- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
1. Name of the medicinal product
Vigam® Liquid is a sterile liquid of 5 g% normal immunoglobulin
2. Qualitative and quantitative composition
2.1 Active ingredientHuman normal immunoglobulin for intravenous administration. This product is prepared from plasma from screened donors. Donors are selected from the USA.2.2 Quantitative compositionVigam® Liquid contains 7 g/100 mL of human protein of which 5 g is human normal immunoglobulin.For excipients see 6.1. Vigam® Liquid has an IgA content of less than 0.02% w/w of the total protein and a sub-class distribution of IgG1:IgG2:IgG3:IgG4 of approximately 64:29:6:1; this is similar to plasma.
3. Pharmaceutical form
Vigam® Liquid is a sterile liquid for intravenous administration which varies from colourless to pale amber or pale green.
4. Clinical particulars
4.1 Therapeutic indications
Replacement therapy in: Primary immunodeficiency syndromes such as: Congenital agammaglobulinaemia and hypogammaglobulinaemia, common variable immunodeficiency, severe combined immunodeficiency; Wiskott Aldrich syndrome, myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections. Children with congenital AIDS and recurrent infections. Immunomodulation: Idiopathic Thrombocytopenic Purpura (ITP) in children or adults at high risk of bleeding spontaneously or prior to surgery to correct the platelet count; Guillain Barré Syndrome and Kawasaki disease. Allogeneic bone marrow transplantation.
4.2 Posology and method of administration
Posology The dose and dosage regimen is dependent on the indication. In replacement therapy the dosage may need to be individualised for each patient depending on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline. Replacement therapy in primary immunodeficiency syndromes The dosage regimen should achieve a trough 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 3 to 4 weeks. Idiopathic Thrombocytopenic Purpura (ITP) 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 g/kg should be administered in divided doses over 2 to 5 days or 2 g/kg as a single dose. Patients should receive concomitant treatment with acetylsalicylic acid. Allogeneic Bone Marrow TransplantationHuman normal immunoglobulin treatment is 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 a persistent lack of antibody production, a dosage of 0.5 g/kg/month is recommended until the antibody level returns to normal. The dosage recommendations are summarised in the following table:
Method of administration
Vigam® Liquid is administered intravenously preferably using an intravenous infusion set fitted with an in line 15 micron filter, at an initial rate of 0.01 - 0.02 mL/kg/minute for 30 minutes. If well tolerated, the rate of administration may be gradually increased to 0.04 mL/kg/minute up to a maximum of 3 mL/minute, for the remainder of the infusion. Due to the absence of any anti-microbial preservatives, it is recommended that administration should begin immediately after piercing the cap.
|Indication||Dose||Frequency of injections|
|Replacement therapy in primary immunodeficiency||Starting dose: 0.4 - 0.8 g/kg|
|Thereafter:0.2 - 0.8 g/kg||Every 2 - 4 weeks to obtain IgG trough level of at least 4 - 6 g/L|
|Replacement therapy in secondary immunodeficiency||0.2 - 0.4 g/kg||Every 3 - 4 weeks to obtain IgG trough level of at least 4 - 6 g/L|
|Children with AIDS||0.2 - 0.4 g/kg||Every 3 - 4 weeks|
|Idiopathic Thrombocytopenic Purpura||0.8 - 1 g/kg||On day 1, possibly repeated once within 3 days|
|0.4 g/kg/d||For 2 - 5 days|
|Guillain Barré Syndrome||0.4 g/kg/d||For 3 - 7 days|
|Kawasaki disease||1.6 - 2 g/kg||In several doses for 2 - 5 days in association with acetylsalicylic acid|
|2 g/kg||In one dose in association with acetylsalicylic acid|
|Allogeneic bone marrow transplantation:|
|- treatment of infections and prophylaxis of graft versus host disease||0.5 g/kg||Every week from day -7 up to 3 months after transplantation.|
|- persistent lack of antibody production||0.5 g/kg||Every month until antibody levels return to normal|
Vigam® Liquid is contra-indicated in patients with selective IgA deficiency who have developed antibodies to IgA. Vigam® Liquid may be contra-indicated in patients with hypersensitivity to any of the product components.
4.4 Special warnings and precautions for use
Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under 4.2 Method of administration 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 a high infusion rate;- in patients with hypo- or agammaglobulinaemia with or without IgA deficiency;- in patients who receive human normal immunoglobulin for the first time or, in rare cases, when the human normal immunoglobulin product is switched or when there has been a long interval since the previous infusion.True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency with anti-IgA antibodies. Rarely, human normal immunoglobulins can induce a fall in blood pressure with anaphylactic reaction, even in patients who 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 Vigam® Liquid slowly (0.01 mL/kg/min);- that patients 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 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 thrombosis 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).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, aged 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 renal failure or thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.In all patients, IVIg administration requires:- adequate hydration prior to the initiation of the infusion of IVIg;- monitoring of urine output;- monitoring of serum creatinine levels;- avoidance of concomitant use of loop diuretics.In case of 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 addition, the product should be administered at the minimum concentration and infusion-rate practicable.In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped. The treatment required depends on the nature and severity of the side effect. In case of shock, the current medical standards for shock treatment 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. 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.
4.5 Interaction with other medicinal products and other forms of interaction
4.5.1 Live attenuated 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 a year. Therefore patients receiving measles vaccine should have their antibody status checked.4.5.2 Interference with serological testing After infusion 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 (reticulocyte count, haptoglobin and Coombs test).
4.6 Pregnancy and lactation
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, or the newborn, are to be expected. Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the newborn.
4.7 Effects on ability to drive and use machines
No effects on the ability to drive or to use machines have been observed.
4.8 Undesirable effects
Adverse reactions such as chills, hypothermia, headache, fever, shortness of breath, vomiting, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally. Although rare, 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 regressive cutaneous reactions, often eczema-like, have been observed with human normal immunoglobulin. Increase in creatininaemia and/or acute renal failure have been observed. Very rarely: Thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis.Events reported for this product are (proportions of patients experiencing at any time):
For information on viral safety see 4.4.
|Nervous system disorders:|
|Headache, common (>1/100 to <1/10)|
|Hypertension NOS, common (>1/100 to <1/10)|
|Hypotension NOS, common (>1/100 to <1/10)|
|Respiratory, thoracic and mediastinal disorders:|
|Pharyngitis, common (>1/100 to <1/10)|
|Vomiting, common (>1/100 to <1/10)|
|Nausea, common (>1/100 to <1/10)|
|Skin and subcutaneous tissue disorders:|
|Dermatitis exfoliative NOS, common (>1/100 to <1/10)|
|Rash macular, common (>1/100 to <1/10)|
|Urticaria NOS, common (>1/100 to <1/10)|
|Musculoskeletal and connective tissue disorders:|
|Arthralgia, common (>1/100 to <1/10)|
|General disorders and administration site conditions:|
|Pyrexia, Very common (>1/10)|
|Infusion site pain/inflammation, common (>1/100 to <1/10)|
|Lethargy, common (>1/100 to <1/10)|
|Fatigue, common (>1/100 to <1/10)|
Overdosage may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.
5. Pharmacological properties
5.1 Pharmacodynamic properties
Vigam® Liquid is in pharmacotherapeutic group: Immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration, ATC code: J06B A02. Vigam® Liquid contains mainly immunoglobulin G (IgG), and has a broad spectrum of antibodies against various infectious agents. Vigam® Liquid contains the IgG antibodies present in the normal population and is prepared from pooled plasma from not fewer than 1000 donors. Vigam®Liquid has a distribution of immunoglobulin 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 Pharmacokinetic properties
Human normal immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration. It is distributed relatively rapidly between the plasma and extravascular fluid, after approximately 3 - 5 days an equilibrium is reached between intra and extravascular compartments. Intravenous immunoglobulins have a half-life of about 23 - 25 days, although this can vary from patient to patient, particularly in primary immunodeficiency. IgG and IgG complexes are broken down in cells of the reticulo-endothelial system.
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 (this contains sodium n-octanoate as a stabiliser), sucrose, sodium acetate and glycine are added to stabilise the immunoglobulin solution. The product pH 4.8 - 5.1 is achieved by adjustment with small quantities of hydrochloric acid and sodium hydroxide as required. This acidic pH has no detrimental effect on the patient because of the substantial buffering capacity of the patient's own blood.
Vigam® Liquid should not be mixed with other medicinal products as their effects on the product have not been established.
6.3 Shelf life
24 months if stored unopened between 2°C and 8°C.
6.4 Special precautions for storage
Vigam® Liquid should be stored in its carton to protect it from light, between 2° and 8°C. DO NOT FREEZE. A short period up to 3 months at 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 oversealed with a tamper-evident cap.
6.6 Special precautions for disposal and other handling
For product stored in a fridge the product container should be left out at room temperature to warm up before use. Vigam® Liquid should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear or slightly opalescent. Products which are cloudy or which have a deposit should not be used. Use of Vigam® Liquid should begin immediately after piercing the cap.Vigam® Liquid is for single use only; any used materials or unused solution should be discarded by approved means.
7. Marketing authorisation holder
Bio Products Laboratory Limited Dagger LaneElstree HertfordshireWD6 3BXUnited Kingdom.Tel: +44 (0)20 8957 2200Fax: +44 (0)20 8957 2608Email: email@example.com
8. Marketing authorisation number(s)
9. Date of first authorisation/renewal of the authorisation
29 October 1997 / 25 April 2003
10. Date of revision of the text
|July 2012||Version Code: VLS10|
BPL (Bio Products Laboratory)
Dagger Lane, Elstree, Hertfordshire, WD6 3BX
+44 (0)20 8957 2601
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