Source: Health Products Regulatory Authority (IE) Revision Year: 2022 Publisher: Neovii Biotech GmbH, Am Haag 6+7, 82166 Graefelfing, Germany
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Grafalon is contraindicated in patients with bacterial, viral or mycotic and parasitic infections, which are not under adequate therapeutic control.
Grafalon is contraindicated in solid organ transplant patients with severe thrombocytopenia, i.e., less than 50,000 platelets/microlitre because Grafalon may enhance thrombocytopenia and thus increase the risk of hemorrhage.
Grafalon is contraindicated in patients with malignant tumors except in cases where stem cell transplantation is performed as part of the treatment.
Patients receiving Grafalon must be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources to provide emergency treatment if necessary. Grafalon must be administered and monitored under appropriately qualified medical supervision.
Hypersensitivity reactions have been reported with the administration of Grafalon. Before the first administration of Grafalon, it is recommended to determine whether the patient has an anamnestical allergic predisposition, in particular to rabbit proteins.
In case of re-exposure in form of re-therapy with Grafalon or treatment with rabbit-immunoglobulin preparations of other manufacturers, the risk of developing an anaphylactic reaction is increased due to a possible sensitisation during the former therapy.
Treatment with Grafalon should be interrupted or stopped in solid organ transplant patients in whom severe thrombocytopenia develops (i.e., less than 50,000 platelets/microlitre) as Grafalon may enhance thrombocytopenia and thus increase the risk of hemorrhage. Clinical personnel should be prepared for appropriate emergency measures.
Grafalon has to be administered with special caution in patients with hepatic diseases as it may aggravate pre-existing clotting disorders. Careful monitoring of thrombocytes and coagulation parameters is recommended.
Grafalon has to be administered with special caution in patients with known or suspected cardiovascular disorders. In patients with hypotension or cardiac decompensation with orthostatic symptoms (e.g., unconsciousness, weakness, vomiting, nausea), slowing/interrupting the infusion should be considered.
Immunosuppressive therapy increases the risk for infections in general. Grafalon treated patients have an increased risk for the development of bacterial, viral, mycotic, and/or parasitic infections. Adequate monitoring and treatment measures are indicated. In patients undergoing stem cell transplantation, monitoring of CMV- and EBV-status and adequate pre-emptive therapy are recommended.
During treatment with Grafalon, patients should be advised that non-live vaccinations might be less efficacious. Live-attenuated virus vaccination is contraindicated in immunosuppressed patients.
Standard measures to prevent infections resulting from the use of medicinal products prepared by using human components include selection of donors, screening of individual donations for specific markers of infection and the inclusion of effective manufacturing steps for the inactivation/removal of viruses.
Despite this, when medicinal products prepared by using human components 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 for Grafalon are considered effective for enveloped viruses such as human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) and for the non-enveloped hepatitis A and parvovirus B19 viruses.
Grafalon contains sodium, but less than 1 mmol (23 mg) sodium per dosing unit, i.e., it is nearly “sodium-free”. The sodium content of the ready-to-use infusion solution is higher and depends on the amount of sodium chloride solution used for the dilution.
In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.
For Grafalon no clinical or animal data on exposed pregnancies and breastfeeding mothers are available. The potential risk for the fetus is unknown. Caution should be exercised when prescribing to pregnant women.
Human immunoglobulin can potentially penetrate the placental barrier or be excreted into human breast milk. Therefore, the decision to treat pregnant or lactating women should be made by the treating physician and based on a risk/benefit evaluation.
No data on fertility are available.
Not relevant.
Grafalon is an immunoglobulin product with immunosuppressive properties. Well-known class-related adverse effects include cytokine-release related symptoms, hypersensitivity reactions such as anaphylaxis and other allergic phenomena, enhanced susceptibility to infections, and occurrence of malignancies.
The nature and frequency of adverse reactions described in this section were analysed in an integrated safety analysis on the basis of 6 clinical studies consisting of 242 patients in the indications prevention of rejection in patients receiving renal transplants (136 patients) and conditioning prior to stem cell transplantation (106 patients). Approximately 94% of the patients analysed experienced at least one adverse reaction. The pattern of adverse reactions reflects in part common complications typically occurring after the respective procedures-renal transplantation (urinary tract infection, renal failure) and stem cell transplantation (pancytopenia, mucosal inflammation).
In the table below, adverse reactions reported with Grafalon are listed and classified according to frequency and System Organ Class. Frequency groupings are defined according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
| Infections and infestations | |
| Very common | CMV infection*, urinary tract infection* |
| Common | bacterial sepsis**, pneumonia**, pyelonephritis*, herpes infection, Influenza, oral Candidiasis, bronchitis, rhinitis, sinusitis, nasopharyngitis, skin infection |
| Uncommon | catheter site infection, Epstein-Barr virus infection, gastrointestinal infection, erysipelas, wound infection |
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| Common | lymphoproliferative disorder* |
| Blood and lymphatic system disorders | |
| Very common | anemia |
| Common | pancytopenia**, thrombocytopenia, leukopenia |
| Uncommon | polycythemia |
| Immune system disorders | |
| Common | anaphylactic shock**, anaphylactic reaction, hypersensitivity |
| Metabolism and nutrition disorders | |
| Common | hyperlipidemia |
| Uncommon | fluid retention, hypercholesterolemia |
| Nervous system disorders | |
| Very common | headache, tremor |
| Common | paresthesia |
| Eye disorders | |
| Common | photophobia |
| Cardiac disorders | |
| Common | tachycardia |
| Vascular disorders | |
| Very common | flushing |
| Common | hypotension*, venoocclusive disease, hypertension |
| Uncommon | shock**, lymphocele |
| Respiratory, thoracic and mediastinal disorders | |
| Very common | dyspnea |
| Common | cough, epistaxis |
| Gastrointestinal disorders | |
| Very common | vomiting, nausea, diarrhea, abdominal pain |
| Common | stomatitis |
| Uncommon | reflux esophagitis, dyspepsia |
| Hepatobiliary disorders | |
| Common | hyperbilirubinemia |
| Skin and subcutaneous tissue disorders | |
| Common | erythema, pruritus, rash |
| Uncommon | drug eruption |
| Musculoskeletal and connective tissue disorders | |
| Common | myalgia, arthralgia, back pain, musculoskeletal stiffness |
| Renal and urinary disorders | |
| Common | renal tubular necrosis*, hematuria |
| Uncommon | renal failure**, renal necrosis* |
| General disorders and administration site conditions | |
| Very common | pyrexia**, chills |
| Common | asthenia, chest pain, hyperthermia, mucosal inflammation, peripheral edema |
| Uncommon | edema |
| Investigations | |
| Common | blood creatinine increased*, Cytomegalovirus antigen positive, C-reactive protein increased |
| Uncommon | hepatic enzymes increased |
* serious reaction
** serious reaction, in single cases with fatal outcome
These reactions occur due to release of cytokines and include fever, chills, headache, nausea, vomiting, tachycardia, and circulatory changes. These reactions could be summarized under the clinical entity of cytokine release syndrome. They are frequently observed during or after the administration of Grafalon. Symptoms are usually well manageable. Prophylactic medication could be administered to alleviate these symptoms.
Reactions such as flushing, rash, erythema, edema, dyspnea with or without bronchospasm, and cough are commonly observed during and after the administration. These reactions usually respond to treatment well. The administration of appropriate prophylactic medication can ameliorate these symptoms. The occurrence of anaphylaxis/anaphylactic shock requires immediate termination of the infusion. Serum sickness, observed if Grafalon is administered for long treatment duration and at lower dosage, is rarely severe and usually responds well to symptomatic treatment.
Transient changes of thrombocyte and leukocyte counts, otherwise documented as thrombocytopenia and leukopenia are commonly observed after Grafalon administration. Anemia is very commonly observed after administration of Grafalon.
The patients treated with immunosuppressive regimens have an increased susceptibility to infections. In the first year after solid organ transplantation, the majority of patients who received Grafalon developed infections of bacterial, viral or mycotic origin. Urinary tract infection is a very common bacterial infection; very common viral infections are caused by CMV. Commonly reported infections include bacterial sepsis, bacterial pneumonia, pyelonephritis, herpetic viral infections, and oral candidiasis. EBV infections, CMV pneumonia and CMV gastroenteritis are uncommon viral infections. Systemic candidiasis is an uncommon fungal infection. The majority of infections are usually manageable with treatment. There were isolated reports of life-threatening or even fatal infections. Appropriate monitoring and prophylactic treatment can reduce the infection rate.
The incidence of malignancy occurring after Grafalon treatment is generally low across studies and publications and is comparable with the incidence observed with other combinations of immunosuppressive medications. Post-transplant lymphoproliferative disease was reported exclusively from patients who underwent allogeneic stem cell transplantation (1.7%).
Rare cases (less than 1 in every 1000 patients) of hemolysis were reported in connection with Grafalon administration and was fatal in isolated cases.
Currently available data are limited. Available information indicates that the safety profile of Grafalon in paediatric patients is not fundamentally different to that seen 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 HPRA Pharmacovigilance, Website: www.hpra.ie.
Grafalon must not be mixed with glucose, blood, blood-derivatives and solutions containing lipids and sodium heparin.
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