One ml solution for infusion contains human plasma protein 50 mg of which at least 95% is immunoglobulin with immunoglobulin M (IgM) 6 mg, immunoglobulin A (IgA) 6 mg and immunoglobulin G (IgG) 38 mg.
Excipients with known effect: One ml solution for infusion contains 0.078 mmol (1.79 mg) sodium and 25 mg glucose (corresponding to approximately 0.0021 bread units).
Excipients/Inactive Ingredients: Glucose monohydrate, sodium chloride, water for injections.
Pharmacotherapeutic group: immune sera and immunoglobulins: immunoglobulins, normal human, for intravascular administration. ATC code: J06B A02.
Pharmacology: Pharmacodynamics: Pentaglobin contains immunoglobulin G (IgG) and elevated concentrations of immunoglobulins A (IgA) and M (IgM) having a broad spectrum of antibodies against various infectious agents and their toxins.
Pentaglobin contains the volume of antibodies which is present in the normal population. Because of the raised IgA and especially IgM content Pentaglobin possesses higher titres of agglutinating antibodies to bacterial antigens than pure IgG preparations.
Pentaglobin is prepared from pooled material from not fewer than 1000 donors. Adequate doses of this medicinal product may restore abnormally low immunoglobulin levels to the normal range.
The mechanism of action in indications other than replacement therapy is not fully elucidated, but includes immunomodulatory effects.
Pharmacokinetics: Human immunoglobulin is immediately and completely bioavailable in the recipient's circulation after intravenous administration. IgG is distributed relatively rapidly between plasma and extravascular fluid, after approximately 3 to 5 days an equilibrium is reached between the intra- and extravascular compartments.
The half-life of the human immunoglobulins contained in Pentaglobin is comparable to native immunoglobulins. The half-life may vary from patient to patient, in particular in primary immunodeficiency.
Immunoglobulins are broken down in cells of the reticulo-endothelial system.
Toxicology: Preclinical safety data: Immunoglobulins are normal constituents of the human body. In animals, single dose toxicity testing is of no relevance since higher doses result in overloading. Repeated dose toxicity testing and embryo-foetal toxic studies are impracticable due to induction of, and interference with antibodies. Effects of the product on the immune system of the new-born have not been studied.
Since clinical experience provides no hint for tumorigenic and mutagenic effects of immunoglobulins experimental studies, particularly in heterologous species, are not considered necessary.
Adjuvant therapy of severe bacterial infections additional to antibiotic therapy.
Immunoglobulin substitution in immunocompromized patients and patients suffering from severe secondary antibody deficiency syndrome (immunocompromized patients and those with a suppressed immune defence).
The dosage is dependent on the patient's immune status and on the severity of the disease. The following dosage suggestions may be used as reference: Neonates and infants:
5 ml (0.25 g)/kg body weight daily on three consecutive days. Further infusions may be required depending on the clinical course.
Children and adults:
a) Therapy of severe bacterial infections: 5 ml (0.25 g)/kg body weight daily on three consecutive days. Further infusions may be required depending on the clinical course.
b) Immunoglobulin substitution in immunocompromized patients and in severe secondary antibody deficiency syndrome patients: 3 - 5 ml (0.15 - 0.25 g)/kg body weight. Repetition at weekly intervals, if necessary.
Pentaglobin should be warmed to room or body temperature before use.
Pentaglobin should be infused intravenously at the following rates: In neonates and infants: 1.7 ml/kg body weight/hour by infusion pump.
In children and adults: 0.4 ml/kg body weight/hour.
the first 100 ml at 0.4 ml/kg body weight/hour then 0.2 ml/kg body weight/hour continuously until 15 ml/kg body weight is reached within 72 hours. (See Table 1.)
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Method of administration:
Overdose may lead to fluid overload and hyperviscosity, particularly in patients at risk, including elderly patients or patients with renal impairment.
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Hypersensitivity to human immunoglobulins, especially in patients with antibodies against IgA.
Certain severe 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 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 (0.4 ml/kg body weight/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 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 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.
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 disease which increase blood viscosity).
Thrombosis: Care should be used when normal immunoglobulin products are given to individuals determined to be at increased risk of thrombosis.
Patients at increased risk of thrombosis include those with acquired or hereditary hypercoagulable states, prolonged immobilization, in-dwelling vascular catheters, advanced age, estrogen use, a history of venous or arterial thrombosis, cardiovascular risk factor (including history of atherosclerosis and/or impaired cardiac output), and hyperviscosity (including cryoglobulins, fasting chylomicronemia and/or high triglyceride levels, and monoclonal gammopathies).
Patients at risk for thrombosis/thromboembolic adverse reactions should receive normal immunoglobulin products at the slowest infusion rate and dose practicable, and these individuals should be monitored for thrombotic complications.
Consideration should also be given to measurement of baseline blood viscosity in individuals at risk of hyperviscosity.
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 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 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.
Pentaglobin does not contain sucrose, but contains glucose (see Pentaglobin contains glucose as follows).
In patients 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.
Hemolysis: Heightened awareness of the potential for hemolysis is recommended in individuals receiving normal immunoglobulin products, particularly those who are determined to be at increased risk.
Patients at increased risk for hemolysis following treatment with normal immunoglobulin include those with non-O blood group types, those who have underlying associated inflammatory conditions, and those receiving high cumulative doses of normal immunoglobulin over the course of several days.
Patients receiving normal immunoglobulin products should be monitored for hemolysis (see Adverse Reactions), particularly those at increased risk.
Clinical symptoms and signs of hemolysis include fever, chills and dark urine. If these occur, appropriate laboratory testing should be obtained.
Interference with serological testing: After injection of an 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 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 Pentaglobin 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.
Pentaglobin contains glucose: 1 ml solution for infusion contains 25 mg glucose (approx. 0.0021 BE). A daily dose for adults of 350 ml contains 8.75 g glucose according to approx. 0.735 BE (bread exchange). This should be taken into account in patients with diabetes mellitus.
Pentaglobin contains sodium: 1 ml solution for infusion contains 0.078 mmol (1.79 mg) sodium. A daily dose of for example 15 ml for neonate contains 1.17 mmol (26.9 mg) sodium. A daily dose of 100 ml for children contains 7.8 mmol (179.3 mg) sodium. A daily dose of 350 ml for adults contains 27.3 mmol (627.6 mg) sodium. To be taken into consideration by patients on a controlled sodium diet.
Effects on ability to drive and use machines: The ability to drive and operate machines may be impaired by some adverse reactions associated with Pentaglobin. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.
Use in Children: The special warnings and precautions for use mentioned for the adults should also be considered for the paediatric population.
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. Intravenously administered IgG has been shown to cross the placenta, increasingly during the third trimester. Pentaglobin also contains IgM which does not cross the placenta. 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.
Breastfeeding: IgG is excreted into the milk and may contribute to protecting the neonate from pathogens which have a mucosal portal of entry. IgM is not excreted into the milk.
Fertility: Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.
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). (See Table 2.)
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For safety with respect to transmissible agents, see Precautions.
Frequency, type and severity of adverse reactions in the paediatric population are expected to be the same as in adults.
Pentaglobin should not be administered to infants concomitantly with calcium gluconate as the suspicion exists that adverse reactions may occur after simultaneous administration.
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 and 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.
Paediatric population: It is expected that the same interaction mentioned for the adults may also occur in the paediatric population.
Special precautions for disposal and other handling: Pentaglobin should be mixed with physiological solution of sodium chloride only.
The medical product should be warmed to room or body temperature before use.
The medical product should be inspected visually prior to administration. The solution must be clear or slightly to moderate opalescent. Do not use solutions which are cloudy or which have deposits.
Any unused product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: This medicinal product must not be mixed with other medicinal products except those mentioned previously.
Store in a refrigerator (2 °C - 8 °C).
Store in the original package in order to protect from light.
Do not freeze.
Once opened the solution for infusion should be used immediately. Due to the risk of bacterial contamination the unused solution should be disposed.
Shelf life: 2 years.
J06BA02 - immunoglobulins, normal human, for intravascular adm. ; Belongs to the class of normal human immunoglobulins. Used in passive immunizations.
Soln for infusion (vial) (slightly to moderate opalescent & colourless to light yellow) 50 mg/mL x 50 mL, 100 mL.