Source: Medicines and Medical Devices Safety Authority (NZ) Revision Year: 2022 Publisher: CSL Behring (NZ) Ltd, PO Box 62590, Greenlane, Auckland 1546, New Zealand customerservice@cslbehring.com.au www.cslbehring.com.au Manufacturer: CSL Behring (Australia) Pty Ltd, 189–209 Camp Road, Broadmeadows, ...
Intragam P is contraindicated in patients:
Intragam P should only be administered intravenously. Other routes of administration have not been evaluated.
Reactions to IVIg tend to be related to the infusion rate and are most likely to occur during the first hour of the infusion. It is recommended that the patient’s vital signs and general status are monitored regularly throughout the infusion. In case of adverse reaction, either the rate of administration must be reduced or the infusion stopped.
Certain adverse reactions may occur more frequently:
Intragam P contains trace amounts of IgA which may provoke anaphylaxis in patients with anti-IgA antibodies, such as those with IgA deficiency.
Rarely, human normal immunoglobulin can induce a precipitous fall in blood pressure with anaphylactic reaction, even in patients who had tolerated previous treatment with human normal immunoglobulin. In case of anaphylactic reaction, the infusion should be stopped immediately. Adrenaline (epinephrine) and oxygen should be available for the treatment of such an acute reaction.
There have been occasional reports of renal dysfunction and acute renal failure in patients receiving IVIg products. Patients at increased risk are those with pre-existing renal insufficiency, diabetes mellitus, age greater than 65 years, volume depletion, sepsis and monoclonal gammopathy, and those taking concomitant nephrotoxic drugs. While these reports of renal dysfunction and acute renal failure have been associated with 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. Intragam P contains maltose but it does not contain sucrose. The following precautions should be followed: patients should be adequately hydrated prior to the initiation of the IVIg infusion and the recommended dose should not be exceeded. Renal function should be monitored in patients at increased risk of developing acute renal failure. If renal function deteriorates, discontinuation of IVIg should be considered.
In patients at risk of acute renal failure, IVIg products should be administered at the minimum rate of infusion and dose possible, based on clinical judgement.
Thromboembolic events have been reported in association with IVIg therapy. Risk factors include advanced age, immobility, estrogen use, in-dwelling vascular catheters, acquired or inherited hypercoagulable states, a history of venous or arterial thrombosis, cardiovascular risk factors (including history of atherosclerosis and/or impaired cardiac output), and conditions associated with increased plasma viscosity, such as cryoglobulins, fasting chylomicronaemia and/or hypertriglyceridaemia and monoclonal gammopathies.
Patients at risk for thromboembolic events should receive IVIg products at the minimum infusion rate and dose possible based on clinical judgement, and should be monitored for thromboembolic complications. Consideration should also be given to measurement of baseline blood viscosity in individuals at risk for hyperviscosity.
Aseptic Meningitis Syndrome (AMS) has been reported to occur in association with IVIg treatment. The syndrome usually begins within several hours to two days following IVIg treatment. It is characterised by symptoms and signs including severe headache, nuchal rigidity, drowsiness, fever, photophobia, painful eye movements, and nausea and vomiting. Cerebrospinal fluid (CSF) studies are frequently positive with pleocytosis, predominantly from the granulocytic series, and elevated protein levels. Patients exhibiting such symptoms and signs should receive a thorough neurological examination, including CSF studies, to rule out other causes of meningitis. AMS may occur more frequently in association with high dose (2 g/kg) IVIg treatment. Discontinuation of IVIg treatment has resulted in remission of AMS within several days without sequelae.
Positive direct antiglobulin tests and red blood cell haemolysis have been reported following high dose infusion of IVIg due to the presence of blood group antibodies (e.g. anti-A, anti-B, and occasionally anti-D or other erythrocyte antibodies) in the product. Such red blood cell sensitisation may cause crossmatching difficulties and transient haemolytic anaemia.
The following risk factors are associated with the development of haemolysis: high doses, non-O blood group, and underlying inflammatory state.
Patients receiving IVIg (>0.4 g/kg every 4 weeks) should have a pre-infusion ABO blood group determined and have their haemoglobin monitored in the days following therapy for evidence of clinically significant haemolysis.
If signs and/or symptoms of haemolysis develop during or after an IVIg infusion, discontinuation of the IVIg treatment should be considered by the treating physician.
In patients with a normal acid-base compensatory mechanism, the acid load delivered by the largest dose of the preparation would be neutralised by the buffering capacity of whole blood alone, even if the dose were to be infused instantaneously. In patients with limited or compromised acid-base compensatory mechanisms including neonates, consideration should be given to the effect of the additional acid load that the preparation might present.
Prolonged administration (over 6 hours) using large doses (>0.4 g/kg) may result in thrombophlebitis at the infusion site.
This product is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses and theoretically Creutzfeldt-Jakob Disease (CJD) agents, that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain infectious agents and by testing for the presence of certain viral markers.
In addition, virus removal and inactivation procedures are included in the manufacturing process. The current procedures applied in the manufacture of this product are effective against enveloped viruses such as HIV (human immunodeficiency virus), hepatitis B and hepatitis C viruses, and the non-enveloped virus, hepatitis A. These procedures may be of limited value against the non-enveloped virus, parvovirus B19. However, the product contains specific antibodies directed against parvovirus B19.
Despite these measures, such products may still potentially transmit disease. There is also the possibility that other known or unknown infectious agents may be present in such products.
Vaccination for patients in receipt of medicinal products from human plasma should be considered where appropriate.
No mutagenicity, carcinogenicity or reproductive toxicity studies have been conducted with Intragam P. There have been no reports of such effects with the use of CSL Behring’s plasma derived products.
It is recommended that every time that Intragam P is administered to a patient, the name and batch number of Intragam P are recorded in order to maintain a link between the patient and the batch of the product.
The interaction of Intragam P with other medicines has not been established in appropriate studies.
Passively acquired antibody can interfere with the response to live, attenuated vaccines. Therefore, administration of such vaccines, e.g. poliomyelitis, mumps, rubella, measles and varicella/chickenpox vaccines, should be deferred until approximately three months after passive immunisation.
Immunoglobulins should not be administered for at least two weeks after a vaccine has been given. In the case of measles vaccinations, the decrease in efficacy may persist for up to a year. Patients given measles vaccine should therefore have their antibody status checked.
After immunoglobulin infusion 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. anti-A, Anti-B, anti-D) may interfere with some serological tests for red cell allo-antibodies (e.g. Coombs' test).
The maltose present in Intragam P may interfere with some blood glucose measurements, resulting in the overestimation of blood glucose results. If this glucose measurement is used to guide treatment, hypoglycaemia may occur. Only certain glucose tests using glucose dehydrogenase have been implicated, so when monitoring glucose levels in patients receiving Intragam P, information from the manufacturer of the glucose meter and/or test strips, should be reviewed to ensure that maltose does not interfere with the blood glucose reading. Infusion of Intragam P may also result in transient glucosuria.
The safety of Intragam P for use in human pregnancy and lactation has not been established in controlled clinical trials. Intragam P should therefore only be given with caution to pregnant women and breast-feeding mothers. Immunoglobulins are excreted in breast milk. 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.
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 Intragam P. Patients who experience adverse reactions during treatment should wait for these to resolve before driving or operating machines.
Patients naive to immunoglobulin may experience a higher frequency of adverse events, including those of a minor nature. Reactions to IVIg tend to be related to the infusion rate and are most likely to occur during the first hour of the infusion. It is recommended that the patient’s vital signs and general status are monitored regularly throughout the infusion.
The following adverse reactions occurred in 35 PID patients receiving Intragam P during the clinical trial (expressed as the number of patients experiencing the adverse reaction): headache (8), migraine (2), anaemia (2), nausea (2), vertigo (1), neutropenia (1), thrombocytopenia (1) and fatigue (1). The dose of Intragam P ranged from 0.2 to 0.67 g/kg/month.
The following adverse reactions occurred in 17 ITP patients receiving Intragam P during the clinical trial (expressed as the number of patients experiencing the adverse reaction): headache (10), positive direct Coombs' test (5), haemolysis (4), nausea (3), rigors (3), fever (2), myalgia (1), somnolence (1), abdominal pain (1), vomiting (1), hypertension (1), flushing (1), haemolytic anaemia (1), leucopenia (1), reticulocytosis (1), lymphopenia (1), allergic reaction (1), hot flushes (1) and injection site inflammation (1). The dose of Intragam P ranged from 0.66 to 2 g/kg received via infusion once daily over 1–3 consecutive days.
Haemolytic anaemia associated with the presence of anti-A and/or anti-B antibodies has been reported following high dose therapy with Intragam P in patients of non-O blood group (blood group A, B or AB).
In addition to the reactions observed in clinical trials, the following were observed post-marketing:
Immune system disorders: Anaphylactic reaction/Hypersensitivity
Nervous system disorders: Meningitis aseptic, Paraesthesia, Tremor
Vascular disorders: Thromboembolism
Musculoskeletal and connective tissue disorders: Arthralgia
General disorders and administration site conditions: Infusion site reactions, Pain.
Reliable estimates of the frequency of these reactions or establishment of a causal relationship to product exposure are not possible because the reporting is voluntary and from a population of uncertain size.
The types of reactions that may occur include: malaise, abdominal pain, headache, chest-tightness, facial flushing or pallor, erythema, hot sensations, dyspnoea or respiratory difficulty, non-urticarial skin rash, cutaneous vasculitis, pompholyx on hands/palms, itching, tissue swelling, change in blood pressure, nausea or vomiting. Should any of these reactions develop during infusion of Intragam P, the infusion should be temporarily stopped until the patient improves clinically (5 to 10 minutes) and then cautiously recommenced at a slower rate.
Some patients may develop delayed adverse reactions to IVIg such as: nausea, vomiting, chest pain, rigors, dizziness, aching legs or arthralgia. These adverse reactions occur after the infusion has stopped but usually within 24 hours.
True hypersensitivity reactions to IVIg such as urticaria, angioedema, bronchospasm or hypotension occur very rarely. Should an anaphylactic reaction to Intragam P develop, the infusion should be stopped and treatment instituted with adrenaline (epinephrine), oxygen, antihistamine and steroids.
Haemolytic anaemia and neutropenia have been reported in rare instances in association with IVIg treatment.
Mild and moderate elevations of serum transaminases (AST, ALT, gamma GT) have been observed in a small number of patients given IVIg. Such changes were transient and not associated with the transmission of hepatitis. Elevated liver function tests have been reported in some untreated patients with Guillain-Barré Syndrome.
AMS and thrombophlebitis have occurred in patients receiving IVIg (see section 4.4).
Thromboembolic events have been reported in association with IVIg therapy. Rarely, renal dysfunction and acute renal failure have been reported (see section 4.4).
Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
Reporting suspected adverse reactions after authorisation of the medicine is important. It allows continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are asked to report any suspected adverse reactions via https://nzphvc.otago.ac.nz/reporting/.
This medicine must not be mixed with other medicines, diluents, or solvents except those mentioned in section 6.6, and should be administered by a separate infusion line.
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