Summary of medicine characteristics - VIGAM LIQUID 5% W/V SOLUTION FOR INFUSION
VigamLiquid 5 % w/v, solution for infusion
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Human normal immunoglobulin (IVIg)
One ml contains: Human normal immunoglobulin 50 mg (Purity of at least 95% IgG).
Each 2.5 g vial of 50 ml contains: 2.5 g of Human normal immunoglobulin.
Each 5 g vial of 100 ml contains: 5 g of Human normal immunoglobulin.
Each 10 g vial of 200 ml contains: 10 g of Human normal immunoglobulin.
Distribution of the IgG subclasses is similar to plasma (approximate values):
IgG1: 64 %
IgG2: 29 %
IgG3: 6 %
IgG4: 1 %
The maximum IgA content is 14 micrograms/ml.
Produced from the plasma of human donors.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
VigamLiquid is a sterile liquid for intravenous administration
4 CLINICAL PARTICULARS
4 CLINICAL PARTICULARS4.1 Therapeutic indications
Replacement therapy in adults, and children and adolescents (0–18 years) in:
Primary immunodeficiency syndromes (PID) with impaired antibody production
Secondary immunodeficiencies (SID) in patients who suffer from severe or recurrent infections, ineffective antimicrobial treatment and either proven specific antibody failure (PSAF)* or serum IgG level of <4 g/l
* PSAF= failure to mount at least a 2-fold rise in IgG antibody titre to pneumococcal polysaccharide and polypeptide antigen vaccines
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 (in conjunction with acetylsalicylic acid; see section 4.2)
Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)
Multifocal motor neuropathy (MMN)
4.2 Posology and method of administration
Replacement therapy should be initiated and monitored under the supervision of a physician experienced in the treatment of immunodeficiency.
Posology
The dose and dosage regimen is dependent on the indication.
The dose may need to be individualised for each patient dependent on the clinical response. Dose based on bodyweight may require adjustment in underweight or overweight patients.
The following dosage 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 6 g/l or within the normal reference range for the population age. Three to 6 months are required after the initiation of therapy for equilibration (steady-state IgG levels) 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 3 –4 weeks.
The dose required to achieve a trough level of IgG 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 3 – 4 weeks.
IgG trough levels should be measured and assessed in conjunction with the incidence of infection. To reduce the rate of bacterial infections, it may be necessary to increase the dosage and aim for higher trough levels.
Secondary immunodeficiencies (as defined in 4.1.)
The recommended dose is 0.2–0.4 g/kg every 3 – 4 weeks.
IgG trough levels should be measured and assessed in conjunction with the incidence of infection. Dose should be adjusted as necessary to achieve optimal protection against infections; an increase may be necessary in patients with persisting infection; a dose decrease can be considered when the patient remains infection free.
Primary immune thrombocytopenia
There are two alternative treatment schedules:
0.8 – 1 g/kg on day 1; this dose may be repeated once within 3 days.
0.4 g/kg given daily for 2 – 5 days.
The treatment can be repeated if relapse occurs.
Guillain Barré Syndrome
0.4 g/kg/day over 5 days (possible repeat of dosing in case of relapse).
Kawasaki Disease
2.0 g/kg should be administered as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid.
Chronic inflammatory demyelinating polyneuropathy (CIDP)
Starting dose: 2 g/kg divided over 2 –5 consecutive days.
Maintenance doses: 1 g/kg over 1–2 consecutive days every 3 weeks.
The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued. If the treatment is effective long-term treatment should be subject to the physicians discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.
Multifocal Motor Neuropathy (MMN)
Starting dose: 2 g/kg given over 2–5 consecutive days.
Maintenance dose: 1 g/kg every 2 to 4 weeks or 2 g/kg every 4 to 8 weeks.
The treatment effect should be evaluated after each cycle; if no treatment effect is seen after 6 months, the treatment should be discontinued. If the treatment is effective long-term treatment should be subject to the physicians’ discretion based upon the patient response and maintenance response. The dosing and intervals may have to be adapted according to the individual course of the disease.
The dosage recommendations are summarised in the following table:
| Indication | Dose | Frequency of injections |
| Replacement therapy | ||
| Primary immunodeficiency | Starting dose: 0.4 – 0.8 g/kg Maintenance dose: 0.2 – 0.8 g/kg | Every 3 – 4 weeks |
| Secondary immunodeficiency (as defined in 4.1) | 0.2 – 0.4 g/kg | Every 3 – 4 weeks |
| Immunomodulation: | ||
| Primary immune thrombocytopenia | 0.8 — 1 g/kg Or 0.4 g/kg/day | On day 1, possibly repeated once within 3 days For 2 – 5 days |
| Guillain Barré Syndrome | 0.4 g/kg/day | For 5 days |
| Kawasaki disease | 2 g/kg | In one dose in association with acetylsalicylic acid |
| Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) | Starting dose: 2 g/kg Maintenance dose: 1 g/kg | In divided doses over 2–5 days Every 3 weeks over 1–2 days |
| Multifocal Motor Neuropathy (MMN) | Starting dose: 2 g/kg Maintenance dose: 1 g/kg Or 2 g/kg | Over 2–5 consecutive days Every 2–4 weeks Or Every 4–8 weeks over 2–5 days |
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.
Hepatic impairment
No evidence is available to require a dose adjustment.
Renal impairment
No dose adjustment unless clinically warranted, see section 4.4.
Elderly
No dose adjustment unless clinically warranted, see section4.4.
Method of administration
For intravenous use.
VigamLiquid should be infused intravenously at an initial rate of 0.60–1.20 ml/kg/hour for
30 minutes. See section 4.4. In case of adverse reaction, either the rate of administration must be reduced, or the infusion stopped. If well tolerated (see section 4.4), the rate of administration may be gradually increased to 2.40 ml/kg/hour up to a maximum of 180 ml/hour.
4.3 Contraindications
Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see section 4.4 and 6.1).
Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA-containing product can result in anaphylaxis.
4.4 Special warnings and precautions for use
Traceability
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
Sucrose
This medicinal product contains 2.4 mg of sucrose per ml as an excipient. Reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products, however those containing sucrose as an excipient accounted for a disproportionate share of the total number. For acute renal failure see below.
Precautions for use
Potential complications can often be avoided by ensuring that patients:
are not sensitive to human normal immunoglobulin by initially injecting the product slowly (0.60 ml/kg/hour)
are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve 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 at the hospital 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 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 (see section 4.5).
In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the adverse reaction.
Infusion reaction
Certain adverse reactions (e.g. headache, flushing, chills, myalgia, wheezing, tachycardia, lower back pain, nausea, and hypotension) 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.
Adverse reactions may occur more frequently:
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
in patients with an untreated infection or underlying chronic inflammation
Hypersensitivity
Hypersensitivity reactions are rare.
Anaphylaxis can develop in patients:
with undetectable IgA who have anti-IgA antibodies
who had tolerated previous treatment with human normal immunoglobulin
In case of shock, standard medical treatment for shock should be implemented.
Thromboembolism
There is clinical evidence of an association between IVIg administration and thromboembolic events such as myocardial infarction, cerebral vascular accident (including stroke), pulmonary embolism and deep vein thromboses which is assumed to be related to a relative increase in blood viscosity through the high influx of immunoglobulin in at-risk patients. Caution should be exercised in prescribing and infusing IVIg in obese patients and in patients with pre-existing risk factors for thrombotic events (such as advanced age, hypertension, diabetes mellitus and a history of vascular disease or thrombotic episodes, patients with acquired or inherited thrombophilic disorders, patients with prolonged periods of immobilisation, severely hypovolemic 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.
Renal parameters should be assessed prior to infusion of IVIG, particularly in patients judged to have a potential increased risk for developing acute renal failure, and again at appropriate intervals. In patients at risk for acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable. In case of renal impairment, IVIg discontinuation should be considered.
While reports of renal dysfunction and acute renal failure have been associated with the use of many of the licensed IVIg products containing various excipients such as sucrose, glucose, and maltose, those containing sucrose as a stabiliser accounted for a disproportionate share of the total number. In patients at risk, the use of IVIg products that do not contain these excipients may be considered. Vigam Liquid contains sucrose.
Aseptic meningitis syndrome (AMS)
Aseptic meningitis syndrome has been reported to occur in association with IVIg treatment. 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 (2g/kg) IVIg treatment.
Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis.
Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.
Haemolytic anaemia
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells with immunoglobulin, causing a positive direct antiglobulin reaction (Coombs’ test) and, rarely, haemolysis. Haemolytic anaemia can develop subsequent to IVIg therapy due to enhanced red blood cells (RBC) sequestration. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis (see section 4.8).
Neutropenia/Leukopenia
A transient decrease in neutrophil count and/or episodes of neutropenia, sometimes severe, have been reported after treatment with IVIgs. This typically occurs within hours or days after IVIg administration and resolves spontaneously within 7 to 14 days.
Transfusion related acute lung injury (TRALI)
In patients receiving IVIg, there have been some reports of acute non-cardiogenic pulmonary oedema [Transfusion Related Acute Lung Injury (TRALI)].
TRALI is characterised by severe hypoxia, dyspnoea, tachypnoea, cyanosis, fever and hypotension. Symptoms of TRALI typically develop during or within 6 hours of a transfusion, often within 1–2 hours. Therefore, IVIg recipients must be monitored for and IVIg infusion must be immediately stopped in case of pulmonary adverse reactions. TRALI is a potentially life-threatening condition requiring immediate intensive-care-unit management.
Interference with serological testing
After the administration 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 Vigam Liquid 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
The listed warnings and precautions apply to both adults and children.
4.5 Interaction with other medicinal products and other forms of interaction
Live attenuated virus vaccines
Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines such as measles, rubella, mumps and varicella. After administration of this medicinal product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked.
Loop diuretics
Avoidance of concomitant use of loop diuretics.
Paediatric population
The listed interaction(s) apply to both adults and children.
4.6 Fertility, pregnancy and lactation
Pregnancy
The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus, and the neonate, are expected.
Breast-feeding
Immunoglobulins are excreted into human milk. No negative effects on the breastfed new-borns/infants are anticipated.
Fertility
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.
4.7 Effects on ability to drive and use machines
The ability to drive and operate machines may be impaired by some adverse reactions associated with Vigam Liquid. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.
4.8 Undesirable effects
Summary of the safety profile
Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4):
chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain
reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion
(rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration
(rarely) transient cutaneous reactions (including cutaneous lupus erythematosus – frequency unknown)
(very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses
cases of reversible aseptic meningitis
cases of increased serum creatinine level and/or occurrence of acute renal failure
cases of Transfusion Related Acute Lung Injury (TRALI)
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 the available data).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Frequency of Adverse Reactions (ADRs) in clinical studies with Vigam Liquid
| MedDRA System Organ Class (SOC) | Adverse Reaction | Frequency |
| Nervous system disorders | Headache | Common |
| Vascular disorders | Hypertension NOS | Common |
| Hypotension NOS | Common | |
| Respiratory, thoracic and mediastinal disorders | Pharyngitis | Common |
| Transfusion related acute lung injuries (TRALI) | Not known | |
| Gastrointestinal disorders | Vomiting | Common |
| Nausea | Common | |
| Skin and subcutaneous tissue disorders | Dermatitis exfoliative NOS | Common |
| Rash macular | Common | |
| Urticaria NOS | Common | |
| Cutaneous lupus erythematosus | Unknown | |
| Musculoskeletal and connective tissue disorders | Arthralgia | Common |
| General disorders and administration site conditions | Pyrexia | Very common |
| Infusion site pain/inflammation | Common | |
| Lethargy | Common | |
| Fatigue | Common |
Description of selected adverse reactions
None of the reported adverse reactions to Vigam Liquid warrant separate description.
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 professional are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseOverdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with cardiac renal impairment (see section 4.4).
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06BA02.
Human normal immunoglobulin contains mainly immunoglobulins G (IgG) with a broad spectrum of antibodies against infectious agents.
Human normal immunoglobulin contains the IgG antibodies present in the normal population. It is usually prepared from pooled plasma from not fewer than 1000 donations. It has a distribution of immunoglobulin G subclasses closely proportional to that in native human plasma. Adequate doses of this medicinal product may restore abnormally low immunoglobulin G levels to the normal range.
The mechanism of action in indications other than replacement therapy is not fully elucidated.
Paediatric population
There is no clinical data on the pharmacodynamics of Vigam Liquid in children.
5.2 Pharmacokinetic properties
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after intravenous administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3 – 5 days equilibrium is reached between intra- and extravascular compartments. Vigam Liquid has a half-life of about 23 – 25 days. This half-life may vary from patient to patient, particularly in primary immunodeficiency.
IgG and IgG complexes are broken down in cells of the reticuloendothelial system.
Paediatric population
There is no clinical data on the pharmacokinetics of Vigam Liquid in children.
5.3 Preclinical safety data
Human proteins include antibodies in heterologous species. Therefore, pre-clinical studies have not been carried out with Vigam Liquid which contains immunoglobulins which are normal constituents of human blood.
6. PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Human Albumin Solution 20% added at 2 g/100 ml
Sodium n-octanoate
Sucrose
Sodium acetate
Glycine
6.2 Incompatibilities
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products nor with any other IVIg products.
6.3 Shelf life
36 months if stored unopened between 2°C and 8°C.
6.4 Special precautions for storage
VigamLiquid should be stored in its carton to protect it from light, between 2°C and 8°C.
Do not freeze.
A short period up to 3 months up to 25°C is possible within the shelf-life period.
Do not use after the expiry date printed on the label. The conditions of expired or incorrectly stored product cannot be guaranteed. Such product may be unsafe and should not be used.
6.5 Nature and contents of container
Vigam Liquid is a sterile colourless to pale amber or pale green liquid immunoglobulin G supplied as 2.5 g, 5 g and 10 g doses. The product is contained in a clear glass bottle and stoppered with a rubber bung. The bung is over-sealed with a tamper-evident cap.
6.6 Special precautions for disposal
6.6 Special precautions for disposalThe product should be brought to room or body temperature before use.
The solution should be clear or slightly opalescent and colourless or pale amber or green. Solutions that are cloudy or have deposits should not be used.
Use of VigamLiquid should begin immediately after piercing the cap.
Vigam Liquid is for single use only.
Any unused product or waste material should be disposed of in accordance with local requirements.
Bio Products Laboratory Ltd
Elstree
WD6 3BX
United Kingdom
8. Marketing Authorisation Number
8. Marketing Authorisation NumberPL 08801/0040
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
Date of first authorisation: 29 October 1997
Date of latest renewal: 25 April 2003
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