Entyvio · 4.6 Fertility, pregnancy and lactation · 1

HOS-096780 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection, bronchitis, influenza and sinusitis), headache, nausea, pyrexia, fatigue, cough, arthralgia. Infusion related reactions (with symptoms such as dyspnoea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) have also been reported in patients treated with vedolizumab. 7 Tabulated list of adverse reactions The following listing of adverse reactions is based on clinical trial and post marketing experience and is displayed by system organ class. Within the system organ classes, adverse reactions are listed under headings of the following frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), very rare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1. Adverse reactions System organ class Frequency Adverse reactions Infections and infestations Very common Nasopharyngitis Common Pneumonia, Clostridium difficile infection, Bronchitis, Gastroenteritis, Upper respiratory tract infection, Influenza, Sinusitis, Pharyngitis, Herpes zoster Uncommon Respiratory tract infection, Vulvovaginal candidiasis, Oral candidiasis Immune system disorders Very rare Anaphylactic reaction, Anaphylactic shock Nervous system disorders Very common Headache Common Paraesthesia Eye disorders Uncommon

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HOS-096786 · has-adverse-reaction-information · PDF-Seite 26

Summary of the safety profile The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection, bronchitis, influenza and sinusitis), headache, nausea, pyrexia, fatigue, cough, arthralgia. No clinically relevant differences in the overall safety profile and adverse reactions were observed in patients who received subcutaneous vedolizumab compared to the safety profile observed in clinical studies with intravenous vedolizumab with the exception of injection site reactions (with subcutaneous administration). Tabulated list of adverse reactions The following listing of adverse reactions is based on clinical trial and post marketing experience and is displayed by system organ class. Within the system organ classes, adverse reactions are listed under headings of the following frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), very rare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 1. Adverse reactions System organ class Frequency Adverse reactions Infections and infestations Very common Nasopharyngitis Common Pneumonia, Clostridium difficile infection, Bronchitis, Gastroenteritis, Upper respiratory tract infection, Influenza, Sinusitis, Pharyngitis, Herpes zoster Uncommon Respiratory tract infection, Vulvovaginal candidiasis, Oral candidiasis Immune system disorders Very rare Anaphylactic reaction, Anaphylactic shock Nervous system disorders Very common Headache Comm

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HOS-096782 · has-contraindication-information · PDF-Seite 23

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active severe infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis, and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) (see section 4.4).

HOS-096776 · has-contraindication-information · PDF-Seite 4

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Active severe infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis, and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) (see section 4.4).

HOS-096781 · has-indication-information · PDF-Seite 21

Ulcerative colitis Entyvio is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist. Crohn’s disease Entyvio is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist.

HOS-096775 · has-indication-information · PDF-Seite 2

Ulcerative colitis Entyvio is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist. Crohn’s disease Entyvio is indicated for the treatment of adult patients with moderately to severely active Crohn’s disease who have had an inadequate response with, lost response to, or were intolerant to either conventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist. Pouchitis Entyvio is indicated for the treatment of adult patients with moderately to severely active chronic pouchitis, who have undergone proctocolectomy and ileal pouch anal anastomosis for ulcerative colitis, and have had an inadequate response with or lost response to antibiotic therapy.

HOS-096778 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed. Vedolizumab has been studied in adult ulcerative colitis and Crohn’s disease patients with concomitant administration of corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate), and aminosalicylates. Population pharmacokinetic analyses suggest that co-administration of such agents did not have a clinically meaningful effect on vedolizumab pharmacokinetics. In adult patients with pouchitis, vedolizumab has been co-administered with antibiotics (see section 5.1). The pharmacokinetics of vedolizumab in patients with pouchitis has not been studied (see section 5.2). The effect of vedolizumab on the pharmacokinetics of commonly co-administered medicinal compounds has not been studied. Vaccinations Live vaccines, in particular live oral vaccines, should be used with caution concurrently with vedolizumab (see section 4.4). 6

HOS-096784 · has-interaction-information · PDF-Seite 24

No interaction studies have been performed. 24 Vedolizumab has been studied in adult ulcerative colitis and Crohn’s disease patients with concomitant administration of corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine, and methotrexate), and aminosalicylates. Population pharmacokinetic analyses suggest that co-administration of such agents did not have a clinically meaningful effect on vedolizumab pharmacokinetics. The effect of vedolizumab on the pharmacokinetics of commonly co-administered medicinal compounds has not been studied. Vaccinations Live vaccines, in particular live oral vaccines, should be used with caution concurrently with vedolizumab (see section 4.4).

HOS-096785 · has-pregnancy-information · PDF-Seite 25

Women of childbearing potential Women of childbearing potential should use adequate contraception to prevent pregnancy and to continue its use for at least 18 weeks after the last treatment. Pregnancy There are limited amount of data from the use of vedolizumab in pregnant women. In a small prospective observational study the rate of major birth defects was 7.4% in 99 women with ulcerative colitis or Crohn’s disease treated with vedolizumab and 5.6% in 76 women with ulcerative colitis or Crohn’s disease treated with other biologic agents (adjusted relative risk (RR) 1.07, 95% Confidence Interval (CI): 0.33, 3.52). Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of vedolizumab during pregnancy unless the benefits clearly outweigh any potential risk to both the mother and foetus. Breast-feeding Vedolizumab has been detected in human milk. The effect of vedolizumab on breast-fed infants, and the effects on milk production are unknown. In a milk-only lactation study assessing the concentration of vedolizumab in breast milk of lactating women with active ulcerative colitis or Crohn’s disease receiving vedolizumab, the concentration of vedolizumab in human breast milk was approximately 0.4% to 2.2% of the maternal serum concentration obtained from historical studies of vedolizumab. The estimated average daily dose of vedolizumab ingested by the infant was 0.02 mg/kg/day, which is approximately 21% of the body weight-adjusted average maternal daily dose. The use of vedolizumab in lactating women should take into account the benefit of therapy to the mother and potential risks to the infant. Fertility There are no data on the effects of vedolizumab on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see section 5.3).

HOS-096779 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential Women of childbearing potential should use adequate contraception to prevent pregnancy and to continue its use for at least 18 weeks after the last treatment. Pregnancy There are limited amount of data from the use of vedolizumab in pregnant women. In a small prospective observational study the rate of major birth defects was 7.4% in 99 women with ulcerative colitis or Crohn’s disease treated with vedolizumab and 5.6% in 76 women with ulcerative colitis or Crohn’s disease treated with other biologic agents (adjusted relative risk (RR) 1.07, 95% Confidence Interval (CI): 0.33, 3.52). Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of vedolizumab during pregnancy unless the benefits clearly outweigh any potential risk to both the mother and foetus. Breast-feeding Vedolizumab has been detected in human milk. The effect of vedolizumab on breast-fed infants, and the effects on milk production are unknown. In a milk-only lactation study assessing the concentration of vedolizumab in breast milk of lactating women with active ulcerative colitis or Crohn’s disease receiving vedolizumab, the concentration of vedolizumab in human breast milk was approximately 0.4% to 2.2% of the maternal serum concentration obtained from historical studies of vedolizumab. The estimated average daily dose of vedolizumab ingested by the infant was 0.02 mg/kg/day, which is approximately 21% of the body weight-adjusted average maternal daily dose. The use of vedolizumab in lactating women should take into account the benefit of therapy to the mother and potential risks to the infant. Fertility There are no data on the effects of vedolizumab on human fertility. Effects on male and female fertility have not been formally evaluated in animal studies (see section 5.3).

HOS-096783 · has-warning-information · PDF-Seite 23

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. Hypersensitivity reactions In clinical studies, hypersensitivity reactions have been reported, with the majority being mild to moderate in severity (see section 4.8). If an anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must be discontinued immediately and appropriate treatment initiated (see section 4.3). Infections Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity (see section 5.1). Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier (see section 4.8). Treatment is not to be initiated in patients with active, severe infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment. Vedolizumab is contraindicated in patients with active tuberculosis (see section 4.3). Before starting treatment with vedolizumab, patients must be screened for tuberculosis according to the local practice. If latent tuberculosis is diagnosed, appropriate treatment must be started with anti-tuberculosis treatment in accordance with local recommendations, before beginning vedolizumab. In patients diagnosed with TB whilst receiving vedolizumab therapy, then vedolizumab therapy should be discontinued until the TB infection has been resolved. Some integrin antagonists and some systemic immunosuppressive agents have been associated with progressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunistic infection caused by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed on gut-homing lymphocytes, vedolizumab exerts an immunosuppressive effect specific to the gut. Although no systemic immunosuppressive effect was noted in healthy subjects the effects on systemic immune system function in patients with inflammatory bowel disease is not known. Healthcare professionals should monitor patients on vedolizu

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HOS-096777 · has-warning-information · PDF-Seite 4

Intravenous vedolizumab should be administered in a healthcare setting equipped to allow management of acute hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering intravenous vedolizumab. All patients should be observed continuously during each infusion. For the first 2 infusions, they should also be observed for approximately 2 hours following completion of the infusion for signs and symptoms of acute hypersensitivity reactions. For all subsequent infusions, patients should be observed for approximately 1 hour following completion of the infusion. 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. Infusion-related reactions and hypersensitivity reactions In clinical studies and post-marketing surveillance, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity (see section 4.8). Hypersensitivity reactions were also reported in patients switching from subcutaneous to intravenous formulation. 4 If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of Entyvio must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines) (see section 4.3). If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated. Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks (see section 4.8). Infections Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity (see section 5.1). Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier (see section 4.8). Vedolizumab treatment is not to be initiated in patients with active, severe infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with ved

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