Ituxredi · 4.1 Therapeutic indications · 1

HOS-100708 · has-adverse-reaction-information · PDF-Seite 15

Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia in adults Summary of the safety profile The overall safety profile of rituximab in non-Hodgkin’s lymphoma and CLL is based on data from patients from clinical trials and from post-marketing surveillance. These patients were treated either with rituximab monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy. The most frequently observed adverse reactions in patients receiving rituximab were IRRs which occurred in the majority of patients during the first infusion. The incidence of infusion-related symptoms decreases substantially with subsequent infusions and is less than 1% after eight doses of rituximab. Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of patients during clinical trials in patients with NHL and in 30-50% of patients during clinical trials in patients with CLL. The most frequently reported or observed serious adverse reactions were: • IRRs (including cytokine-release syndrome, tumour-lysis syndrome), see section 4.4. • Infections, see section 4.4. • Cardiovascular events, see section 4.4. Other serious adverse reactions reported include hepatitis B reactivation and PML (see section 4.4.). Tabulated list of adverse reactions The frequencies of adverse reactions reported with rituximab alone or in combination with chemotherapy are summarised in Table 3. Frequencies are defined as very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1000), very rare (< 1/10,000) and not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in the order of decreasing seriousness.  The adverse reactions identified only during post-marketing surveillance, and for which a frequency could not be estimated, are listed under “not known”, see footnotes. Table 3 Adverse reactions reported in clinical trials or during post-marketing surveillance in patients with NHL and CLL disease treated with rituximab monotherapy/maintenance or in combination with chemotherapy MedDRA Very System Common Uncommon Rare Very Rare Not known Common Organ Class Infections bacterial sepsis,

Auszug; vollständigen Abschnitt im Original lesen.

HOS-100704 · has-contraindication-information · PDF-Seite 9

Hypersensitivity to the active substance or to murine proteins, or to any of the excipients listed in section 6.1. Active, severe infections (see section 4.4). Patients in a severely immunocompromised state. Severe heart failure (New York Heart Association Class IV) or severe, uncontrolled cardiac disease for use in rheumatoid arthritis, granulomatosis with polyangiitis, microscopic polyangiitis and pemphigus vulgaris only (see section 4.4 regarding other cardiovascular diseases).

HOS-100703 · has-indication-information · PDF-Seite 2

Non-Hodgkin’s lymphoma (NHL) Ituxredi is indicated for the treatment of previously untreated adult patients with stage III-IV follicular lymphoma in combination with chemotherapy. Ituxredi maintenance therapy is indicated for the treatment of adult follicular lymphoma patients responding to induction therapy. Ituxredi monotherapy is indicated for treatment of adult patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy. Ituxredi is indicated for the treatment of adult patients with CD20 positive diffuse large B cell non- Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy. Ituxredi in combination with chemotherapy is indicated for the treatment of paediatric patients (aged 6 months to less than 18 years old) with previously untreated advanced stage CD20 positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL)/Burkitt leukaemia (mature B- cell acute leukaemia) (BAL) or Burkitt-like lymphoma (BLL). Chronic lymphocytic leukaemia (CLL) Ituxredi in combination with chemotherapy is indicated for the treatment of adult patients with previously untreated and relapsed/refractory CLL. Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including Ituxredi or patients refractory to previous Ituxredi plus chemotherapy. See section 5.1 for further information. Rheumatoid arthritis Ituxredi in combination with methotrexate is indicated for the treatment of adult patients with severe active rheumatoid arthritis who have had an inadequate response or intolerance to other disease-modifying anti-rheumatic drugs (DMARD) including one or more tumour necrosis factor (TNF) inhibitor therapies. Ituxredi has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with methotrexate. Granulomatosis with polyangiitis and microscopic polyangiitis Ituxredi, in combination with glucocorticoids, is indicated for the treatment of adult patients with severe, active granulomatosis with polyangiitis (Wegener’s) (GPA) and microscopic polyangiitis (MPA). Ituxredi, in combination with glucocorticoids, is indicated for the induction of remission in paediatric patients (aged 2 to less than 18 years old) with severe, active GPA (Wegener’s) and MPA. Pemphigus vulgaris Ituxredi is indi

Auszug; vollständigen Abschnitt im Original lesen.

HOS-100706 · has-interaction-information · PDF-Seite 14

Currently, there are limited data on possible drug interactions with rituximab. In CLL patients, co-administration with rituximab did not appear to have an effect on the pharmacokinetics of fludarabine or cyclophosphamide. In addition, there was no apparent effect of fludarabine and cyclophosphamide on the pharmacokinetics of rituximab. Co-administration with methotrexate had no effect on the pharmacokinetics of rituximab in rheumatoid arthritis patients. Patients with human anti-mouse antibody (HAMA) or anti-drug antibody (ADA) titres may have allergic or hypersensitivity reactions when treated with other diagnostic or therapeutic monoclonal antibodies. In patients with rheumatoid arthritis, 283 patients received subsequent therapy with a biologic DMARD following rituximab. In these patients the rate of clinically relevant infection while on rituximab was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

HOS-100707 · has-pregnancy-information · PDF-Seite 14

Contraception in males and females Due to the long retention time of rituximab in B cell depleted patients, women of childbearing potential should use effective contraceptive methods during and for 12 months following treatment with rituximab. Pregnancy IgG immunoglobulins are known to cross the placental barrier. B cell levels in human neonates following maternal exposure to rituximab have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to rituximab during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons rituximab should not be administered to pregnant women unless the possible benefit outweighs the potential risk. Breast-feeding Limited data on rituximab excretion into breast milk suggest very low rituximab concentrations in milk (relative infant dose less than 0.4%). Few cases of follow-up of breastfed infants describe normal growth and development up to 2 years. However, as these data are limited and the long- term outcomes of breastfed infants remain unknown, breast-feeding is not recommended while being treated with rituximab and optimally for 6 months following rituximab treatment. Fertility Animal studies did not reveal deleterious effects of rituximab on reproductive organs.

HOS-100705 · has-warning-information · PDF-Seite 9

Traceability In order to improve the traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded. Progressive multifocal leukoencephalopathy All patients treated with rituximab for rheumatoid arthritis, GPA, MPA or pemphigus vulgaris must be given the patient alert card with each infusion. The alert card contains important safety information for patients regarding potential increased risk of infections, including progressive multifocal leukoencephalopathy (PML). Very rare cases of fatal PML have been reported following use of rituximab for the treatment of rheumatoid arthritis and autoimmune diseases [including Systemic Lupus Erythematosus (SLE) and vasculitis] and during post-marketing use of rituximab in NHL and CLL (where the majority of patients had received rituximab in combination with chemotherapy or as part of haematopoietic stem cell transplant). Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been excluded. The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of PML. Consultation with a Neurologist should be considered as clinically indicated. If any doubt exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid (CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered. The physician should be particularly alert to symptoms suggestive of PML that the patient may not notice (e.g., cognitive, neurological or psychiatric symptoms). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of. If a patient develops PML, the dosing of rituximab must be permanently discontinued. Following reconstitution of the immune system in immunocompromised patients with PML, stabilisation or improved outcome has been seen. It remains unknown if early detection of PML and suspension of rituximab therapy may lead to similar stabilisation or improved outcome. Cardiac disorders Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or myocardial infarction have occurred in patients treated with rituximab. Therefore, p

Auszug; vollständigen Abschnitt im Original lesen.