Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
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 allogeneic stem cell transplantation (106 patients). Approx. 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.
Tabulated list of adverse reactions
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

Description of selected adverse reactions
Cytokine release related symptoms
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.
Hypersensitivity reactions
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 when Grafalon is administered for long treatment duration and at lower dosage, is rarely severe and usually responds well to symptomatic treatment.

Hematological changes
Transient changes of thrombocyte and leukocyte counts, also known as thrombocytopenia and leukopenia are commonly observed after Grafalon administration. Anemia is also very commonly observed after administration of Grafalon.
Infections
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 cytomegalovirus (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 the respective treatment. There were isolated reports of life-threatening or even fatal infections. Appropriate monitoring and prophylactic treatment can reduce the infection rate.
Malignancy
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%).
Hemolysis
Rare cases (less than 1 in every 1000 patients) of hemolysis were reported in connection with Grafalon administration and were fatal in isolated cases.
Reporting of suspected adverse reactions
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il/ and emailed to the Registration Holder’s Patient Safety Unit at: drugsafety@neopharmgroup.com