Special Warning : אזהרת שימוש

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.

Certain severe adverse reactions 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 with hypogammaglobulinaemia 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.

Potential complications can often be avoided by ensuring that patients: – are not sensitive to human normal immunoglobulin by initially infusing the product slowly (0.3 ml/kg bw/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 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.).

For patients suffering from diabetes mellitus and requiring dilution of Privigen to lower concentrations, the presence of glucose in the recommended diluent should be taken into account.

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 anaphylactoid 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.


Haemolytic anaemia
IVIg products can contain blood group antibodies which may act as haemolysins and induce in vivo coating of red blood cells (RBC) 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 RBC sequestration. The Privigen manufacturing process includes an immunoaffinity chromatography (IAC) step that specifically reduces blood group A and B antibodies (isoagglutinins A and B). Clinical data with Privigen manufactured with the IAC step show statistically significant reductions of haemolytic anaemia (see section 4.8, section 5).

Isolated cases of haemolysis-related renal dysfunction/renal failure or disseminated intravascular coagulation and death have occurred.
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. As this event was commonly reported in non-0 blood group patients receiving high doses for non-PID indications, increased vigilance is recommended. Haemolysis has rarely been reported in patients given replacement therapy for PID.

IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. If signs and/or symptoms of haemolysis develop during or after an IVIg infusion, discontinuation of the IVIg treatment should be considered by the treating physician (see also section 4.8).

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 (2 g/kg bw) 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.

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 immunoglobulins 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 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 based on clinical judgement.

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 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 sucrose should therefore be considered. Privigen does not contain sucrose, maltose or glucose.

In patients at risk of acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose practicable based on clinical judgement.

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
Privigen is made from human plasma. 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) and for the non-enveloped viruses such as hepatitis A virus (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.


Sodium content
This medicinal product contains less than 2.3 mg sodium per 100 ml, equivalent to 0.12% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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.

Effects on Driving

4.7 Effects on ability to drive and use machines
Privigen has minor influence on the ability to drive and use machines, e.g. dizziness (see section 4.8). Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.