GAMUNEX Solution for infusion Ref.[27524] Active ingredients: Human normal immunoglobulin G

All patients should be closely monitored when high rates of infusion (8.4 ml/kg/hr) are used. In children or patients at risk of renal failure, the maximum infusion rate should not exceed 4.8 ml/kg/hr.

Gamunex 10% must not be mixed with other solutions for infusion (e.g. saline solution) and other medicinal products. If dilution is necessary prior to infusion, 50 mg/ml glucose solution may be used for this purpose. However, in case of latent diabetes (where transient glycosuria could appear), diabetes, or in patients on a low sugar diet use of a 50 mg/ml glucose solution should be carefully monitored. Also see warning about acute renal failure below.

Simultaneous administration of Gamunex 10% and heparin through a single lumen delivery device must be avoided.

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

Potential complications can often be avoided by ensuring that patients:

• are not sensitive to normal human immunoglobulin by initially injecting the product slowly (0.1 ml/kg/hr),
• are carefully monitored for any symptoms throughout the infusion period. In particular, patients naïve to human 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 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 to 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. Gamunex 10% 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).

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. Increased vigilance is recommended for non-0 blood group patients receiving high doses for non-PID indications. Haemolysis has rarely been reported in patients given replacement therapy for PID.

Isolated cases of haemolysis-related renal dysfunction/renal failure with fatal outcome have occurred.

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). The measures taken may be of limited value against non-enveloped viruses such as 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.

It is strongly recommended that every time that Gamunex 10% 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

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.

Physicians need to strongly consider monitoring haemoglobin levels 24 to 48 hours after completion of IVIg if haemolysis is suspected. If retreatment is required it is strongly recommended to monitor haemoglobin levels one week after subsequent IVIg dosing if haemolysis is suspected. Families should be instructed to return if their child develops symptoms of haemolysis, such as; pallor, lethargy, dark urine, dyspnoea or palpitations.

Live attenuated virus vaccines

Immunoglobulin administration may impair for a period of at least 6 weeks and up to 3 months the efficacy of live attenuated virus vaccines, such as measles, rubella, mumps or varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In the case of measles, this impairment may persist for up to 1 year. Therefore patients receiving measles vaccine should have their antibody status checked.

Loop diuretics

Avoidance of concomitant use of loop diuretics

Paediatric population

Although specific interaction studies have not been performed in the paediatric population, no differences between adults and children are to be expected.

Pregnancy

The safety of this medicinal product for use in human pregnancy has not been established in controlled clinical trials and therefore should only be given with caution to pregnant women and breast-feeding mothers. IVIg products have been shown to cross the placenta, increasingly during the third trimester. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are expected.

Breast-feeding

Immunoglobulins are excreted into human milk. No negative effects on the breastfed newborns/infants are anticipated.

Fertility

Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.

The ability to drive and operate machines may be impaired by some adverse reactions associated with Gamunex 10%. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.

Summary of the safety profile

Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also Section 4.4):

• chills, headache, dizziness, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain
• reversible haemolytic reactions; especially in those patients with blood groups A, B, and AB and (rarely) haemolytic anaemia requiring transfusion
• (rarely) a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration
• (rarely) transient cutaneous reactions (including cutaneous lupus erythematosus – frequency unknown)
• (very rarely) thromboembolic reactions such as myocardial infarction, stroke, pulmonary embolism, deep vein thromboses
• cases of reversible aseptic meningitis
• cases of increased serum creatinine level and/or occurrence of acute renal failure
• cases of Transfusion Related Acute Lung Injury (TRALI).

Tabulated list of adverse reactions

The table presented below is according to the MedDRA system organ classification (SOC and Preferred Term Level). Frequencies have been evaluated according to the following convention: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Source of the safety data base: clinical trials in a total of 703 patients exposed to Gamunex 10% (with a total of 4378 infusions):

Paediatric population

Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system: Yellow Card Scheme; website: www.mhra.gov.uk/yellowcard

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.