Human normal immunoglobulin.
Flebogamma 5% DIF also contains the following excipients: D-sorbitol and water for injections.
The percentage of IgG subclasses is approximately 66.6% IgG1, 28.5% IgG2, 2.7% IgG3 and 2.2% IgG4. It contains trace amounts of IgA (<0.05 mg/mL).
Pharmacotherapeutic Group: Immune sera and immunoglobulins: Immunoglobulins, normal human, for intravascular administration. ATC Code: J06BA02.
Human normal immunoglobulin is immediately and completely bioavailable in the recipient’s circulation after IV administration. It is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3-5 days equilibrium is reached between the intra- and extravascular compartments.
Flebogamma 5% DIF has a half-life of about 30-32 days. This half-life may vary from patient to patient, in particular in primary immunodeficiency.
IgG and IgG-complexes are broken down in cells of the reticuloendothelial system.
Replacement Therapy: Primary immunodeficiency syndromes eg, congenital agammaglobulinaemia and hypogammaglobulinaemia, common variable immunodeficiency, severe combined immunodeficiency, Wiskott-Aldrich syndrome. Myeloma or chronic lymphocytic leukaemia with severe secondary hypogammaglobulinaemia and recurrent infections.
Children with congenital AIDS and recurrent infections.
Immunomodulation: Idiopathic thrombocytopenic purpura (ITP), in children or adults at high risk of bleeding or prior to surgery to correct the platelet count; Guillain-Barré syndrome; Kawasaki disease.
Allogeneic bone marrow transplantation.
The dose and dosage regimen is dependent on the indication.
In replacement therapy, the dosage may need to be individualised for each patient dependent on the pharmacokinetic and clinical response. The following dosage regimens are given as a guideline.
Replacement Therapy in Primary Immunodeficiency Syndromes: The dosage regimen should achieve a trough level of IgG (measured before the next infusion) of at least 4-6 g/L. Three to six months are required after the initiation of therapy for equilibration to occur. The recommended starting dose is 0.4-0.8 g/kg followed by at least 0.2 g/kg every 3 weeks.
The dose required to achieve a trough level of 6 g/L is of the order of 0.2-0.8 g/kg/month. The dosage interval when steady state has been reached varies from 2-4 weeks.
Trough levels should be measured in order to adjust the dose and dosage interval.
Replacement Therapy in Myeloma or Chronic Lymphocytic Leukaemia with Severe Secondary Hypogammaglobulinaemia and Recurrent Infections; Replacement Therapy in Children with AIDS and Recurrent Infections: Recommended Dose: 0.2-0.4 g/kg every 3-4 weeks.
Idiopathic Thrombocytopenic Purpura: For the treatment of an acute episode, 0.8-1 g/kg on day 1, which may be repeated once within 3 days, or 0.4 g/kg daily for 2-5 days. The treatment can be repeated if relapse occurs.
Guillain-Barré Syndrome: 0.4 g/kg/day for 3-7 days. Experience in children is limited.
Kawasaki Disease: 1.6-2 g/kg should be administered in divided doses over 2-5 days or 2 g/kg as a single dose.
Patients should receive concomitant treatment with acetylsalicylic acid.
Allogeneic Bone Marrow Transplantation: Human normal immunoglobulin treatment can be used as part of the conditioning regimen and after the transplant.
For the treatment of infections and prophylaxis of graft versus host disease, dosage is individually tailored. The starting dose is normally 0.5 g/kg/week, starting 7 days before transplantation and for up to 3 months after transplantation.
In case of persistent lack of antibody production, dosage of 0.5 g/kg/month is recommended until antibody level returns to normal.
Administration: Flebogamma 5% DIF should be infused IV at an initial rate of 0.01-0.02 mL/kg/min for the first 30 min. If well tolerated, the rate of administration may gradually be increased to a maximum of 0.1 mL/kg/min.
Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.
Hypersensitivity to any of the components of Flebogamma 5% DIF; to homologous immunoglobulins, especially in very rare cases of IgA deficiency, when the patient has antibodies against IgA.
Flebogamma 5% DIF contains sorbitol 50 mg/mL as 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. Interferences with determination of blood glucose levels are not expected.
Certain severe adverse drug reactions may be related to the rate of infusion. The recommended infusion rate given under Dosage & Administration 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 hypo- 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.
True hypersensitivity reactions are rare. They can occur in the very seldom cases of IgA deficiency with anti-IgA antibodies.
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.
Potential complications can often be avoided by ensuring: That patients are not sensitive to human normal immunoglobulin by first injecting the product slowly at an initial rate of 0.01-0.02 mL/kg/min; that patients 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 1st infusion and for the 1st hour after the 1st infusion, in order to detect potential adverse signs. All other patients should be observed for at least 20 min after administration.
There is clinical evidence of an association between IVIg administration and thromboembolic events eg, myocardial infarction, 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 preexisting risk factors for thrombotic events (eg, 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, and patients with diseases which increase blood viscosity).
Cases of acute renal failure have been reported in patients receiving IVIg therapy. In most cases, risk factors have been identified eg, preexisting renal insufficiency, diabetes mellitus, hypovolemia, overweight, concomitant nephrotoxic medicinal products or age >65 years.
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, 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 may be considered.
In patients at risk for acute renal failure or thromboembolic adverse reactions, IVIg products should be administered at the minimum rate of infusion and dose practicable.
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.
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 side effect.
In case of shock, standard medical treatment for shock should be implemented.
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, and for the non-enveloped viruses 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 viral safety.
It is strongly recommended that every time Flebogamma 5% DIF 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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. Since Flebogamma 5% DIF might induce dizziness, patients should be cautioned when driving or operating machines.
Use in pregnancy & lactation: The safety of Flebogamma 5% DIF 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 breastfeeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.
Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.
The safety of Flebogamma 5% DIF 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 breastfeeding mothers. Clinical experience with immunoglobulins suggests that no harmful effects on the course of pregnancy, or on the foetus and the neonate are to be expected.
Immunoglobulins are excreted into the milk and may contribute to the transfer of protective antibodies to the neonate.
Adverse reactions eg, chills, headache, fever, vomiting, allergic reactions, nausea, arthralgia, low blood pressure and moderate low back pain may occur occasionally.
Rarely human normal immunoglobulins may cause a sudden fall in blood pressure and, in isolated cases, anaphylactic shock, even when the patient has shown no hypersensitivity to previous administration.
Cases of reversible aseptic meningitis, isolated cases of reversible haemolytic anaemia/haemolysis and rare cases of transient cutaneous reactions, have been observed with human normal immunoglobulin.
Increase in serum creatinine level and/or acute renal failure have been observed.
Thromboembolic reactions eg, myocardial infarction, stroke, pulmonary embolism, deep vein thromboses.
For safety with respect to transmissible agents, see Precautions.
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 eg, measles, rubella, mumps and varicella. After administration of Flebogamma 5% DIF, 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.
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 eg, A, B, D, may interfere with some serological tests for red cell antibodies eg, the antiglobulin test (Coomb's test).
Incompatibilities: Flebogamma 5% DIF must not be mixed with other medicinal products or IV fluids. It should be administered by a separate IV line.
Flebogamma 5% DIF must be brought to room or body temperature before use.
The solution should be clear to slightly opalescent. Do not use solutions that are cloudy or have deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
Do not store above 30°C. Do not freeze.
J06BA - Immunoglobulins, normal human ; Used in passive immunizations.
Soln for infusion 2.5 g/50 mL x 1's. 5 g/100 mL x 1's. 10 g/200 mL x 1's.