Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Biotest Pharma GmbH, Landsteinerstrasse 5, 63303 Dreieich, Germany, Tel.: (49) 6103 801-0, fax: (49) 6103 801 150, Email: mail@biotest.com
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
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:
Especially if applied at higher doses, intravenous human immunoglobulin administration requires:
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.
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
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.
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).
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.
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.
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 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.
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.).
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.
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.
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 rubella, mumps, measles and varicella. After administration of this product, an interval of 3 months should elapse before vaccination with live attenuated virus vaccines. In case of measles vaccination, this impairment may persist for up to 1 year. Therefore, patients receiving measles vaccine should have their antibody status checked.
Avoidance of concomitant use of loop diuretics.
The listed interactions apply to adults and children.
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. Intravenous immunoglobulin G 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.
Immunoglobulins are excreted into human milk. No negative effects on the breastfed newborns/infants are anticipated.
Clinical experience with immunoglobulins suggests that no harmful effects on fertility are to be expected.
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.
Adverse reactions caused by human normal immunoglobulins (in decreasing frequency) encompass (see also section 4.4):
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).
Adverse reactions from clinical trials: In four clinical trials no adverse reactions with Hepatect CP were identified.
Adverse reactions from post-marketing experience and non-interventional studies (frequencies not known – cannot be estimated from the available data):
| MedDRA Standard System Organ Class | Adverse reactions |
|---|---|
| Immune system disorders | Anaphylactic shock, hypersensitivity |
| Nervous system disorders | Headache, dizziness |
| Cardiac disorders | Tachycardia |
| Vascular disorders | Hypotension |
| Gastrointestinal disorders | Nausea |
| Skin and subcutaneous tissue disorders | Skin reaction, rash, pruritus |
| General disorders and administration site conditions | Pyrexia, malaise |
For safety information with respect to transmissible agents, see section 4.4.
Adverse reactions in children are expected to be the same as in adults.
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
This medicinal product must not be mixed with other medicinal products, nor with any other IVIg products.
No other preparations may be added to the Hepatect CP solution as any change in the electrolyte concentration or the pH may result in precipitation or denaturisation of the proteins.
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