RoActemra

HOS-095136 · has-adverse-reaction-information · PDF-Seite 81

Summary of the safety profile The safety profile comes from 4 510 patients exposed to tocilizumab in clinical trials; the majority of these patients were participating in adult RA trials (n = 4 009), while the remaining experience comes from GCA (n = 149), pJIA (n = 240) and sJIA (n = 112) trials. The safety profile of tocilizumab across these indications remains similar and undifferentiated. The most commonly reported adverse reactions were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The most serious adverse reactions were serious infections, complications of diverticulitis, and hypersensitivity reactions. Tabulated list of adverse reactions Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional trial programs are listed in Table 1 and are presented by MedDRA system organ class. The corresponding frequency category is based on 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), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 81 Table 1. List of adverse reactions occurring in patients treated with tocilizumab MedDRA Frequency category with preferred term SOC Very common Common Uncommon Rare Very rare Infections and Upper Cellulitis, Diverticulitis infestations respiratory tract Pneumonia, Oral infections herpes simplex, Herpes zoster Blood and Leukopenia, lymphatic Neutropenia, system Hypofibrinogenae disorders mia Immune Anaphylaxis system (fatal)1, 2 ,3 disorders Endocrine Hypothyroidism disorders Metabolism Hypercholester Hypertriglycerida and nut

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HOS-095130 · has-adverse-reaction-information · PDF-Seite 46

Summary of the safety profile The safety profile comes from 4 510 patients exposed to tocilizumab in clinical trials; the majority of these patients were participating in adult RA trials (n = 4 009), while the remaining experience comes from GCA (n = 149), pJIA (n = 240) and sJIA (n = 112) trials. The safety profile of tocilizumab across these indications remains similar and undifferentiated. The most commonly reported adverse reactions were upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. The most serious adverse reactions were serious infections, complications of diverticulitis, and hypersensitivity reactions. Tabulated list of adverse reactions Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional trial programs are listed in Table 1 and are presented by MedDRA system organ class. The corresponding frequency category is based on 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), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. 46 Table 1. List of adverse reactions occurring in patients treated with tocilizumab MedDRA Frequency category with preferred term SOC Very common Common Uncommon Rare Very rare Infections and Upper Cellulitis, Pneumonia, Diverticulitis infestations respiratory tract Oral herpes simplex, infections Herpes zoster Blood and Leukopenia, lymphatic Neutropenia, system Hypofibrinogenaemia disorders Immune Anaphylaxis system (fatal)1, 2 ,3 disorders Endocrine Hypothyroidi disorders sm Metabolism Hypercholestero Hypertriglyc and nutrition laemia*

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HOS-095124 · has-adverse-reaction-information · PDF-Seite 12

Summary of the safety profile RA, sJIA, pJIA and CRS The most commonly reported adverse reactions are upper respiratory tract infections, nasopharyngitis, headache, hypertension and increased ALT. 12 The most serious adverse reactions are serious infections, complications of diverticulitis, and hypersensitivity reactions. COVID-19 The most commonly reported adverse reactions are hepatic transaminases increased, constipation, and urinary tract infection. Tabulated list of adverse reactions Adverse reactions from clinical trials and/or post-marketing experience with tocilizumab based on spontaneous case reports, literature cases and cases from non-interventional trial programs are listed in Table 1 and in Table 2 by MedDRA system organ class (SOC). The corresponding frequency category for each adverse reaction is based on 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), and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. RA patients Table 1. List of adverse reactions occurring in patients with RA receiving tocilizumab as monotherapy or in combination with MTX or other DMARDs in the double-blind controlled period or during post-marketing experience MedDRA Frequency categories with preferred terms SOC Very Common Uncommon Rare Very rare common Infections Upper Cellulitis, Diverticulitis and respiratory Pneumonia, infestations tract Oral herpes infections simplex, Herpes zoster Blood and Leukopenia, lymphatic Neutropenia, system Hypofibrino- disorders genaemia Immune Anaphylaxis system (fatal)1, 2 ,3 disorders Endocrine Hypothy- disorders roidism Metabolism Hypercholeste Hypertri- and rolaemia* gly

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HOS-095120 · has-contraindication-information · PDF-Seite 8

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active, severe infections with the exception of COVID-19 (see section 4.4).

HOS-095132 · has-contraindication-information · PDF-Seite 77

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active, severe infections (see section 4.4).

HOS-095126 · has-contraindication-information · PDF-Seite 42

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active, severe infections (see section 4.4).

HOS-095131 · has-indication-information · PDF-Seite 72

Rheumatoid arthritis (RA) RoActemra, in combination with methotrexate (MTX), is indicated for  the treatment of severe, active and progressive RA in adults not previously treated with MTX.  the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease- modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. RoActemra 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. Systemic juvenile idiopathic arthritis (sJIA) RoActemra is indicated for the treatment of active sJIA in patients 12 years of age and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX. Polyarticular juvenile idiopathic arthritis (pJIA) RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factor positive or negative and extended oligoarthritis) in patients 12 years of age and older, who have responded inadequately to previous therapy with MTX. 72 RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Giant cell arteritis (GCA) RoActemra is indicated for the treatment of GCA in adult patients.

HOS-095119 · has-indication-information · PDF-Seite 2

Rheumatoid arthritis (RA) RoActemra, in combination with methotrexate (MTX), is indicated for:  the treatment of severe, active and progressive RA in adults not previously treated with MTX.  the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease- modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. RoActemra 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 MTX. Coronavirus disease 2019 (COVID-19) RoActemra is indicated for the treatment of COVID-19 in adults who are receiving systemic corticosteroids and require supplemental oxygen or mechanical ventilation. Systemic juvenile idiopathic arthritis (sJIA) RoActemra is indicated for the treatment of active sJIA in patients 2 years of age and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and 2 systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX. Polyarticular juvenile idiopathic arthritis (pJIA) RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. Cytokine release syndrome (CRS) RoActemra is indicated for the treatment of chimeric antigen receptor (CAR) T cell induced severe or life-threatening CRS in adults and paediatric patients 2 years of age and older.

HOS-095125 · has-indication-information · PDF-Seite 37

Rheumatoid arthritis (RA) RoActemra, in combination with methotrexate (MTX), is indicated for  the treatment of severe, active and progressive RA in adults not previously treated with MTX.  the treatment of moderate to severe active RA in adult patients who have either responded inadequately to, or who were intolerant to, previous therapy with one or more disease- modifying anti-rheumatic drugs (DMARDs) or tumour necrosis factor (TNF) antagonists. In these patients, RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. RoActemra 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. Systemic juvenile idiopathic arthritis (sJIA) RoActemra is indicated for the treatment of active sJIA in patients 1 year of age and older, who have responded inadequately to previous therapy with non-steroidal anti-inflammatory drugs (NSAIDs) and systemic corticosteroids. RoActemra can be given as monotherapy (in case of intolerance to MTX or where treatment with MTX is inappropriate) or in combination with MTX. Polyarticular juvenile idiopathic arthritis (pJIA) RoActemra in combination with MTX is indicated for the treatment of pJIA (rheumatoid factor positive or negative and extended oligoarthritis) in patients 2 years of age and older, who have responded inadequately to previous therapy with MTX. RoActemra can be given as monotherapy in case of intolerance to MTX or where continued treatment with MTX is inappropriate. 37 Giant cell arteritis (GCA) RoActemra is indicated for the treatment of GCA in adult patients.

HOS-095128 · has-interaction-information · PDF-Seite 45

Interaction trials have only been performed in adults. Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Population pharmacokinetic analyses did not detect any effect of MTX, NSAIDs or corticosteroids on tocilizumab clearance in RA patients. In GCA patients, no effect of cumulative corticosteroid dose on tocilizumab exposure was observed. The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced. In vitro trials with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes. In a trial in RA patients, levels of simvastatin (CYP3A4) were decreased by 57 % one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects. When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) must be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. 45

HOS-095134 · has-interaction-information · PDF-Seite 80

Interaction trials have only been performed in adults. Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. Population pharmacokinetic analyses did not detect any effect of MTX, NSAIDs or corticosteroids on tocilizumab clearance in RA patients. In GCA patients, no effect of cumulative corticosteroid dose on tocilizumab exposure was observed. The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced. In vitro trials with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes. In a trial in RA patients, levels of simvastatin (CYP3A4) were decreased by 57 % one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects. When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) must be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy. 80

HOS-095122 · has-interaction-information · PDF-Seite 11

Interaction trials have only been performed in adults. Concomitant administration of a single dose of 10 mg/kg tocilizumab with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure. 11 Population pharmacokinetic analyses did not detect any effect of MTX, NSAIDs or corticosteroids on tocilizumab clearance. The expression of hepatic CYP450 enzymes is suppressed by cytokines, such as IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, such as tocilizumab, is introduced. In vitro trials with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19 and CYP3A4 enzyme expression. Tocilizumab normalises expression of these enzymes. In a trial in RA patients, levels of simvastatin (CYP3A4) were decreased by 57 % one week following a single dose of tocilizumab, to the level similar to, or slightly higher than, those observed in healthy subjects. When starting or stopping therapy with tocilizumab, patients taking medicinal products which are individually adjusted and are metabolised via CYP450 3A4, 1A2 or 2C9 (e.g. methylprednisolone, dexamethasone, (with the possibility for oral glucocorticoid withdrawal syndrome), atorvastatin, calcium channel blockers, theophylline, warfarin, phenprocoumon, phenytoin, ciclosporin, or benzodiazepines) must be monitored as doses may need to be increased to maintain therapeutic effect. Given its long elimination half-life (t1/2), the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.

HOS-095123 · has-pregnancy-information · PDF-Seite 12

Women of childbearing potential Women of childbearing potential have to use effective contraception during and up to 3 months after treatment. Pregnancy There are no adequate data from the use of tocilizumab in pregnant women. A trial in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown. RoActemra should not be used during pregnancy unless clearly necessary. Breast-feeding It is unknown whether tocilizumab is excreted in human milk. The excretion of tocilizumab in milk has not been studied in animals. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from RoActemra therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

HOS-095129 · has-pregnancy-information · PDF-Seite 46

Women of childbearing potential Women of childbearing potential have to use effective contraception during and up to 3 months after treatment. Pregnancy There are no adequate data from the use of tocilizumab in pregnant women. A trial in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown. RoActemra should not be used during pregnancy unless clearly necessary. Breast-feeding It is unknown whether tocilizumab is excreted in human milk. The excretion of tocilizumab in milk has not been studied in animals. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from RoActemra therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

HOS-095135 · has-pregnancy-information · PDF-Seite 81

Women of childbearing potential Women of childbearing potential have to use effective contraception during and up to 3 months after treatment. Pregnancy There are no adequate data from the use of tocilizumab in pregnant women. A trial in animals has shown an increased risk of spontaneous abortion/embryo-foetal death at a high dose (see section 5.3). The potential risk for humans is unknown. RoActemra should not be used during pregnancy unless clearly necessary. Breast-feeding It is unknown whether tocilizumab is excreted in human milk. The excretion of tocilizumab in milk has not been studied in animals. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from RoActemra therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Available non-clinical data do not suggest an effect on fertility under tocilizumab treatment.

HOS-095127 · has-warning-information · PDF-Seite 42

RoActemra subcutaneous formulation is not intended for intravenous administration. RoActemra subcutaneous formulation is not intended to be given to children with sJIA weighing less than 10 kg. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. All indications Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of this medicinal product in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infections. Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents such as tocilizumab as signs and symptoms of acute inflammation may be 42 lessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating a patient for a potential infection. Patients, (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment. Tuberculosis As recommended for other biological treatments, all patients should be screened for latent tuberculosis (TB) infection prior to starting tocilizumab therapy. Patients with latent TB must be treated with standard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised. Patients, and parents/guardians of sJIA or pJIA patients should be advised to seek medical advice if signs/symptoms (e.g., persistent coug

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HOS-095121 · has-warning-information · PDF-Seite 8

Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. RA, pJIA and sJIA patients Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of this medicinal product in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infections. Vigilance for the timely detection of serious infection is recommended for patients receiving biological treatments as signs and symptoms of acute inflammation may be lessened, associated with suppression of the acute phase reaction. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating a patient for a potential infection. Patients (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment. 8 Tuberculosis (TB) As recommended for other biological treatments, RA, pJIA and sJIA patients should be screened for latent TB infection prior to starting tocilizumab therapy. Patients with latent TB must be treated with standard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised. Patients should be instructed to seek medical advice if signs/symptoms (e.g., persistent cough, wasting/weight loss, low grade fever) suggestive of a tuberculosis infection occur during or after therapy with this medicinal product. Viral reactivation Viral reactivation (e.g. hepatitis B virus) has been reported with biologic therap

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HOS-095133 · has-warning-information · PDF-Seite 77

RoActemra subcutaneous formulation is not intended for intravenous administration. RoActemra subcutaneous formulation is not intended to be given to children with sJIA weighing less than 10 kg. Traceability In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. All indications Infections Serious and sometimes fatal infections have been reported in patients receiving immunosuppressive agents including tocilizumab (see section 4.8). Treatment must not be initiated in patients with active infections (see section 4.3). Administration of tocilizumab must be interrupted if a patient develops a serious infection until the infection is controlled (see section 4.8). Healthcare professionals should exercise caution when considering the use of this medicinal product in patients with a history of recurring or chronic infections or with underlying conditions (e.g. diverticulitis, diabetes and interstitial lung disease) which may predispose patients to infections. Vigilance for the timely detection of serious infection is recommended for patients receiving immunosuppressive agents such as tocilizumab as signs and symptoms of acute inflammation may be lessened, due to suppression of the acute phase reactants. The effects of tocilizumab on C-reactive protein (CRP), neutrophils and signs and symptoms of infection must be considered when evaluating a patient for a potential infection. Patients, (which includes younger children with sJIA or pJIA who may be less able to communicate their symptoms) and parents/guardians of sJIA or pJIA patients, 77 should be instructed to contact their healthcare professional immediately when any symptoms suggesting infection appear, in order to assure rapid evaluation and appropriate treatment. Tuberculosis As recommended for other biological treatments, all patients should be screened for latent tuberculosis (TB) infection prior to starting tocilizumab therapy. Patients with latent TB must be treated with standard anti-mycobacterial therapy before initiating treatment. Prescribers are reminded of the risk of false negative tuberculin skin and interferon-gamma TB blood test results, especially in patients who are severely ill or immunocompromised. Patients, and parents/guardians of sJIA or pJIA patients should be advised to seek medical advice if signs/symptoms (e.g., persistent coug

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