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.
Fructose
This medicinal product contains 50 mg of sorbitol per ml as an excipient.
Patients with rare hereditary problems of fructose intolerance should not take this medicine. In babies and young children hereditary fructose intolerance may not yet be diagnosed, as they may not yet have been exposed to fructose- containing foods such as fruit or sucrose and infusion of sorbitol may be fatal.
Therefore, babies and young children who have not been exposed to fructose containing foods or sucrose should not receive this medicine until it is known whether they can metabolise fructose.

In other patients, in case of inadvertent administration and suspicion of fructose intolerance, the infusion has to be stopped immediately, normal glycaemia has to be re-established and organ function has to be stabilised by means of intensive care.

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 (0.01 – 0.02 ml/kg/min)
- 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 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.
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. Gammaplex does not contain sucrose, maltose or glucose.

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) 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 human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the non-enveloped hepatitis A (HAV) and parvovirus B19 viruses.
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 Gammaplex 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
This medicinal product contains 50 mg of sorbitol per ml as an excipient.
Patients with rare hereditary problems of fructose intolerance should not take this medicine. Special precautions should be taken with babies and young children because this fructose intolerance may not yet be diagnosed and may be fatal.
Home therapy

Gammaplex must only be used by patients themselves at home after thorough training in hospital by a qualified health care professional, expert in infusion of IVIg products. The patient should first be stabilised on the product under supervision in hospital.



Effects on Driving

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 Gammaplex. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.