Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with cardiac or renal impairment.
3 years
Hypersensitivity to the active substance or to any of the excipients , especially in patients with antibodies against IgA.
Glycine.
Solution for infusion
Summary of the safety profile
Adverse reactions such as chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.
Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.
Cases of reversible aseptic meningitis and rare cases of transient cutaneous reactions have been observed with human normal immunoglobulin.).
Increase in serum creatinine level and/or acute renal failure have been observed.
Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.
For safety with respect to transmissible agents, see 4.4.
Tabulated list of adverse reactions
The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (>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 available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
ADRs which have been reported in clinical trials with Gamunex 10% in rare frequencies:
Haemolytic anaemia, dyspnoea, sinusitis, skin exfoliation, anxiety, myalgia, haemoglobin decreased, dyspepsia, contusion, dermatitis, flushing, musculoskeletal stiffness, palmar erythema, aphonia.
Frequency of Adverse Drug Reactions (ADRs) in clinical trials with Gamunex 10%
| MedDRA System Organ Class | MedDRA preferred term | ADR frequency category |
| Investigations | White blood cell count decreased | Uncommon |
| Nervous system disorders | Headache | Common |
| Dizziness | Uncommon | |
| Skin and subcutaneous tissue disorders | Urticaria, dermatitis, pruritus, rash, | Uncommon |
| Gastrointestinal disorders | Abdominal pain, diarrhoea, nausea, vomiting | Uncommon |
| Vascular disorders | Hypertension, hypotension | Uncommon |
| Respiratory, thoracic and mediastinal disorders | Pharyngitis, cough, nasal congestion, wheezing | Uncommon |
| Musculoskeletal and connective tissue disorders | Arthralgia, back pain, neck pain, shoulder pain | Uncommon |
| Cardiac disorders | Chest pain | Uncommon |
| General disorders and administration site conditions | Pyrexia | Common |
| Influenza like illness, malaise, fatigue, chills, asthenia, injection site reaction | Uncommon |
Paediatric population
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via UK Yellowcard Scheme: https://yellowcard.mhra.gov.uk/. Tel: Freephone 0808 100 3352
Immunoglobulins are normal components of the human body. Because administration of immunoglobulins in animal studies may lead to the formation of antibodies, preclinical safety data are limited. In the acute and sub-acute animal studies that were performed, Gamunex 10% did not show special risks for humans.
Replacement therapy in adults, and children and adolescents (0-18 years):
- Primary immunodeficiency syndromes with impaired antibody production.
- Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.
- Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.
- Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell transplantation (HSCT).
- Congenital AIDS with recurrent bacterial infections.
Immunomodulation in adults, and children and adolescents (0-18 years) in:
- Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.
- Guillain Barré syndrome.
- Kawasaki disease.
- Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration. ATC code: J06BA02
Human normal immunoglobulin contains unmodified immunoglobulin G (IgG) with a broad spectrum of antibodies against various infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is prepared from plasma from not fewer than 1,000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range. The mechanism of action in indications other than replacement therapy is not fully elucidated but includes immunomodulatory effects.
Clinical trials conducted with Gamunex 10% on patients with Chronic Inflammatory Demyelinating Polyneuropathy (CIDP):
The IVIG-C CIDP efficacy trial (ICE study), a double-blind, randomised, placebo-controlled study investigated the efficacy and safety of Gamunex 10% in the treatment of CIDP. A total of 117 CIDP patients were randomised to receive either Gamunex 10% or placebo every three weeks. Loading dose was 2 g/kg BW; maintenance dose was 1 g/kg BW.
Responder rates (determined by improvement in INCAT disability score and maintenance of > 1 improvement over the 24 week efficacy period) were significantly higher in the Gamunex 10% group (54%), compared to the placebo group (21%, p=0.0002). Muscle strength as measured by the MRC score and grip strength, as well as sensation as measured by the ISS score improved significantly more in the Gamunex 10% group compared to placebo.
In view of the limited number of patients > 65 years included in the study, a precise treatment effect could not be determined with regard to the INCAT score; for grip strength, a statistically significant treatment effect was shown in favour of Gamunex 10%.
Of the responders, less than half responded after the loading dose (by week 3), but most responded after the second dose (by week 6). Non-responders were crossed over to the alternative treatment, for again up to a maximum of 24 weeks of therapy.
All responders were re-randomised in an extension phase for another 6 months period of maintenance therapy with either Gamunex 10% or placebo. Of the former responders to Gamunex 10%, the actual relapse rate was significantly higher in the patients randomised to placebo (42%) than in those randomised to Gamunex 10% (13%, p=0.012).
The ICE study has shown short-term and long-term efficacy of Gamunex 10% in the treatment of CIDP. The results are summarised in the following table.
Primary endpoint and other results of the ICE study
| Gamunex 10% | Placebo | p | |
| Responder rate during the efficacy period (primary endpoint) | 54% | 21% | 0.0002 |
| Probability of relapse in the extension period | 13% | 45% | 0.013 |
| Grip strength (kPA)1 (change from baseline) | |||
| Dominant hand | 13.2 | 1.5 | 0.0008 |
| Non-dominant hand | 13.3 | 4.3 | 0.005 |
| Muscle strength (MRC3 sum score)1 (change from baseline) | 3.3 | 0.2 | 0.001 |
| Sensibility (ISS4 score)2 (change from baseline) | -1.2 | 0.2 | 0.021 |
1 Improvement indicated by positive figure
2 Improvement indicated by negative figure
3 MRC: Medical Research Council
4 ISS: INCAT Sensory Sum Score
The proprietary product is adjusted to a weakly acidic pH. Since Gamunex 10% has a low buffering capacity, it is rapidly neutralised by the blood during the infusion. Even after administration of high doses of Gamunex 10%, no change in the pH of the blood was recorded. Osmolality is 258 mOsmol/kg solution and thus approximates to the normal range (285-295 mOsmol/kg).
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 and after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.
Human normal immunoglobulin has a half-life of about 35 days as determined in patients with primary antibody deficiency syndrome and therefore exceeds that of 21 days described in the literature in healthy subjects. 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.
July 2014
Gamunex 10%,
100 mg/ml, solution for infusion
Grifols Deutschland GmbH
Lyoner Strasse 15
60528 Frankfurt
Germany
Tel.: +49 69-660 593 100
Store at +2 °C to +8 °C (in a refrigerator). Do not freeze.
The product may be stored in its outer carton for a one-off period of up to 6 months at room temperature (not above 25°C). In that case, the shelf life of the product expires at the end of this 6-month period. The new expiry date must be noted on the outer carton and the vial label. The new expiry date must be no later than the printed expiry date. Thereafter, it must be used or destroyed. Subsequent refrigeration is not possible.
Solution for intravenous infusion in Type I or II glass vials with halobutyl/isoprene rubber stoppers or chlorobutyl stoppers.
Pack sizes: 10 ml, 50 ml, 100 ml, 200 ml; hospital packs. Not all pack sizes may be marketed.
PL 29527/0001
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.
Breast-feeding
Immunoglobulins are excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry.
Fertility
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.
Human normal immunoglobulin (IVIg)
One ml contains:
human normal immunoglobulin...............................................................................100 mg
(purity of at least 98% IgG)
One vial of 10 ml contains: 1 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):
IgG1.................... 62.8%
IgG2.................... 29.7%
IgG3...................... 4.8%
IgG4................ ....2.7%
1 ml Gamunex 10% contains 100 mg protein with an IgG content of at least 98% (IgA content: mean: 59 micrograms/ml; max.: 84 micrograms/ml; results from 5 different batches).
Produced from plasma of human donors.
All patients should be closely monitored when high rates of infusion (8.4 ml/kg/hr) are used. 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 infusion rate,
- 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 normal human immunoglobulin by initially infusing the product slowly (0.1 ml/kg/hr),
- are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve to human 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 an adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction. In case of shock, standard medical treatment for shock should be implemented.
In all patients, IVIg administration requires:
- adequate hydration prior to the initiation of the infusion of IVIg
- monitoring of urine output
- monitoring of serum creatinine levels
- avoidance of concomitant use of loop diuretics.
This medicinal product is essentially 'sodium free'.
Hypersensitivity
True hypersensitivity reactions are rare. They can occur in patients with anti-IgA antibodies.
IVIg is not indicated in patients with selective IgA deficiency where the IgA deficiency is the only abnormality of concern.
Rarely, human normal immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.
Thromboembolism
There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilization, severely hypovolaemic patients, patients with diseases which increase blood viscosity).
In patients at risk for thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.
Acute renal failure
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified, such as pre-existing renal insufficiency, diabetes mellitus, hypovolaemia, 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 use of many of the licensed immunoglobulin products containing various excipients such as sucrose, glucose and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain theses excipients may be considered. Gamunex 10% does not contain sucrose, maltose or glucose.
In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable.
Aseptic meningitis syndrome (AMS)
Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment.
Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae. The syndrome usually begins within several hours to 2 days following IVIg treatment. Cerebrospinal fluid studies are frequently positive with pleocytosis up to several thousand cells per mm3, predominantly from the granulocytic series, and elevated protein levels up to several hundred mg/dl. AMS may occur more frequently in association with high-dose (2 g/kg) IVIg treatment.
Haemolytic anaemia
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs' test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis.
The following risk factors are associated with the development of haemolysis: high doses, whether given as a single administration or divided over several days; non-0 blood group; and underlying inflammatory state. Increased vigilance is recommended for non-0 blood group patients receiving high doses for non-PID indications. Haemolysis has rarely been reported in patients given replacement therapy for PID.
Isolated cases of haemolysis-related renal dysfunction/renal failure with fatal outcome have occurred.
Interference with serological testing
After injection of immunoglobulin the transitory rise of the various passively transferred antibodies in the patient's blood may result in misleading positive results in serological testing.
Passive transmission of antibodies to erythrocyte antigens, e.g. A, B, D may interfere with some serological tests for red cell antibodies, for example the direct antiglobulin test (DAT, direct Coombs' test).
Transmissible agents
Standard measures to prevent infections resulting from the use of medicinal products prepared from human blood or plasma include selection of donors, screening of individual donations and plasma pools for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses. Despite this, when medicinal products prepared from human blood or plasma are administered, the possibility of transmitting infective agents cannot be totally excluded. This also applies to unknown or emerging viruses and other pathogens.
The measures taken are considered effective for enveloped viruses such as HIV, HBV and HCV. The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.
There is reassuring clinical experience regarding the lack of hepatitis A or parvovirus B19 transmission with immunoglobulins and it is also assumed that the antibody content makes an important contribution to the viral safety.
It is strongly recommended that every time that Gamunex 10% 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.
Paediatric population
Although limited data is available, it is expected that the same warnings, precautions and risk factors apply to the paediatric population. In post-marketing reports it is observed that IVIg high-dose indications in children, particularly Kawasaki disease, are associated with an increased reporting rate of haemolytic reactions compared to other IVIg indications in children.
Physicians need to strongly consider monitoring haemoglobin levels 24 to 48 hours after completion of IVIg if haemolysis is suspected. If retreatment is required it is strongly recommended to monitor haemoglobin levels one week after subsequent IVIg dosing if haemolysis is suspected. Families should be instructed to return if their child develops symptoms of haemolysis, such as; pallor, lethargy, dark urine, dyspnoea or palpitations.
The ability to drive and operate machines may be impaired by some adverse reactions associated with Gamunex 10%. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.
Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.
Posology
The dose and dose regimen is dependent on the indication.
In replacement therapy the dose may need to be individualised for each patient dependent on pharmacokinetic and clinical response. The following dose regimens are given as a guideline.
Replacement therapy in primary immunodeficiency syndromes
The dose regimen should achieve a trough level of IgG (measured before the next infusion) of at least 5 to 6 g/l. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4-0.8 g/kg given once, followed by at least 0.2 g/kg given every three to four weeks.
The dose required to achieve a trough level of 5-6 g/l is of the order of 0.2-0.8 g/kg/month. The dosage interval when steady state has been reached varies from 3-4 weeks. Trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of infection, it may be necessary to increase the dosage and aim for higher trough levels.
Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed; hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation; congenital AIDS with recurrent bacterial infections
The recommended dose is 0.2-0.4 g/kg every three to four weeks.
Hypogammaglobulinaemia in patients after allogeneic 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 5g/l.
Primary immune thrombocytopenia
There are two alternative treatment schedules:
- 0.8-1g/kg given on day one; this dose may be repeated once within 3 days
- 0.4 g/kg given daily for two to five days.
The treatment can be repeated if relapse occurs.
Guillain Barré syndrome
0.4 g/kg/daily for 5 days.
Chronic Inflammatory Demyelinating Polyneuropathy
2 g/kg (20 ml/kg) in divided doses over 2 to 4 consecutive days as loading dose. Maintenance dose of 1 g/kg administered over 1 day (10 ml/kg) or divided into two doses of 0.5 g/kg (5 ml/kg) given on two consecutive days, every 3 weeks.
Only limited experience is available of use of intravenous immunoglobulins in children with Chronic Inflammatory Demyelinating Polyneuropathy.
Clinical studies of Gamunex 10% did not include sufficient numbers of subjects aged 65 and over to determine a precise treatment effect.
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 dosage recommendations are summarised in the following table:
| Indication | Dose | Frequency of administration |
| Replacement therapy in primary immunodeficiency | - starting dose: 0.4 - 0.8 g/kg | |
|
- thereafter: 0.2 - 0.8 g/kg |
every 3 - 4 weeks to obtain IgG trough serum level of at least 5 - 6 g/l | |
|
Replacement therapy in secondary immunodeficiency |
0.2 - 0.4 g/kg |
every 3 - 4 weeks to obtain IgG trough serum level of at least 5 - 6 g/l |
|
Congenital AIDS |
0.2 - 0.4 g/kg |
every 3 - 4 weeks |
|
Hypogammaglobulinaemia (< 4 g/l) in patients after allogeneic haematopoietic stem cell transplantation |
0.2 - 0.4 g/kg |
every 3 - 4 weeks to obtain IgG trough serum level above 5 g/l. |
| Immunomodulation: | ||
|
- Primary immune thrombocytopenia |
0.8 - 1 g/kg or 0.4 g/kg/d |
on day 1, possible to repeat once within 3 days
for 2 - 5 days |
|
- Guillain Barré syndrome |
0.4 g/kg/d |
for 5 days |
|
- Chronic Inflammatory Demyelinating Polyneuropathy# |
loading dose 2 g/kg |
in divided doses over 2 to 4 consecutive days |
|
maintenance dose 1 g/kg |
administered over 1 day or divided into two doses of 0.5 g/kg (5 mL/kg) given on 2 consecutive days, every 3 weeks | |
|
- Kawasaki disease |
1.6 - 2 g/kg or |
in divided doses over 2 - 5 days in association with acetylsalicylic acid |
|
2 g/kg |
in one dose in association with acetylsalicylic acid |
# Dose is based on the dose used in the clinical study conducted with Gamunex 10%.
The duration of treatment beyond 48 weeks should be subject to the physicians discretion based upon the patient response and maintenance response in the long-term.
The dosing and intervals may have to be adopted according to the individual course of the disease.
Paediatric population
The posology in children and adolescents (0-18 years) is not different to that of adults as the posology for each indication is given by body weight and adjusted to the clinical outcome of the above mentioned conditions.
Method of administration
For intravenous use.
Human normal immunoglobulin should be infused intravenously at an initial rate of 0.6 - 1.2 ml/kg/hr for 0.5 hr. If well tolerated , the rate of administration may gradually be increased to a maximum of 4.8 - 8.4 ml/kg/hr.
The product should be brought to room or body temperature before use. The solution should be clear or slightly opalescent and colourless or pale yellow. Solutions that are cloudy or have deposits should not be used. Any unused product or waste material should be disposed of in accordance with local requirement. Once the container has been opened, the contents should be infused immediately. Subsequent storage, even in a refrigerator, is not permitted on account of possible microbial colonisation.
If dilution is necessary prior to infusion, 50 mg/ml glucose solution may be used for this purpose. Do not dilute with saline solutions.
Simultaneous administration of Gamunex 10% and heparin through a single lumen delivery device must be avoided.
Gamunex 10% infusion lines can be flushed with 50 mg/ml glucose or with sodium chloride solution (9 mg/ml) and should not be flushed with heparin.
Heparin Lock through which Gamunex 10% was administered should be flushed with 50 mg/ml glucose or sodium chloride solution (9 mg/ml) and should not be flushed with heparin.
Date of renewal: 26 November 2011
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 or 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 a year. Therefore patients receiving measles vaccine should have their antibody status checked.
Paediatric population
Although specific interaction studies have not been performed in the paediatric population, no differences between adults and children are to be expected.
