QUALITATIVE AND QUANTITATIVE COMPOSITION :
Human normal immunoglobulin (IVIg).
One ml of solution contains:
Human normal immunoglobulin 50 mg
(purity of at least 95% IgG)
Each vial of 50 ml contains: 2.5 g of human normal immunoglobulin
INDICATIONS :
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).
- Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP).
DOSAGE AND ADMISNISTRATIONS :
| Indication | Dose | Frequency of injections |
| Replacement Therapy: | ||
| Primary immunodeficiency syndromes
|
Starting dose:
0.4 – 0.8 g/kg Maintenance dose: 0.2 – 0.8 g/kg |
every 3 – 4 weeks |
| Secondary immunodeficiencies (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/d |
on day 1, possibly repeated once within 3 days
for 2 – 5 days |
| Guillain-Barré syndrome | 0.4 g/kg/d | 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 |
CONTRAINDICATIONS :
Hypersensitivity to the active substance (human immunoglobulins) or to any of the excipients (see section 4.4 and 6.6).
Patients with selective IgA deficiency who developed antibodies to IgA, as administering an IgA-containing product can result in anaphylaxis.
WARNINGS AND PRECAUTIONS :
This medicinal product contains 100 mg of maltose per ml as an excipient. The interference of maltose in blood glucose assays may result in falsely elevated glucose readings and, consequently, in the inappropriate administration of insulin, resulting in life-threatening hypoglycaemia and death. Also, cases of true hypoglycaemia may go untreated if the hypoglycaemic state is masked by falsely elevated glucose readings.
Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under 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 initially injecting the product slowly (rate of administration 0.46 – 0.92 ml/kg/hr);
- are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human normal immunoglobulin, patients switched from an alternative IVIg product or when there has been a long interval since the previous infusion should be monitored during the first infusion and for 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 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.
Hypersensitivity
True 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. 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.
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, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age over 65.
Renal parameters should be assessed prior to infusion of IVIg, particularly in patient judged to have a potential increased risk for developing acute renal failure, and again at appropriate intervals.
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 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. Ig VENA contains maltose.
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.
Patients exhibiting such signs and symptoms should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis.
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.
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 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, HCV and for the non-enveloped virus HAV.
The measures taken may be of limited value against non-enveloped viruses such as 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 IgVENA 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
Cases of glycosuria have been reported in paediatric patients after administration of Ig VENA. These events are usually mild and transient with no clinical signs.
Ig VENA contains 100 mg of maltose per ml as an excipient. In the renal tubules, maltose is hydrolysed to glucose which is reabsorbed and generally very little is excreted in the urine. The glucose reabsorption is age dependent. The transitory increase of maltose in plasma may exceed the renal capacity of sugar re-absorption, and result in positive testing for glucose in the urine.
ADVERSE REACTIONS :
Frequencies of undesirable effects from clinical trials are based on percentage per infusions (total number of infusions: 1189).
Adverse reactions from post-marketing experience are listed with unknown frequency as post-marketing reporting of adverse reactions is voluntary and from a population of uncertain size and it is not possible to reliably estimate the frequency of these reactions.
Source of the safety database (e.g. from clinical trials, post-authorisation safety studies and/or
spontaneous reporting)
| Table 1
Frequency of Adverse Reactions from Clinical Trials |
|||
| MedDRASystem Organ Class (SOC) | Adverse reaction | Frequency per patient | Frequency per infusion |
| Nervous system disorders | Headache, somnolence | Common | Rare |
| Gastrointestinal disorders | Nausea | Common | Rare |
| Musculoskeletal and connective tissue disorders | Back pain | Common | Uncommon |
| Myalgia | Common | Rare | |
| General disorders and administration site conditions | Asthenia, fatigue, pyrexia | Common | Rare |
| Table 2
Post-marketing Adverse Reactions |
|||
| MedDRA SOC | Adverse reaction | Frequency per patient | Frequency per infusion |
| Infections and infestations | Meningitis aseptic | Not known | Not known |
| Blood and lymphatic system disorders | Haemolysis, haemolytic anaemia | Not known | Not known |
| Immune system disorders | Anaphylactic shock, hypersensitivity | Not known | Not known |
| Psychiatric disorders | Confusional state | Not known | Not known |
| Nervous system disorders | Cerebrovascular accident, headache, dizziness, tremor, paraesthesia | Not known | Not known |
| Cardiac disorders | Myocardial infarction, cyanosis, tachycardia, bradycardia, palpitations | Not known | Not known |
| Vascular disorders | Deep vein thrombosis, embolism, hypotension, hypertension, pallor | Not known | Not known |
| Respiratory, thoracic and mediastinal disorders | Pulmonary embolism, pulmonary oedema, bronchospasm, dyspnoea, cough | Not known | Not known |
| Gastrointestinal disorders | Vomiting, diarrhoea, nausea, abdominal pain | Not known | Not known |
| Skin and subcutaneous tissue disorders | Angioedema, urticaria, erythema, dermatitis, rash, pruritus, eczema, hyperhidrosis | Not known | Not known |
| Musculoskeletal and connective tissue disorders | Arthralgia, back pain, myalgia, neck pain, muscoloskeletal stiffness | Not known | Not known |
| Renal and urinary disorders | Acute kidney injury | Not known | Not known |
| General disorders and administration site conditions | Injection site phlebitis, pyrexia, chills, chest pain, face oedema, malaise | Not known | Not known |
| Investigations | Blood pressure decreased, blood creatinine increased | Not known | Not known |
PRESENTATION :
Ig VENA 5% solution for infusion, 50 ml vial + hanger
Reg. No. : DKI2111400349A1
STORAGE :
Store in a refrigerator (2°C – 8°C). Keep the vial in the outer carton.
Before use and within the shelf-life, the vials of 50, 100 and 200 ml can be stored at room temperature, not exceeding 25°C, for a maximum of 6 consecutive months.
After this period, the product must be discarded. In any case, the product can no longer be put back in the refrigerator if kept at room temperature.
The starting date of the storage at room temperature should be reported on the outer box.
Do not freeze.
Manufactured by:
Kedrion S.p.A.
Barga (Lucca)
Italy
Imported, Registered and Marketed by:
BERNOFARM
Sidoarjo – Indonesia