clear or slightly opalescent. Do not use Flebogamma DIF if you notice that the
solution is cloudy or has deposits.
Any unused product or waste material should be disposed of in accordance with local requirements
- 45 -
PACKAGE LEAFLET: INFORMATION FOR THE USER
Flebogamma DIF 100 mg/ml 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 pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
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 pharmacist.
In this leaflet
:
1.
What Flebogamma DIF is and what it is used for
2.
Before you use Flebogamma DIF
3.
How to use Flebogamma DIF
5.
How to store Flebogamma DIF
6.
Further information
1.
WHAT FLEBOGAMMA DIF IS AND WHAT IT IS USED FOR
What Flebogamma DIF is
Flebogamma DIF is one of the group of medicines called intravenous immunoglobulins. These are
used to treat conditions where the body’s defence system against disease is not working properly.
What Flebogamma DIF is used for
Treatment of adults, children and adolescents (0-18 years) who do not have sufficient antibodies
(replacement therapy) such as:
Patients with Primary Immunodeficiency Syndromes (PID), an inborn lack of antibodies.
Hypogammaglobulinaemia (a condition implying low immunoglobulin levels in your blood)
and recurrent bacterial infections in patients with chronic lymphocytic leukaemia (cancer of the
blood where too many white blood cells are produced), in whom prophylactic antibiotics have
failed.
Hypogammaglobulinaemia (a condition implying low immunoglobulin levels in your blood)
and recurrent bacterial infections in myeloma (tumour composed of cells derived from the bone
marrow) patients who failed to respond to pneumococcal immunisation.
Hypogammaglobulinaemia (a condition implying low immunoglobulin levels in your blood) in
patients after a stem cell transplantation (allogeneic haematopoietic stem cell transplantation),
when you are given stem cells from another person.
Treatment of children and adolescents (0-18 years) who do not have sufficient antibodies (replacement
therapy) in:
The Acquired Immune Deficiency Syndrome (AIDS), it can be used to prevent troublesome
infections.
- 46 -
4.
Possible side effects
Treatment of adults, children and adolescents (0-18 years) with certain autoimmune disorders
(immunomodulation). There are three groups:
Idiopathic Thrombocytopenic Purpura (ITP), a condition where the number of platelets in the
blood stream is greatly reduced. Platelets form an important part of the clotting process and a
reduction in their numbers may cause unwanted bleeding and bruising. The product is also used
in patients at high risk of bleeding or prior to surgery to correct the platelet count.
Guillain Barré syndrome, where the immune system damages the nerves and hinders them from
working properly.
Kawasaki disease, an illness in children where the blood vessels (arteries) in the body become
enlarged.
2.
BEFORE YOU USE FLEBOGAMMA DIF
Do not use Flebogamma DIF
-
If you are allergic (hypersensitive) to human normal immunoglobulin or any of the other
ingredients of Flebogamma DIF (for a complete list of ingredients see section 6 of this leaflet).
-
If you do not have enough immunoglobulins of the type IgA in your blood or have developed
antibodies to IgA.
-
If you have hereditary fructose intolerance, a quite rare genetic condition where the enzyme for
breaking down fructose is not produced.
Take special care with Flebogamma DIF
Certain side effects may occur more frequently:
in case of high rate of infusion
if you have hypo- or agammaglobulinaemia (a condition implying low immunoglobulin levels
in your blood) with or without IgA deficiency
if you are having Flebogamma DIF for the first time, or it has been switched from an alternative
human normal immunoglobulin (IVIg) product, or it is a long time since your last infusion (e.g.
several weeks). You will be watched carefully until an hour after the infusion to detect potential
side effects.
Allergic reactions are rare. It may happen particularly if you do not have enough immunoglobulins of
the type IgA in your blood or have developed antibodies to IgA.
Rarely, human normal immunoglobulin can induce a fall in blood pressure with allergic reaction, even
if you had tolerated previous treatment with human normal immunoglobulin.
Patients with pre-existing risk factors
Please tell your doctor if you have any other condition and/or illness, as caution is required in patients
with pre-existing risk factors for thrombotic events. In particular, tell your doctor if you have:
diabetes
high blood pressure
history of vascular disease or thrombosis
overweight
blood volume decrease
diseases which increase blood viscosity
- 47 -
advanced age
Patients with a kidney problem
If you have a kidney problem, your doctor should consider whether to stop treatment since cases of
acute renal failure have been reported in patients receiving IVIg therapy, generally in patients with risk
factors.
Tell your doctor, even when any of the above-mentioned circumstances had happened to you in the
past.
Special safety warning
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 applies to any unknown or emerging viruses or 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
parvovirus B19 viruses.
Immunoglobulins have not been associated with hepatitis A or parvovirus B19 infections possibly
because the antibodies against these infections, which are contained in the product, are protective.
Taking other medicines
Please tell your doctor or pharmacist if you are taking or have recently taken any other
medicines, including medicines obtained without a prescription.
Effects on vaccines: Flebogamma DIF may reduce the effectiveness of certain type of vaccines
(live attenuated virus vaccines) such as measles, rubella, mumps and varicella.
Effects on blood tests
After receiving Flebogamma DIF, the results of certain blood tests (serological tests) may be interfered
for a certain time. If you have a blood test after receiving Flebogamma DIF, please tell the analyst or
your doctor that you have been given this medicine.
Pregnancy and breast-feeding
If you are pregnant or breast-feeding you must tell your doctor. Your doctor will decide if
Flebogamma DIF can be used during pregnancy and breast-feeding.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Dizziness can sometimes occur and might affect the ability to drive and use machines.
- 48 -
Important information about some of the ingredients of Flebogamma DIF
This medicine contains 50 mg of sorbitol per ml. If you have been told by your doctor that you have
intolerance to some sugars, contact your doctor before taking this medicine.
In babies and young children hereditary fructose intolerance may not yet be diagnosed and may
be fatal, thus, they should not receive this medicine.
3.
HOW TO USE FLEBOGAMMA DIF
Flebogamma DIF is given by injection into your veins (intravenous administration). It may be self
administered if you have been fully trained by hospital staff. You must make up the infusion in exactly
the way you have been shown in order to stop germs getting in. You must never self administer it
alone; a responsible adult must be always present
.
The dose that you will be given will depend on your illness and body weight and will be worked out
by your doctor (please see section “Instructions for healthcare professionals” given at the end of this
leaflet).
At the beginning of your infusion you will receive Flebogamma DIF at a slow rate (0.01 ml/kg/min).
Depending on how comfortable you feel, your doctor may then gradually increase the infusion rate (up
to 0.08 ml/kg/min).
Use in children
The dose in children is not considered to be different to that of adults as it will be given depending on
the illness and body weight of the children.
If you use more Flebogamma DIF than you should
If you get more Flebogamma DIF than you should, your body may take on too much fluid. This could
particularly happen when you are a patient at risk, e.g. an elderly patient or a patient having problems
with your kidneys. Tell your doctor immediately.
If you forget to use Flebogamma DIF
Tell your doctor or pharmacist immediately and follow his/her instructions.
You must not be given a double dose to make up for a forgotten dose.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Flebogamma DIF can cause side effects, although not everybody gets them.
In rare and isolated cases, the following side effects have been reported with immunoglobulin
preparations.
Tell your doctor if any of the following side effects happen during or after the
infusion:
A sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even if you have
shown no hypersensitivity to previous administration.
Cases of temporary meningitis (reversible aseptic meningitis).
Cases of temporary reduction in the number of the red cells in the blood (reversible haemolytic
anaemia/haemolysis).
Cases of transient cutaneous reactions.
Increase in serum creatinine level and/or acute renal failure.
- 49 -
Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep
vein thromboses.
Three clinical studies with Flebogamma DIF 100 mg/ml were conducted. In these studies different
side effects have been observed. These side effects and frequency are detailed below
using the
following convention:
-
very common (affects more than 1 user in 10)
-
common (affects 1 to 10 users in 100)
-
uncommon (affects 1 to 10 users in 1,000)
-
very rare (affects less than 1 user in 10,000)
-
not known (frequency cannot be estimated from the available data)
Very common
:
●
headache
Common
:
●
tachycardia (acceleration of the heart activity)
●
hypotension (low blood pressure)
●
back pain
●
myalgia (muscle pain)
●
pain
●
fever (body temperature increased)
●
rigors (cold shivering sensation)
Uncommon
:
●
influenza (flu)
●
urinary infection
●
red blood cells and white blood cells decreased
●
dizziness (motion sickness)
●
radicular syndrome (neck or back pain and other symptoms such as numbness, tingling and
weakness in the arms or legs)
●
syncope vasovagal (temporary loss of consciousness)
●
tremor/chills (to tremble)
●
conjunctivitis (inflammation of the conjuntiva of the eyes)
●
maculopathy (illness of the macula, in the retina of the eyes)
●
photophobia (excessive sensitivity to light)
●
ear pain
●
vertigo
●
blood pressure increased or decreased
●
flushing (to blush)
●
haematoma
●
thrombosis
●
postnasal drip (excessive mucus)
●
sinus pain
●
wheezing
●
abdominal pain (including abdominal pain upper and abdominal pain distension)
●
diarrhoea
●
flatulence
●
vomiting
●
acne
●
ecchymosis (large skin hematoma)
●
erythema (redness of the skin)
- 50 -
-
rare (affects 1 to 10 users in 10,000)
●
nausea
●
anorexia (lack of appetite)
●
pruritus (itching)
●
rash (eruption of the skin)
●
muscle spasms or muscle tightness
●
neck pain
●
pain in extremities
●
chest discomfort/chest pain
●
feeling cold
●
infusion related reaction and infusion site reaction (including infusion site erythema and
infusion site pain)
●
fatigue
●
feeling jittery (nervousness)
●
influenza like illness
●
malaise
●
oedema peripheral
●
haemoglobin decreased
●
heart rate increased
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 pharmacist.
5.
HOW TO STORE FLEBOGAMMA DIF
Keep out of the reach and sight of children.
Do not use Flebogamma DIF after the expiry date which is stated on the label and carton after EXP.
The expiry date refers to the last day of that month.
Do not store above 30 ºC. Do not freeze.
The solution should be clear or slightly opalescent. Do not use Flebogamma DIF if you notice that the
solution is cloudy or has deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
Medicines should not be disposed via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Flebogamma DIF contains
-
The active substance is human normal immunoglobulin (IVIg). One ml contains 100 mg of
human normal immunoglobulin, of which at least 97% is IgG.
One vial of 50 ml contains: 5g of human normal immunoglobulin
One vial of 100 ml contains: 10 g of human normal immunoglobulin
One vial of 200 ml contains: 20 g of human normal immunoglobulin
The percentage of IgG subclasses is approximately 66.6% IgG
1
, 27.9% IgG
2
, 3.0% IgG
3
and
2.5% IgG
4
. It contains trace amounts of IgA (lower than 100 micrograms/ml).
-
The other ingredients are sorbitol and water for injections (see section 2 for further information
about ingredients).
- 51 -
●
arthralgia (joint pain)
What Flebogamma DIF looks like and contents of the pack
Flebogamma DIF is a solution for infusion. The solution is clear or slightly opalescent and colourless
or pale yellow.
Flebogamma DIF is supplied as 5 g/50 ml, 10 g/100 ml and 20 g/200 ml.
Pack size of 1 vial.
Not all sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
08150 Barcelona - Spain
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tél/Tel: +34 93 571 01 00
Luxembourg/Luxemburg
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tél/Tel: +34 93 571 01 00
България
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Teл.: +34 93 571 01 00
Magyarország
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel.: +34 93 571 01 00
Česká republika
Grifols S.R.O.
Žitná 2
CZ-120 00 Praha 2
Tel: +4202 2223 1415
Malta
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Danmark
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tlf: +34 93 571 01 00
Nederland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Deutschland
Grifols Deutschland GmbH
Siemensstraße 32
D-63225 Langen
Tel: +49 6103 75020
Norge
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tlf: +34 93 571 01 00
Eesti
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Österreich
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
- 52 -
Ελλάδα
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Τηλ: +34 93 571 01 00
Polska
Grifols Polska
Sp. z o. o.
UL. Nowogrodzka 68
PL-02-014 Warsaw
Tel.: +48 22 504 06 41
España
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Portugal
Grifols Portugal, Lda.
Rua de São Sebastião, nº 2
Zona Industrial de Cabra Figa
P-2635-448 Rio de Mouro
Tel: +351 219 255 200
France
Grifols France, SARL
Parc Technologique Sainte Victoire
Bâtiment 10, 1er étage
F-13590 Meyreuil
Tél: +33 442 54 44 00
România
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Ireland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Slovenija
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Ísland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Sími: +34 93 571 01 00
Slovenská republika
Grifols International, S.A.
Trnavská cesta 50
821 02, Bratislava
Tel: +421 2 44 63 82 01
Italia
Grifols Italia S.p.A.
Via Carducci, 62 d
I-56010 Ghezzano (Pisa)
Tel: +39 050 8755 113
Suomi/Finland
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Puh/Tel: +34 93 571 01 00
Κύπρος
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Τηλ: +34 93 571 01 00
Sverige
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
Latvija
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
United Kingdom
Grifols UK Ltd.
Byron House
Cambridge Business Park
Cambridge, CB4 0WZ
Tel: +44 01 223 395 700
- 53 -
Lietuva
Instituto Grifols, S.A.
Can Guasch, 2 - Parets del Vallès
E-08150, Barcelona
Tel: +34 93 571 01 00
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
The following information is intended for medical or healthcare professionals only (see section 3 for
further information):
The dose and posology is dependent on the indication.
In replacement therapy the dose may need to be individualised for each patient dependent on the
pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.
The dose recommendations are summarised in the following table:
Indication
Dose
Frequency
Replacement therapy in primary
immunodeficiency
- starting dose:
0.4 - 0.8 g/kg
- thereafter:
0.2 - 0.8 g/kg
0.2 - 0.4 g/kg
every 3 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
Replacement therapy in secondary
immunodeficiency
every 3 - 4 weeks to obtain IgG
trough level of at least 4 - 6 g/l
0.2 - 0.4 g/kg
0.2 - 0.4 g/kg
Children and adolescents with AIDS
every 3 - 4 weeks
Hypogammaglobulinaemia (< 4 g/l) in
patients after allogeneic haematopoietic
stem cell transplantation
every 3 - 4 weeks
Immunomodulation:
0.8 - 1 g/kg
or
0.4 g/kg/d
0.4 g/kg/d
1.6 - 2 g/kg
or
2 g/kg
Idiopathic Thrombocytopenic Purpura
on day 1, possibly repeated once
within 3 days
for 2 - 5 days
Guillain Barré syndrome
for 5 days
Kawasaki disease
in several doses for 2 - 5 days in
association with acetylsalicylic acid
in one dose in association with
acetylsalicylic acid
Paediatric population
See above
See above
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Flebogamma DIF should be infused intravenously at an initial rate of 0.01 ml/kg/min for the first
thirty minutes. If tolerated, advance to 0.02 ml/kg/min for the second 30 minutes. Again, if tolerated,
advance to 0.04 ml/kg/min for the third 30 minutes. If the patient tolerates the infusion well, additional
increments of 0.02 ml/kg/min may be made at 30-minute intervals up to a maximum of
0.08 ml/kg/min.
It has been reported that the frequency of adverse reactions to IVIg increases with the infusion rate.
Infusion rates during the initial infusions should be slow. If there are no adverse reactions, the infusion
rate for subsequent infusions can be slowly increased to the maximum rate. For patients experiencing
adverse reactions, it is advisable to reduce the infusion rate in subsequent infusions and limit the
maximum rate to 0.04 ml/kg/min, or administer IVIg at a 5% concentration.
Paediatric population
As the dosage for each indication is given by body weight and adjusted to the clinical outcome of the
above mentioned conditions, the dosage in children is not considered to be different to that of adults.
Incompatibilities
Flebogamma DIF should not be mixed with other medicines or intravenous solutions and it should be
administered by a separate intravenous line.
Special precautions
Sorbitol
Each ml of this medicinal product contains 50 mg of sorbitol. Patients with rare hereditary
problems of fructose intolerance must not take this medicine.
In case of inadvertent application and suspicion of hereditary fructose intolerance the infusion
has to be stopped immediately, normal glycaemia has to be re-established and organ function
has to be stabilized by means of intensive care.
Interferences with determination of blood glucose levels are not expected.
Paediatric population
In babies and young children hereditary fructose intolerance may not yet be diagnosed and may
be fatal, thus, they should not receive this medicinal product.
It is strongly recommended that every time Flebogamma DIF is administered, the name and batch
number of the product is recorded in order to maintain a record of the batches used.
Instructions for handling and disposal
The product should be brought at room temperature (no more than 30 ºC) before use.
The solution should be clear or slightly opalescent. Do not use Flebogamma DIF if you notice that the
solution is cloudy or has deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
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Source: European Medicines Agency
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