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.

Precautions for use

Monitoring of anti-HBs antibody level:
Patients should be monitored for serum anti-HBs antibody levels regularly. The dosage shall be adjusted to maintain the therapeutic antibody levels and to avoid underdosing (see section 4.2).

Potential complications can often be avoided by ensuring that patients: 
•   are not sensitive to human immunoglobulins by initially injecting Hepatect CP slowly (0.1 ml/kg/hr).
•   are carefully monitored for any symptoms throughout the infusion period. In particular, patients naive to human immunoglobulin products, patients switched from other immunoglobulins or when there has been a long interval since the previous infusion.
These patients 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.

Especially if applied at higher doses, intravenous human immunoglobulin administration requires:
• adequate hydration prior to the initiation of the infusion of human immunoglobulins 
•   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 “Method of administration“ 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 case of high rate of infusion,
• in patients with hypo- or agammaglobulinemia with or without IgA deficiency, • in patients who receive human immunoglobulins for the first time or, in rare cases, when the human 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.

Hepatect CP contains a small quantity of IgA. Individuals who are deficient in IgA have the potential for developing IgA antibodies and may have anaphylactic reactions after administration of blood components containing IgA. The physician must therefore weigh the benefit of treatment with Hepatect CP against the potential risk of hypersensitivity reactions.
Rarely, human hepatitis B immunoglobulin can induce a fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with immunoglobulin.

Suspicion of allergic or anaphylactic type reactions requires immediate discontinuation of the injection. In case of shock, standard medical treatment for shock should be implemented.

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). The measures taken may be of limited value against 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.

The following adverse reactions have been associated with the use of human normal immunoglobulin for intravenous administration (IVIg):

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 human immunoglobulin products that do not contain these excipients may be considered. Hepatect CP 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 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.

Effects on Driving

4.7     Effects on ability to drive and use machines
Hepatect CP has minor influence on the ability to drive and use machines. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.