MabThera · 4.4 Special warnings and precautions for use · 3

HOS-083534 · 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 MabThera 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 MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combination with chemotherapy. The most frequently observed adverse reactions in patients receiving MabThera 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 MabThera. 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 MabThera 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 < 1/1 000), 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. 15 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 MabThera monotherapy/maintenance or in combination with chemotherapy MedDRA Very Common Common Uncommon Rare Very Rare Not known System Organ Class Infections and bacteria

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HOS-083540 · has-adverse-reaction-information · PDF-Seite 63

The information provided in this section pertains to the use of MabThera in oncology. For information related to the autoimmune indications, please refer to the SmPC of MabThera intravenous formulation. Summary of the safety profile During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions. Local cutaneous reactions, including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the phase 3 SABRINA trial (BO22334), local cutaneous reactions were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the MabThera subcutaneous arm were injection erythema (13%), injection pain (7%) and injection site oedema (4%). Events seen following subcutaneous administration were mild or moderate, apart from one patient who reported a local cutaneous reaction of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration (Cycle 2). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections. Adverse reactions reported in MabThera subcutaneous formulation usage The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in two open-label trials involving patients with follicular lymphoma during induction and maintenance (SABRINA/BO22334) and during maintenance only (SparkThera/BP22333). In SABRINA, severe administration-related reactions (grade ≥ 3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth. In SparkThera, no severe administration-related reactions were reported. Adverse reactions reported in MabThera intravenous formulation usage 63 Experience from non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia The overall safety profile of MabThera 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 MabThera monotherapy (as induction treatment or maintenance treatment following induction treatment) or in combinat

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HOS-083546 · has-adverse-reaction-information · PDF-Seite 87

The information provided in this section pertains to the use of MabThera in oncology. For information related to the autoimmune indications, please refer to the SmPC of MabThera intravenous formulation. Summary of the safety profile During the development programme, the safety profile of MabThera subcutaneous formulation was comparable to that of the intravenous formulation with the exception of local cutaneous reactions. Local cutaneous reactions including injection site reactions were very common in patients receiving MabThera subcutaneous formulation. In the NHL phase 3 trial SABRINA (BO22334), local cutaneous reactions were reported in up to 20% of patients receiving subcutaneous MabThera. The most common local cutaneous reactions in the MabThera subcutaneous arm were injection site erythema (13%), injection site pain (7%), and injection site oedema (4%). Events seen following subcutaneous administration were mild or moderate, apart from one patient who reported a local cutaneous reaction 87 of Grade 3 intensity (injection site rash) following the first MabThera subcutaneous administration (Cycle 2). Local cutaneous reactions of any grade in the MabThera subcutaneous arm were most common during the first subcutaneous cycle (Cycle 2), followed by the second, and the incidence decreased with subsequent injections. Similar events were observed in the CLL SAWYER trial (BO25341) and were reported in up to 42% of patients in the MabThera subcutaneous arm. Most common local cutaneous reactions were injection site erythema (26%), injection site pain (16%), and injection site swelling (5%). Two patients in SAWYER trial who experienced Grade 3 local cutaneous reactions (injection site erythema, injection site pain and injection site swelling). Adverse reactions reported in MabThera subcutaneous formulation usage The risk of acute administration-related reactions associated with the subcutaneous formulation of MabThera was assessed in three clinical trials: SparkThera and SABRINA (the two trials in NHL)and SAWYER the CLL trial. In trial SABRINA, severe administration-related reactions (grade≥ 3) were reported in two patients (2%) following administration of MabThera subcutaneous formulation. These events were Grade 3 injection site rash and dry mouth. In trial SparkThera, no severe administration-related reactions were reported. In SAWYER (BO25341), severe administration--related reactions (Grade ≥ 3) were re

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HOS-083530 · has-contraindication-information · PDF-Seite 9

Hypersensitivity to the active substance or to murine proteins, or to any of the excipients listed insection 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-083536 · has-contraindication-information · PDF-Seite 58

Hypersensitivity to the active substance or to murine proteins, hyaluronidase or to any of the excipients listed in section 6.1. Active, severe infections (see section 4.4). Patients in a severely immunocompromised state.

HOS-083542 · has-contraindication-information · PDF-Seite 83

Hypersensitivity to the active substance or to murine proteins, hyaluronidase or to any of the excipients listed in section 6.1. Active, severe infections (see section 4.4). Patients in a severely immunocompromised state.

HOS-083529 · has-indication-information · PDF-Seite 2

Non-Hodgkin’s lymphoma (NHL) MabThera is indicated for the treatment of previously untreated adult patients with stage III-IV follicular lymphoma in combination with chemotherapy. MabThera maintenance therapy is indicated for the treatment of adult follicular lymphoma patients responding to induction therapy. MabThera 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. 2 MabThera 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. MabThera 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) MabThera 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 MabThera or patients refractory to previous MabThera plus chemotherapy. See section 5.1 for further information. Rheumatoid arthritis MabThera 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. MabThera 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 MabThera, 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). MabThera, 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 (Wege

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HOS-083541 · has-indication-information · PDF-Seite 81

MabThera is indicated in adults in combination with chemotherapy for the treatment of patients with previously untreated and relapsed/refractory chronic lymphocytic leukaemia (CLL). Only limited data are available on efficacy and safety for patients previously treated with monoclonal antibodies including MabThera or patients refractory to previous MabThera plus chemotherapy. See section 5.1 for further information.

HOS-083535 · has-indication-information · PDF-Seite 56

MabThera is indicated in adults for non-Hodgkin’s lymphoma (NHL): MabThera is indicated for the treatment of previously untreated patients with stage III-IV follicular lymphoma in combination with chemotherapy. MabThera maintenance therapy is indicated for the treatment of follicular lymphoma patients responding to induction therapy. MabThera is indicated for the treatment of patients with CD20 positive diffuse large B-cell non-Hodgkin’s lymphoma in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy.

HOS-083538 · has-interaction-information · PDF-Seite 62

Currently, there are limited data on possible drug interactions with MabThera. Co-administration with MabThera 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 MabThera. 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.

HOS-083532 · has-interaction-information · PDF-Seite 14

Currently, there are limited data on possible drug interactions with MabThera. In CLL patients, co-administration with MabThera 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 MabThera. Co-administration with methotrexate had no effect on the pharmacokinetics of MabThera 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 MabThera. In these patients the rate of clinically relevant infection while on MabThera was 6.01 per 100 patient years compared to 4.97 per 100 patient years following treatment with the biologic DMARD.

HOS-083544 · has-interaction-information · PDF-Seite 86

Currently, there are limited data on possible drug interactions with MabThera. In CLL patients, co-administration with MabThera 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 MabThera. 86 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.

HOS-083545 · has-pregnancy-information · PDF-Seite 87

Contraception in males and females Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potential must employ effective contraceptive methods during and for 12 months after treatment with MabThera. Pregnancy IgG immunoglobulins are known to cross the placental barrier. B-cell levels in human neonates following maternal exposure to MabThera 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 MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera 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 or recombinant human hyaluronidase (rHuPH20) on reproductive organs.

HOS-083533 · 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 MabThera. Pregnancy IgG immunoglobulins are known to cross the placental barrier. B-cell levels in human neonates following maternal exposure to MabThera have not been studied in clinical trials. There are no adequate and well-controlled data from studies in pregnant women, however 14 transient B-cell depletion and lymphocytopenia have been reported in some infants born to mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera 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-083539 · has-pregnancy-information · PDF-Seite 62

Contraception in males and females Due to the long retention time of rituximab in B-cell depleted patients, women of childbearing potential must employ effective contraceptive methods during and for 12 months after treatment with MabThera. Pregnancy IgG immunoglobulins are known to cross the placental barrier. B-cell levels in human neonates following maternal exposure to MabThera 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 62 mothers exposed to MabThera during pregnancy. Similar effects have been observed in animal studies (see section 5.3). For these reasons MabThera 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 or recombinant human hyaluronidase (rHuPH20) on reproductive organs.

HOS-083531 · 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 MabThera 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 MabThera for the treatment of rheumatoid arthritis and autoimmune diseases [including Systemic Lupus Erythematosus (SLE) and vasculitis] and during post-marketing use of MabThera in NHL and CLL (where the majority of patients had received MabThera in combination with chemotherapy or as part of haematopoietic stem 9 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, cerebrospinalfluid (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 MabThera 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 MabThera 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

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HOS-083537 · has-warning-information · PDF-Seite 58

Traceability In order to improve the traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded. The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment of chronic lymphocytic leukaemia (strength 1600 mg). For information related to the other indications, please refer to the SmPC of MabThera intravenous formulation. The use of MabThera subcutaneous formulation as monotherapy in patients with stage III-IV follicular lymphoma who are chemoresistant or are in their second or subsequent relapse after chemotherapy 58 cannot be recommended as the safety of the once weekly subcutaneous administration has not been established. Progressive multifocal leukoencephalopathy Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). 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 MabThera 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 MabThera therapy may lead to similar stabilisation or improved outcome. Infusion/Administration-related reactions MabThera is associated with infusion/administration-re

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HOS-083543 · has-warning-information · PDF-Seite 83

Traceability In order to improve the traceability of biological medicinal products, the tradename and batch number of the administered product should be clearly recorded. The information provided in the section 4.4 pertains to the use of MabThera subcutaneous formulation in the approved indications Treatment of non-Hodgkin’s lymphoma (strength 1400 mg) and Treatment of CLL (strength 1600 mg). For information related to the other indications, please refer to the SmPC of MabThera intravenous formulation. Progressive multifocal leukoencephalopathy Use of MabThera may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML). 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, cerebrospinalfluid (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 MabThera 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 MabThera therapy may lead to similar stabilisation or improved outcome. Infusion/Administration-related reactions MabThera is associated with infusion/administration-related reactions, which may be related to release of cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically indistinguishable from acute hypersensitivity reactions. This set of reactions which includes syndrome of cytokine release, tumour lysis syndrome and anaphylactic and hypersensitivity reactions are described below. They are not specifically related t

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