Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
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 (see Section 4.5). For acute renal failure see below.
OCTAGAM contains maltose, a disaccharide sugar, which is derived from corn.
Anaphylactoid / anaphylactic reactions have been reported in association with infusion of other maltose / corn starch related products. Patients known to have corn allergies should either avoid using OCTAGAM or be closely observed for signs and symptoms of acute hypersensitivity reactions.

Certain severe adverse drug 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 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 (1 ml/kg/hour);
• 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 to OCTAGAM 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 

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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.
This medicinal product contains not more than 0.015 mmol (or 0.35 mg) sodium per ml.
To be taken into consideration by patients on a controlled sodium diet.

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 anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin.

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.



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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. OCTAGAM contains maltose (see excipients above).

In patient 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.

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.
The development of haemolysis is associated with the following risk factors: high IVIg doses administered as a single dose or in divided doses over several days; blood groups other than group O; underlying inflammatory disease. Haemolysis has only rarely been observed in patients receiving substitution therapy for PID. IVIg recipients should be monitored for clinical signs and symptoms of haemolysis. (See section 4.8.) 
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 and HCV.
The measures taken may be of limited value against non-enveloped viruses such as HAV and parvovirus B19.

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There is a 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 OCTAGAM 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.

Transfusion-related acute lung injury (TRALI)
There have been reports of non-cardiogenic pulmonary oedema [Transfusion-Related Acute Lung Injury (TRALI)] in patients treated with IVIG, therefore, this side effect cannot be totally excluded for Octagam even though no case has been observed so far for Octagam. TRALI is characterised by severe respiratory distress, pulmonary oedema, hypoxaemia, normal left ventricular function, and fever and typically occurs within 1-6 hours after transfusion.


(Falsely) raised erythrocyte sedimentation rate
In patients who are receiving IVIG as a therapy, the erythrocyte sedimentation rate (ESR) may falsely be increased (noninflammatory rise).


Circulatory (volume) overload
Circulatory (volume) overload can occur when the volume of the infused IVIG (or any other blood or plasma-derived product) and other coincidental infusions cause acute hypervolaemia and acute pulmonary oedema.

Local injection site reactions:
Local reactions at the injection site have been identified which might include extravasation, infusion site erythema, infusion site pruritus, and similar symptoms.

Paediatric population
There are no specific or additional warnings or precautions applicable for the paediatric population.

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