ENTYVIO 108mg solution for injection in pre-filled syringe medication leaflet

Entyvio 108 mg solution for injection in pre-filled syringe

Entyvio 108 mg solution for injection in pre-filled pen

Entyvio 108 mg solution for injection in pre-filled syringe

Each pre-filled syringe contains 108 mg of vedolizumab in 0.68 mL.

Entyvio 108 mg solution for injection in pre-filled pen

Each pre-filled pen contains 108 mg of vedolizumab in 0.68 mL.

Vedolizumab is a humanised IgG1 monoclonal antibody produced in Chinese hamster ovary (CHO)cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection).

Colourless to yellow solution.

Entyvio is indicated for the treatment of adult patients with moderately to severely active ulcerativecolitis who have had an inadequate response with, lost response to, or were intolerant to eitherconventional therapy or a tumour necrosis factor-alpha (TNFα) antagonist.

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

Treatment should be initiated and supervised by specialist healthcare professionals experienced in thediagnosis and treatment of ulcerative colitis or Crohn’s disease (see section 4.4). Patients should begiven the package leaflet.

Ulcerative colitis and Crohn’s disease

The recommended dose regimen of subcutaneous vedolizumab as a maintenance treatment, followingat least 2 intravenous infusions, is 108 mg administered by subcutaneous injection once every2 weeks. The first subcutaneous dose should be administered in place of the next scheduledintravenous dose and every 2 weeks thereafter.

For the intravenous dose regimen, see section 4.2 of the Entyvio 300 mg powder for concentrate forsolution for infusion SmPC.

Insufficient data are available to determine if patients who experience a decrease in response onmaintenance treatment with subcutaneous vedolizumab would benefit from an increase in dosingfrequency.

There are no data on transition of patients from subcutaneous vedolizumab to intravenousvedolizumab during maintenance treatment.

In patients who have responded to treatment with vedolizumab, corticosteroids may be reduced and/ordiscontinued in accordance with standard of care.

Retreatment and missed dose(s)

If treatment with subcutaneous vedolizumab is interrupted or if a patient misses a scheduled dose(s) ofsubcutaneous vedolizumab, patient should be advised to inject the next subcutaneous dose as soon aspossible and then every 2 weeks thereafter. The treatment interruption period in clinical trials extendedup to 46 weeks with no evident increase in adverse reactions or injection site reactions duringre-initiation of treatment with subcutaneous vedolizumab (see section 4.8).

No dose adjustment is required in elderly patients. Population pharmacokinetic analyses showed noeffect of age (see section 5.2).

Vedolizumab has not been studied in these patient populations. No dose recommendations can bemade.

The safety and efficacy of vedolizumab in children aged 0 to 17 years old have not been established.

No data are available.

Entyvio solution for injection (in a pre-filled syringe or a pre-filled pen) is for subcutaneous injectiononly.

After proper training on correct subcutaneous injection technique, a patient or caregiver may injectwith subcutaneous vedolizumab if their physician determines it is appropriate. Comprehensiveinstructions for administration using the pre-filled syringe or the pre-filled pen are given in therespective package leaflet.

For further instructions on preparation and special precautions for handling, see section 6.6.

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, andopportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) (see section 4.4).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

In clinical studies, hypersensitivity reactions have been reported, with the majority being mild tomoderate in severity (see section 4.8).

If an anaphylactic reaction, or other severe reaction occurs, administration of vedolizumab must bediscontinued immediately and appropriate treatment initiated (see section 4.3).

Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressiveactivity (see section 5.1).

Physicians should be aware of the potential increased risk of opportunistic infections or infections forwhich the gut is a defensive barrier (see section 4.8). Treatment is not to be initiated in patients withactive, severe infections until the infections are controlled, and physicians should consider withholdingtreatment 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 controlledchronic severe infection or a history of recurring severe infections. Patients should be monitoredclosely for infections before, during and after treatment.

Vedolizumab is contraindicated in patients with active tuberculosis (see section 4.3). Before startingtreatment 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-tuberculosistreatment in accordance with local recommendations, before beginning vedolizumab. In patientsdiagnosed with TB whilst receiving vedolizumab therapy, then vedolizumab therapy should bediscontinued until the TB infection has been resolved.

Some integrin antagonists and some systemic immunosuppressive agents have been associated withprogressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunisticinfection caused by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed ongut-homing lymphocytes, vedolizumab exerts an immunosuppressive effect specific to the gut.

Although no systemic immunosuppressive effect was noted in healthy subjects the effects on systemicimmune system function in patients with inflammatory bowel disease is not known.

Healthcare professionals should monitor patients on vedolizumab for any new onset or worsening ofneurological signs and symptoms and consider neurological referral if they occur. If PML is suspected,treatment with vedolizumab must be withheld; if confirmed, treatment must be permanentlydiscontinued.

The risk of malignancy is increased in patients with ulcerative colitis and Crohn’s disease.

Immunomodulatory medicinal products may increase the risk of malignancy (see section 4.8).

Prior and concurrent use of biological products

No vedolizumab clinical trial data are available for patients previously treated with natalizumab orrituximab. Caution should be exercised when considering the use of vedolizumab in these patients.

Patients previously exposed to natalizumab should normally wait a minimum of 12 weeks prior toinitiating therapy with vedolizumab, unless otherwise indicated by the patient’s clinical condition.

No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants areavailable. Therefore, the use of vedolizumab in such patients is not recommended.

Live and oral vaccines

In a placebo-controlled study of healthy volunteers, a single 750 mg dose of vedolizumab did notlower rates of protective immunity to hepatitis B virus in subjects who were vaccinatedintramuscularly with 3 doses of recombinant hepatitis B surface antigen. Vedolizumab-exposedsubjects had lower seroconversion rates after receiving a killed, oral cholera vaccine. The impact onother oral and nasal vaccines is unknown. It is recommended that all patients be brought up to datewith all immunisations in agreement with current immunisation guidelines prior to initiatingvedolizumab therapy. Patients receiving vedolizumab treatment may continue to receive non-livevaccines. There are no data on the secondary transmission of infection by live vaccines in patientsreceiving vedolizumab. Administration of the influenza vaccine should be by injection in line withroutine clinical practice. Other live vaccines may be administered concurrently with vedolizumab onlyif the benefits clearly outweigh the risks.

Induction of remission in Crohn’s disease

Induction of remission in Crohn’s disease may take up to 14 weeks in some patients. The reasons forthis are not fully known and are possibly related to the mechanism of action. This should be taken intoconsideration, particularly in patients with severe active disease at baseline not previously treated with

TNFα antagonists (see also section 5.1).

Exploratory subgroup analyses from the clinical trials in Crohn’s disease suggested that vedolizumabadministered in patients without concomitant corticosteroid treatment may be less effective forinduction of remission in Crohn’s disease than in those patients already receiving concomitantcorticosteroids (regardless of use of concomitant immunomodulators; see section 5.1).

This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially‘sodium-free’.

No interaction studies have been performed.

Vedolizumab has been studied in adult ulcerative colitis and Crohn’s disease patients withconcomitant administration of corticosteroids, immunomodulators (azathioprine, 6-mercaptopurine,and methotrexate), and aminosalicylates. Population pharmacokinetic analyses suggest thatco-administration of such agents did not have a clinically meaningful effect on vedolizumabpharmacokinetics. The effect of vedolizumab on the pharmacokinetics of commonly co-administeredmedicinal compounds has not been studied.

Live vaccines, in particular live oral vaccines, should be used with caution concurrently withvedolizumab (see section 4.4).

Women of childbearing potential should use adequate contraception to prevent pregnancy and tocontinue its use for at least 18 weeks after the last treatment.

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 withulcerative colitis or Crohn’s disease treated with vedolizumab and 5.6% in 76 women with ulcerativecolitis 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 unlessthe benefits clearly outweigh any potential risk to both the mother and foetus.

Vedolizumab has been detected in human milk. The effect of vedolizumab on breast-fed infants, andthe effects on milk production are unknown. In a milk-only lactation study assessing the concentrationof vedolizumab in breast milk of lactating women with active ulcerative colitis or Crohn’s diseasereceiving vedolizumab, the concentration of vedolizumab in human breast milk was approximately0.4% 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 isapproximately 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 themother and potential risks to the infant.

There are no data on the effects of vedolizumab on human fertility. Effects on male and femalefertility have not been formally evaluated in animal studies (see section 5.3).

Vedolizumab has minor influence on the ability to drive and use machines, as dizziness has beenreported in a small number of patients.

The most commonly reported adverse reactions are infections (such as nasopharyngitis, upperrespiratory 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 inpatients who received subcutaneous vedolizumab compared to the safety profile observed in clinicalstudies with intravenous vedolizumab with the exception of injection site reactions (with subcutaneousadministration).

The following listing of adverse reactions is based on clinical trial and post marketing experience andis displayed by system organ class. Within the system organ classes, adverse reactions are listed underheadings 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 fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1. Adverse reactions

System organ class Frequency Adverse reaction(s)

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 Blurred vision

Vascular disorders Common Hypertension

Respiratory, thoracic and Common Oropharyngeal pain,mediastinal disorders Nasal congestion,

Cough

Not known Interstitial lung disease

Gastrointestinal disorders Common Anal Abscess,

Anal fissure,

Nausea,

Dyspepsia,

Constipation,

Abdominal distension,

Flatulence,

Haemorrhoids

Hepatobiliary disorders Common Liver enzyme increased

Very rare Hepatitis

Skin and subcutaneous tissue Common Rash,disorders Pruritus,

Eczema,

Erythema,

Night sweats,

Acne

Uncommon Folliculitis

System organ class Frequency Adverse reaction(s)

Musculoskeletal and connective Very common Arthralgiatissue disorders Common Muscle spasms,

Back pain,

Muscular weakness,

Fatigue,

Pain in the extremity

General disorders and Common Pyrexia,administration site conditions Infusion site reaction (including: Infusion sitepain and Infusion site irritation),

Infusion related reaction,

Injection site reactions#

Uncommon Chills,

Feeling cold#Subcutaneous administration only.

Injection site reactions (including pain, oedema, erythema or pruritus) were reported in 5.1% ofpatients receiving subcutaneous vedolizumab (pooled safety analysis). None resulted indiscontinuation of study treatment or changes to the dosing schedule. The majority of injection sitereactions resolved within 1-4 days. There were no reports of anaphylaxis following subcutaneousvedolizumab administration.

In GEMINI 1 and 2 controlled studies with intravenous vedolizumab, the rate of infections was0.85 per patient-year in the vedolizumab-treated patients and 0.70 per patient-year in theplacebo-treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tractinfection, sinusitis, and urinary tract infections. Most patients continued on vedolizumab after theinfection resolved.

In GEMINI 1 and 2 controlled studies with intravenous vedolizumab, the rate of serious infections was0.07 per patient year in vedolizumab-treated patients and 0.06 per patient year in placebo-treatedpatients. Over time, there was no significant increase in the rate of serious infections.

In controlled and open-label studies in adults with intravenous vedolizumab, serious infections havebeen reported, which include tuberculosis, sepsis (some fatal), salmonella sepsis, listeria meningitis,and cytomegaloviral colitis.

In clinical studies with subcutaneous vedolizumab, the rate of infections was 0.26 per patient year invedolizumab-treated patients. The most frequent infections were nasopharyngitis, upper respiratorytract infection, bronchitis and influenza.

In clinical studies with subcutaneous vedolizumab, the rate of serious infections was 0.02 per patientyear in subcutaneous vedolizumab-treated patients.

In clinical studies with intravenous and subcutaneous vedolizumab, the rate of infections invedolizumab-treated patients with BMI of 30 kg/m2 and above was higher than for those with BMI lessthan 30 kg/m2.

In clinical studies with intravenous and subcutaneous vedolizumab, a slightly higher incidence ofserious infections was reported in vedolizumab-treated patients who had prior exposure to TNFαantagonist therapy compared to patients who were naïve to previous TNFα antagonist therapy.

Overall, results from the clinical program to date do not suggest an increased risk for malignancy withvedolizumab treatment; however, the number of malignancies was small and long-term exposure waslimited. Long-term safety evaluations are ongoing.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Doses up to 10 mg/kg (approximately 2.5 times the recommended dose) have been administeredintravenously in clinical trials. No dose-limiting toxicity was seen in clinical trials.

Pharmacotherapeutic group: immunosuppressants, monoclonal antibodies, ATC code: L04AG05.

Vedolizumab is a gut-selective immunosuppressive biologic. It is a humanised monoclonal antibodythat binds specifically to the α4β7 integrin, which is preferentially expressed on gut homing T helperlymphocytes. By binding to α4β7 on certain lymphocytes, vedolizumab inhibits adhesion of these cellsto mucosal addressin cell adhesion molecule-1 (MAdCAM-1), but not to vascular cell adhesionmolecule-1 (VCAM-1). MAdCAM-1 is mainly expressed on gut endothelial cells and plays a criticalrole in the homing of T lymphocytes to tissues within the gastrointestinal tract. Vedolizumab does notbind to, nor inhibit function of, the α4β1 and αEβ7 integrins.

The α4β7 integrin is expressed on a discrete subset of memory T helper lymphocytes whichpreferentially migrate into the gastrointestinal (GI) tract and cause inflammation that is characteristicof ulcerative colitis and Crohn’s disease, both of which are chronic inflammatory immunologicallymediated conditions of the GI tract. Vedolizumab reduces gastrointestinal inflammation in UC and CDpatients. Inhibiting the interaction of α4β7 with MAdCAM-1 with vedolizumab prevents transmigrationof gut-homing memory T helper lymphocytes across the vascular endothelium into parenchymal tissuein nonhuman primates and induced a reversible 3-fold elevation of these cells in peripheral blood. Themurine precursor of vedolizumab alleviated gastrointestinal inflammation in colitic cotton-toptamarins, a model of ulcerative colitis.

In healthy subjects, ulcerative colitis patients, or Crohn’s disease patients, vedolizumab does notelevate neutrophils, basophils, eosinophils, B-helper and cytotoxic T lymphocytes, total memory Thelper lymphocytes, monocytes or natural killer cells, in the peripheral blood with no leukocytosisobserved.

Vedolizumab did not affect immune surveillance and inflammation of the central nervous system in

Experimental Autoimmune Encephalomyelitis in non-human primates, a model of multiple sclerosis.

Vedolizumab did not affect immune responses to antigenic challenge in the dermis and muscle (seesection 4.4). In contrast, vedolizumab inhibited an immune response to a gastrointestinal antigenicchallenge in healthy human volunteers (see section 4.4).

Antibodies to vedolizumab may develop during vedolizumab treatment most of which are neutralising.

The formation of anti-vedolizumab antibodies is associated with increased clearance of vedolizumaband lower rates of clinical remission.

In clinical trials with intravenous vedolizumab at doses ranging from 0.2 to 10 mg/kg, > 95%saturation of α4β7 receptors on subsets of circulating lymphocytes involved in gut immune surveillancewas observed in patients.

Vedolizumab did not affect CD4+ and CD8+ trafficking into the CNS as evidenced by the lack ofchange in the ratio of CD4+/CD8+ in cerebrospinal fluid pre- and post-vedolizumab administration inhealthy human volunteers. These data are consistent with investigations in nonhuman primates whichdid not detect effects on immune surveillance of the CNS.

Ulcerative colitis - vedolizumab for intravenous administration

The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with moderatelyto severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥ 2) wasdemonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints atweek 6 and week 52 (GEMINI 1). Enrolled patients had failed at least 1 conventional therapy,including corticosteroids, immunomodulators, and/or the TNFα antagonist infliximab (includingprimary non-responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/orimmunomodulators were permitted.

For the evaluation of the week 6 endpoints, 374 patients were randomised in a double-blind fashion(3:2) to receive vedolizumab 300 mg or placebo at week 0 and week 2. Primary endpoint was theproportion of patients with clinical response (defined as reduction in complete Mayo score of≥ 3 points and ≥ 30% from baseline with an accompanying decrease in rectal bleeding subscore of≥ 1 point or absolute rectal bleeding subscore of ≤ 1 point) at week 6. Table 2 shows the results fromthe primary and secondary endpoints evaluated.

Table 2. Week 6 efficacy results of GEMINI 1

Placebo Vedolizumab

Endpoint n = 149 n = 225

Clinical response 26% 47%*

Clinical remission§ 5% 17%†

Mucosal healing¶ 25% 41%‡

*p < 0.0001†p ≤ 0.001‡p < 0.05§Clinical remission: Complete Mayo score of ≤ 2 points and no individual subscore > 1 point¶Mucosal healing: Mayo endoscopic subscore of ≤ 1 point

The beneficial effect of vedolizumab on clinical response, remission and mucosal healing wasobserved both in patients with no prior TNFα antagonist exposure as well as in those who had failedprior TNFα antagonist therapy.

In GEMINI 1, 2 cohorts of patients received vedolizumab at week 0 and week 2: cohort 1 patientswere randomised to receive either vedolizumab 300 mg or placebo in a double-blind fashion, andcohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacy at week 52,373 patients from cohort 1 and 2 who were treated with vedolizumab and had achieved clinicalresponse at week 6 were randomised in a double-blind fashion (1:1:1) to 1 of the following regimensbeginning at week 6: vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, orplacebo every 4 weeks. Beginning at week 6, patients who had achieved clinical response and werereceiving corticosteroids were required to begin a corticosteroid-tapering regimen. Primary endpointwas the proportion of patients in clinical remission at week 52. Table 3 shows the results from theprimary and secondary endpoints evaluated.

Table 3. Week 52 efficacy results of GEMINI 1

Vedolizumab IV Vedolizumab IV

Placebo every 8 weeks every 4 weeks

Endpoint n = 126* n = 122 n = 125

Clinical remission 16% 42%† 45%†

Durable clinical response¶ 24% 57%† 52%†

Mucosal healing 20% 52%† 56%†

Durable clinical remission# 9% 20%§ 24%‡

Corticosteroid-free clinical remission♠ 14% 31%§ 45%†

*The placebo group includes those subjects who received vedolizumab at week 0 and week 2, and wererandomised to receive placebo from week 6 through week 52.†p < 0.0001‡p < 0.001§p < 0.05¶Durable clinical response: Clinical response at weeks 6 and 52#Durable clinical remission: Clinical remission at weeks 6 and 52♠Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who haddiscontinued corticosteroids beginning at week 6 and were in clinical remission at week 52. Patientnumbers were n = 72 for placebo, n = 70 for vedolizumab every 8 weeks, and n = 73 for vedolizumabevery 4 weeks

Exploratory analyses provide additional data on key subpopulations studied. Approximately one-thirdof patients had failed prior TNFα antagonist therapy. Among these patients, 37% receivingvedolizumab every 8 weeks, 35% receiving vedolizumab every 4 weeks, and 5% receiving placeboachieved clinical remission at week 52. Improvements in durable clinical response (47%, 43%, 16%),mucosal healing (42%, 48%, 8%), durable clinical remission (21%, 13%, 3%) and corticosteroid-freeclinical remission (23%, 32%, 4%) were seen in the prior TNFα antagonist failure population treatedwith vedolizumab every 8 weeks, vedolizumab every 4 weeks and placebo, respectively.

Patients who failed to demonstrate response at week 6 remained in the study and receivedvedolizumab every 4 weeks. Clinical response using partial Mayo scores was achieved at week 10 andweek 14 by greater proportions of vedolizumab patients (32% and 39%, respectively) compared withplacebo patients (15% and 21%, respectively).

Patients who lost response to vedolizumab when treated every 8 weeks were allowed to enter anopen-label extension study and receive vedolizumab every 4 weeks. In these patients, clinicalremission was achieved in 25% of patients at week 28 and week 52.

Patients who achieved a clinical response after receiving vedolizumab at week 0 and 2 and were thenrandomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-labelextension study and receive vedolizumab every 4 weeks. In these patients, clinical remission wasachieved in 45% of patients by 28 weeks and 36% of patients by 52 weeks.

In this open-label extension study, the benefits of vedolizumab treatment as assessed by partial Mayoscore, clinical remission, and clinical response were shown for up to 196 weeks.

Health-related quality of life (HRQOL) was assessed by Inflammatory Bowel Disease Questionnaire(IBDQ), a disease specific instrument, and SF-36 and EQ-5D, which are generic measures.

Exploratory analysis show clinically meaningful improvements were observed for vedolizumabgroups, and the improvements were significantly greater as compared with the placebo group atweek 6 and week 52 on EQ-5D and EQ-5D VAS scores, all subscales of IBDQ (bowel symptoms,systemic function, emotional function and social function), and all subscales of SF-36 including the

Physical Component Summary (PCS) and Mental Component Summary (MCS).

Ulcerative colitis - vedolizumab for subcutaneous administration

The efficacy and safety of subcutaneous vedolizumab for the treatment of adult patients withmoderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥ 2)was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacyendpoints at week 52 (VISIBLE 1). In VISIBLE 1, enrolled patients (n = 383) had failed at least1 conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists(including primary non responders). Concomitant stable doses of oral aminosalicylates, corticosteroidsand/or immunomodulators were permitted.

Patients who achieved clinical response to open-label treatment with intravenous vedolizumab atweek 6 were eligible to be randomised For the evaluation of the week 52 endpoints, 216 (56.4%)patients were randomised and treated in a double-blind fashion (2:1:1) to 1 of the following regimens:

subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, orplacebo.

The baseline demographics were similar for patients in vedolizumab and placebo groups. The baseline

Mayo score was between 9 to 12 (severe ulcerative colitis) in about 62% and 6 to 8 (moderateulcerative colitis) in about 38% of the overall study population.

Primary study endpoint clinical remission was defined as a complete Mayo score of ≤ 2 points and noindividual subscore > 1 point at 52 weeks in patients who had achieved a clinical response at week 6of intravenous vedolizumab induction treatment. Clinical response was defined as a reduction incomplete Mayo score of ≥ 3 points and ≥ 30% from baseline with an accompanying decrease in rectalbleeding subscore of ≥ 1 point or absolute rectal bleeding subscore of ≤ 2 points and no individualsubscore >1 point.

Table 4 shows the evaluated results from the primary and secondary endpoints.

Table 4. Week 52 efficacy results of VISIBLE I

Estimatec of

Vedolizumab

Vedolizumab treatment

IVa Placebob SC 108 mg difference

Endpoint 300 mg P-valuecn = 56 every 2 weeks (95% CI)every 8 weeksn = 106 Vedolizumab SCn = 54vs. Placebo

Clinical remissiond 14.3% 46.2% 42.6% 32.3 (19.7, 45.0) p < 0.001

Mucosal healinge 21.4% 56.6% 53.7% 35.7 (22.1, 49.3) p < 0.001

Durable clinicalf 28.6% 64.2% 72.2% 36.1 (21.2, 50.9) p < 0.001response

Durable clinical p = 0.076g 5.4% 15.1% 16.7% 9.7 (-6.6, 25.7)remission (NS)

Corticosteroid-free p = 0.067h 8.3% 28.9% 28.6% 20.6 (-4.5, 43.7)remission (NS)aEndpoints are presented in the order that fixed-sequence testing was performed for control of Type 1 error at 5%bThe placebo group includes those subjects who received intravenous vedolizumab at week 0 and week 2, andwere randomised to receive placebo from week 6 through week 52.

cEstimate of treatment difference and the p-value for all endpoints is based on the Cochrane-Mantel-HaenszelmethoddClinical remission: Complete Mayo score of ≤ 2 points and no individual subscore > 1 point at week 52eMucosal healing: Mayo endoscopic subscore of ≤ 1 pointfDurable clinical response: Clinical response at weeks 6 and 52gDurable clinical remission: Clinical remission at weeks 6 and 52hCorticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinuedcorticosteroids and were in clinical remission at week 52. Patient numbers using oral corticosteroids at baselinewere n = 24 for placebo, n = 45 for subcutaneous vedolizumab and n = 21 for intravenous vedolizumab

NS = non significant (2-tailed p-value > 0.05)

The primary and secondary endpoints were analysed in subgroups of patients who had failed prior

TNFα antagonist therapy (37%; n = 80) and patients who were naïve to previous TNFα antagonisttherapy (63%; n = 136). Results of study patients treated with placebo and subcutaneous vedolizumabin these subgroups are presented in Table 5.

Table 5. VISIBLE 1 Study results at week 52 analysed by response to prior previous TNFαantagonist therapy

Treatment once every 2 weeks

Placebo Vedolizumab SC 108 mg

Failure prior TNFα antagonist therapy n = 19 n = 39

Clinical remission 5.3% 33.3%

Mucosal healing 5.3% 46.2%

Durable clinical response 15.8% 66.7%

Durable clinical remission 0% 2.6%

Corticosteroid free clinical remissiona 8.3% 27.3%

Naive TNFα antagonist therapy n = 37 n = 67

Clinical remission 18.9% 53.7%

Mucosal healing 29.7% 62.7%

Durable clinical response 35.1% 62.7%

Durable clinical remission 8.1% 22.4%

Corticosteroid free clinical remissionb 8.3% 30.4%a Patients who had failed prior TNFα antagonist therapy and using oral corticosteroids at baseline were n = 12 forplacebo and n = 22 for subcutaneous vedolizumabb Patients who were naïve to prior TNFα antagonist therapy and using oral corticosteroids at baseline weren = 12 for placebo and n = 23 for subcutaneous vedolizumab

Health related quality of life (HRQOL) was assessed by Inflammatory Bowel Disease Questionnaire(IBDQ), a disease specific instrument, and EuroQol-5 Dimension (EQ-5D, including EQ 5D VAS),which is a generic measure. Work productivity was assessed by work productivity and activityimpairment questionnaire (WPAI-UC). Patients treated with subcutaneous vedolizumab maintainedimprovements in IBDQ, EQ-5D and WPAI-UC scores at week 52 to a greater extent than patients whoreceived placebo.

Patients who completed VISIBLE 1 were eligible to enrol in an ongoing, open-label extension study toevaluate long-term safety and efficacy of subcutaneous vedolizumab treatment in patients withulcerative colitis or Crohn’s disease.

Patients in VISIBLE 1 who did not achieve clinical response at week 6 received a third dose ofvedolizumab 300 mg by intravenous infusion at week 6. Of patients who received a third dose ofvedolizumab 300 mg by intravenous infusion at week 6, 79.7% (114/143) achieved a clinical responseat week 14. Patients who achieved a clinical response at week 14 were eligible to enter the open-labelextension study and receive subcutaneous vedolizumab 108 mg every 2 weeks. Clinical remission asassessed by the partial Mayo score (a standardised measure that includes 3 of the 4 scored subscales ofthe complete Mayo score: stool frequency, rectal bleeding, and physician global assessment) wasachieved by 39.2% (40/102) of these patients at week 40 after transitioning to subcutaneousvedolizumab in the open-label extension study.

Patients randomised to intravenous vedolizumab treatment group in VISIBLE 1 received vedolizumab300 mg intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter until week 52. At week 52,these patients entered the open-label extension study and received subcutaneous vedolizumab 108 mgevery 2 weeks. Clinical remission as assessed by the partial Mayo score was maintained in 77% ofpatients at 24 weeks after transitioning to subcutaneous vedolizumab in the open-label extensionstudy.

Crohn’s disease - vedolizumab for intravenous administration

The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with moderatelyto severely active Crohn’s disease (Crohn’s Disease Activity Index [CDAI] score of 220 to 450) wereevaluated in 2 studies (GEMINI 2 and 3). Enrolled patients have failed at least 1 conventional therapy,including corticosteroids, immunomodulators, and/or TNFα antagonists (including primarynon-responders). Concomitant stable doses of oral corticosteroids, immunomodulators, and antibioticswere permitted.

The GEMINI 2 Study was a randomised, double-blind, placebo-controlled study evaluating efficacyendpoints at week 6 and week 52. Patients (n = 368) were randomised in a double-blind fashion (3:2)to receive 2 doses of vedolizumab 300 mg or placebo at week 0 and week 2. The 2 primary endpointswere the proportion of patients in clinical remission (defined as CDAI score ≤ 150 points) at week 6and the proportion of patients with enhanced clinical response (defined as a ≥ 100-point decrease in

CDAI score from baseline) at week 6 (see Table 6).

GEMINI 2 contained 2 cohorts of patients that received vedolizumab at weeks 0 and 2:

cohort 1 patients were randomised to receive either vedolizumab 300 mg or placebo in a double-blindfashion, and cohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacyat week 52, 461 patients from cohorts 1 and 2, who were treated with vedolizumab and had achievedclinical response (defined as a ≥ 70-point decrease in CDAI score from baseline) at week 6, wererandomised in a double-blind fashion (1:1:1) to 1 of the following regimens beginning at week 6:

vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, or placebo every 4 weeks.

Patients showing clinical response at week 6 were required to begin corticosteroid tapering. Primaryendpoint was the proportion of patients in clinical remission at week 52 (see Table 7).

The GEMINI 3 Study was a second randomised, double-blind, placebo-controlled study that evaluatedefficacy at week 6 and week 10 in the subgroup of patients defined as having failed at least1 conventional therapy and failed TNFα antagonist therapy (including primary non-responders) aswell as the overall population, which also included patients who failed at least 1 conventional therapyand were naïve to TNFα antagonist therapy. Patients (n = 416), which included approximately 75%

TNFα antagonist failures patients, were randomised in a double-blind fashion (1:1) to receive eithervedolizumab 300 mg or placebo at weeks 0, 2, and 6. The primary endpoint was the proportion ofpatients in clinical remission at week 6 in the TNFα antagonist failure subpopulation. As noted in

Table 6, although the primary endpoint was not met, exploratory analyses show that clinicallymeaningful results were observed.

Table 6. Efficacy results for GEMINI 2 and 3 studies at week 6 and week 10

Study

Endpoint Placebo Vedolizumab IV

GEMINI 2 Study

Clinical remission, week 6

Overall 7% (n = 148) 15%* (n = 220)

TNFα Antagonist(s) Failure 4% (n = 70) 11% (n = 105)

TNFα Antagonist(s) Naïve 9% (n = 76) 17% (n = 109)

Enhanced clinical response, week 6

Overall 26% (n = 148) 31%† (n = 220)

TNFα Antagonist(s) Failure 23% (n = 70) 24% (n = 105)

TNFα Antagonist(s) Naïve 30% (n = 76) 42% (n = 109)

Serum CRP change from baseline toweek 6, median (mcg/mL)

Overall‡ -0.5 (n = 147) -0.9 (n = 220)

GEMINI 3 Study

Clinical remission, week 6

Overall‡ 12% (n = 207) 19% (n = 209)

TNFα Antagonist(s) Failure¶ 12% (n = 157) 15%§ (n = 158)

TNFα Antagonist(s) Naïve 12% (n = 50) 31% (n = 51)

Clinical remission, week 10

Overall 13% (n = 207) 29% (n = 209)

TNFα Antagonist(s) Failure¶,‡ 12% (n = 157) 27% (n = 158)

TNFα Antagonist(s) Naïve 16% (n = 50) 35% (n = 51)

Sustained clinical remission#,¶

Overall 8% (n = 207) 15% (n = 209)

TNFα Antagonist(s) Failure¶,‡ 8% (n = 157) 12% (n = 158)

TNFα Antagonist(s) Naïve 8% (n = 50) 26% (n = 51)

Enhanced clinical response, week 6

Overall^ 23% (n = 207) 39% (n = 209)

TNFα Antagonist(s) Failure‡ 22% (n = 157) 39% (n = 158)

TNFα Antagonist(s) Naïve^ 24% (n = 50) 39% (n = 51)

*p < 0.05†not statistically significant‡secondary endpoint to be viewed as exploratory by pre-specified statistical testing procedure§not statistically significant, the other endpoints were therefore not tested statistically¶n = 157 for placebo and n = 158 for vedolizumab#Sustained clinical remission: clinical remission at weeks 6 and 10^Exploratory Endpoint

Table 7. Efficacy results for GEMINI 2 at week 52

Vedolizumab IV Vedolizumab IV

Placebo every 8 weeks every 4 weeksn = 153* n = 154 n = 154

Clinical remission 22% 39%† 36%‡

Enhanced clinical response 30% 44%‡ 45%‡

Corticosteroid-free clinical remission§ 16% 32%‡ 29%‡

Durable clinical remission¶ 14% 21% 16%

*The placebo group includes those subjects who received vedolizumab at week 0 and week 2, and wererandomised to receive placebo from week 6 through week 52.†p < 0.001‡p < 0.05§Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinuedcorticosteroids beginning at week 6 and were in clinical remission at week 52. Patient numbers were n = 82for placebo, n = 82 for vedolizumab every 8 weeks, and n = 80 for vedolizumab every 4 weeks¶Durable clinical remission: Clinical remission at ≥ 80% of study visits including final visit (week 52)

Exploratory analyses examined the effects of concomitant corticosteroids and immunomodulators oninduction of remission with vedolizumab. Combination treatment, most notably with concomitantcorticosteroids, appeared to be more effective in inducing remission in Crohn’s disease thanvedolizumab alone or with concomitant immunomodulators, which showed a smaller difference fromplacebo in the rate of remission. Clinical remission rate in GEMINI 2 at week 6 was 10% (differencefrom placebo 2%, 95% CI: -6, 10) when administered without corticosteroids compared to 20%(difference from placebo 14%, 95% CI: -1, 29) when administered with concomitant corticosteroids.

In GEMINI 3 at week 6 and 10 the respective clinical remission rates were 18% (difference fromplacebo 3%, 95% CI: -7, 13) and 22% (difference from placebo 8%, 95% CI: -3, 19) whenadministered without corticosteroids compared to 20% (difference from placebo 11%, 95% CI: 2, 20)and 35% (difference from placebo 23%, 95% CI: 12, 33) respectively when administered withconcomitant corticosteroids. These effects were seen whether or not immunomodulators were alsoconcomitantly administered.

Exploratory analyses provide additional data on key subpopulations studied. In GEMINI 2,approximately half of patients had previously failed TNFα antagonist therapy. Among these patients,28% receiving vedolizumab every 8 weeks, 27% receiving vedolizumab every 4 weeks, and 13%receiving placebo achieved clinical remission at week 52. Enhanced clinical response was achieved in29%, 38%, 21%, respectively, and corticosteroid-free clinical remission was achieved in 24%, 16%,0%, respectively.

Patients who failed to demonstrate response at week 6 in GEMINI 2 were retained in the study andreceived vedolizumab every 4 weeks. Enhanced clinical response was observed at week 10 andweek 14 for greater proportions of vedolizumab patients 16% and 22%, respectively, compared withplacebo patients 7% and 12%, respectively. There was no clinically meaningful difference in clinicalremission between treatment groups at these time points. Analyses of week 52 clinical remission inpatients who were non-responders at week 6 but achieved response at week 10 or week 14 indicatethat non-responder CD patients may benefit from a dose of vedolizumab at week 10.

Patients who lost response to vedolizumab when treated every 8 weeks in GEMINI 2 were allowed toenter an open-label extension study and received vedolizumab every 4 weeks. In these patients,clinical remission was achieved in 23% of patients at week 28 and 32% of patients at week 52.

Patients who achieved a clinical response after receiving vedolizumab at week 0 and 2 and were thenrandomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-labelextension study and receive vedolizumab every 4 weeks. In these patients, clinical remission wasachieved in 46% of patients by 28 weeks and 41% of patients by 52 weeks.

In this open-label extension study, clinical remission and clinical response were observed in patientsfor up to 196 weeks.

Exploratory analysis showed clinically meaningful improvements were observed for the vedolizumabevery 4 weeks and every 8 weeks groups in GEMINI 2 and the improvements were significantlygreater as compared with the placebo group from baseline to week 52 on EQ-5D and EQ-5D VASscores, total IBDQ score, and IBDQ subscales of bowel symptoms and systemic function.

Crohn’s disease - vedolizumab for subcutaneous administration

The efficacy and safety of subcutaneous vedolizumab for the treatment of adult patients withmoderately to severely active Crohn’s disease (CDAI score of 220 to 450) was demonstrated in arandomised, double-blind, placebo-controlled study evaluating efficacy endpoints atweek 52 (VISIBLE 2). In VISIBLE 2, enrolled patients (n = 644) had inadequate response to, loss ofresponse to, or intolerance to one conventional therapy, including corticosteroids, immunomodulators,and/or TNFα antagonists (including primary non-responders). Concomitant stable doses of oralaminosalicylates, corticosteroids and/or immunomodulators were permitted.

Patients who achieved clinical response to open-label treatment with intravenous vedolizumab atweek 6 were eligible to be randomised. For the evaluation of the week 52 endpoints, 409 (64%)patients were randomised and treated in a double-blind fashion (2:1) to receive subcutaneousvedolizumab 108 mg (n = 275) or subcutaneous placebo (n = 134) every 2 weeks.

The baseline demographics were similar for patients in vedolizumab and placebo groups. The baseline

CDAI was > 330 (severe Crohn’s disease) in about 41% and ≤ 330 (moderate Crohn’s disease) inabout 59% of the overall study population.

Beginning at week 6, patients who had achieved clinical response (defined as a ≥ 70-point decrease inthe CDAI score from baseline) and were receiving corticosteroids were required to begin acorticosteroid tapering regimen. Primary endpoint was the proportion of patients with clinicalremission (CDAI score ≤ 150) at week 52. The secondary endpoints were the proportion of patientswith enhanced clinical response ( ≥ 100 point decrease in CDAI score from baseline) at week 52, theproportion of patients with corticosteroid-free remission (patients using oral corticosteroids at baselinewho had discontinued corticosteroids and were in clinical remission) at week 52, and the proportion of

TNFα antagonist naïve patients who achieved clinical remission (CDAI score ≤ 150) at week 52.

Table 8 shows the evaluated results from the primary and secondary endpoints.

Table 8. Week 52 efficacy results of VISIBLE 2

Estimate‡ of

Vedolizumab† treatment difference

Placebo SC 108 mg

Endpoint* (95% CI) P-value‡n = 134 every 2 weeks

Vedolizumab SC vs.n = 275

Placebo

Clinical remission§ 34.3% 48.0% 13.7 (3.8, 23.7) p = 0.008p = 0.167

Enhanced clinical response# 44.8% 52.0% 7.3 (-3.0, 17.5)(NS)

Corticosteroid-free

** 18.2% 45.3% 27.1 (11.9, 42.3) p = 0.002‡‡remission

Clinical remission in TNFᆆ 42.9% 48.6% 4.3 (-11.6, 20.3) p = 0.591‡‡antagonist naïve patients

*Endpoints are presented in the order that fixed-sequence testing was performed for control of Type 1 error at5%†The placebo group includes those subjects who received intravenous vedolizumab at week 0 and week 2, andwere randomised to receive placebo from week 6 through week 52.‡Estimate of treatment difference and the p-value for all endpoints is based on the Cochrane-Mantel-Haenszelmethod§Clinical remission: CDAI score ≤ 150, at week 52#Enhanced clinical response: ≥ 100-point decrease in CDAI score from baseline (week 0), at week 52

**Corticosteroid-free clinical remission: Patients using oral corticosteroids at baseline who had discontinuedcorticosteroids and were in clinical remission at week 52. Patient numbers using oral corticosteroids atbaseline were n = 44 for placebo and n = 95 for subcutaneous vedolizumab.

†† Clinical remission (CDAI score ≤ 150, at week 52) in TNFα antagonist naïve patients (n = 63 placebo;n = 107 subcutaneous vedolizumab‡‡ nominal p-value

NS = non significant (2-tailed p-value > 0.05)

The primary and secondary endpoints were analysed in subgroups of patients who were naïve to prior

TNFα antagonist therapy (42%; n = 170), patients who had failed prior TNFα antagonist therapy(51%; n = 210), and patients who had exposure to prior TNFα antagonist therapy but did notexperience treatment failure (7%; n = 29). Results of study patients treated with placebo andsubcutaneous vedolizumab in these subgroups are presented in Tables 9 and 10.

Table 9. Week 52 efficacy results in TNFα antagonist naïve patients in VISIBLE 2

Treatment difference

Vedolizumab SC 108 mg (95% CI)

Placebo every 2 weeks Vedolizumab SC vs.

Endpoint n = 63 n = 107 Placebo

Clinical remission 42.9% 48.6% 4.3 (-11.6, 20.3)

Enhanced clinical response 47.6% 54.2% 4.4 (-11.6, 20.3)

Corticosteroid-free 22.8 (-3.2, 46.8)

** 18.2% 41.0%remission

** Patients who were naïve to prior TNFα antagonist therapy and using oral corticosteroids at baseline weren = 22 for placebo and n = 39 for subcutaneous vedolizumab

Table 10. Week 52 efficacy results in patients who failed TNFα antagonist therapy in

VISIBLE 2

Treatment difference

Vedolizumab SC 108 mg (95% CI)

Placebo every 2 weeks Vedolizumab SC vs.

Endpoint n = 59 n = 151 Placebo

Clinical remission 28.8% 46.4% 17.6 (3.8, 31.4)

Enhanced clinical response 45.8% 49.0% 3.2 (-11.8, 18.2)

Corticosteroid-free 31.2 (5.2, 54.5)

** 15.0% 46.2%remission

** Patients who had failed prior TNFα antagonist therapy and using oral corticosteroids at baseline weren = 20 for placebo and n = 52 for subcutaneous vedolizumab

HRQOL was assessed by IBDQ, a disease specific instrument, and EQ-5D (including EQ-5D VAS),which is a generic measure. Work productivity was assessed by WPAI-CD. Patients treated withsubcutaneous vedolizumab maintained improvements in IBDQ, EQ-5D and WPAI-CD scores atweek 52 to a greater extent than patients who received placebo.

Patients who completed VISIBLE 2 were eligible to enrol in an ongoing, open-label extension study toevaluate long-term safety and efficacy of subcutaneous vedolizumab treatment in patients withulcerative colitis or Crohn’s disease.

The European Medicines Agency has deferred the obligation to submit the results of studies withvedolizumab in 1 or more subsets of the paediatric population in ulcerative colitis and Crohn’s disease(see section 4.2 for information on paediatric use).

The single and multiple dose pharmacokinetics of vedolizumab have been studied in healthy subjectsand in patients with moderate to severely active ulcerative colitis or Crohn’s disease.

In patients administered 300 mg intravenous vedolizumab as a 30 minute intravenous infusion onweeks 0 and 2, mean serum trough concentrations at week 6 were 27.9 mcg/mL (SD ± 15.51) inulcerative colitis and 26.8 mcg/mL (SD ± 17.45) in Crohn’s disease. In studies with intravenousvedolizumab, starting at week 6, patients received 300 mg intravenous vedolizumab every 8 or4 weeks. In patients with ulcerative colitis, mean steady-state serum trough concentrations were11.2 mcg/mL (SD ± 7.24) and 38.3 mcg/mL (SD ± 24.43), respectively. In patients with Crohn'sdisease mean steady-state serum trough concentrations were 13.0 mcg/mL (SD ± 9.08)and 34.8 mcg/mL (SD ± 22.55), respectively.

In studies in patients with ulcerative colitis or Crohn’s disease receiving subcutaneous vedolizumab,starting at week 6, patients received 108 mg subcutaneous vedolizumab every 2 weeks. The meansteady state serum trough concentrations were 35.8 mcg/mL (SD ± 15.2) in patients with ulcerativecolitis and 31.4 mcg/mL (SD ± 14.7) in patients with Crohn’s disease. The bioavailability ofvedolizumab following single-dose subcutaneous administration of 108 mg relative to single-doseintravenous administration was approximately 75%. The median time to reach maximum serumconcentration (tmax) was 7 days (range 3 to 14 days), and the mean maximum serum concentration(Cmax) was 15.4 mcg/mL (SD ± 3.2).

Population pharmacokinetic analyses indicate that the distribution volume of vedolizumab isapproximately 5 litres. The plasma protein binding of vedolizumab has not been evaluated.

Vedolizumab is a therapeutic monoclonal antibody and is not expected to bind to plasma proteins.

Vedolizumab does not pass the blood brain barrier after intravenous administration. Vedolizumab450 mg administered intravenously was not detected in the cerebrospinal fluid of healthy subjects.

Population pharmacokinetic analyses based on intravenous and subcutaneous data indicate that theclearance of vedolizumab is approximately 0.162 L/day (through linear elimination pathway) and theserum half-life is 26 days. The exact elimination route of vedolizumab is not known. Populationpharmacokinetic analyses suggest that while low albumin, higher body weight and prior treatmentwith anti-TNF drugs may increase vedolizumab clearance, the magnitude of their effects is notconsidered to be clinically relevant.

Vedolizumab exhibited linear pharmacokinetics at serum concentrations greater than 1 mcg/mL.

Age does not impact the vedolizumab clearance in ulcerative colitis and Crohn’s disease patientsbased on the population pharmacokinetic analyses. No formal studies have been conducted to examinethe effects of either renal or hepatic impairment on the pharmacokinetics of vedolizumab.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Long-term animal studies with vedolizumab to assess its carcinogenic potential have not beenconducted because pharmacologically responsive models to monoclonal antibodies do not exist. In apharmacologically responsive species (cynomolgus monkeys), there was no evidence of cellularhyperplasia or systemic immunomodulation that could potentially be associated with oncogenesis in13- and 26-week toxicology studies. Furthermore, no effects were found of vedolizumab on theproliferative rate or cytotoxicity of a human tumour cell line expressing the α4β7 integrin in vitro.

No specific fertility studies in animals have been performed with vedolizumab. No definitiveconclusion can be drawn on the male reproductive organs in cynomolgus monkey repeated dosetoxicity study. Given the lack of binding of vedolizumab to male reproductive tissue in monkey andhuman, and the intact male fertility observed in β7 integrin-knockout mice, it is not expected thatvedolizumab will affect male fertility.

Administration of vedolizumab to pregnant cynomolgus monkeys during most of gestation resulted inno evidence of effects on teratogenicity, prenatal or postnatal development in infants up to 6 months ofage. Low levels (< 300 mcg/L) of vedolizumab were detected on post-partum day 28 in the milk of 3of 11 cynomolgus monkeys treated 100 mg/kg of vedolizumab dosed every 2 weeks and not in anyanimals that received 10 mg/kg.

Citric acid monohydrate

Sodium citrate dihydrate

L-histidine

L-histidine monohydrochloride

L-arginine hydrochloride

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

24 months

Store in a refrigerator (2 °C-8 °C). Keep the pre-filled syringes or pre-filled pens in the outer carton inorder to protect from light.

Do not freeze.

If needed, a single pre-filled syringe or pre-filled pen can be left out of the refrigerator protected fromlight at room temperature (up to 25 °C) for up to 7 days. Do not use the pre-filled syringe or pre-filledpen if left out of the refrigerator for more than 7 days.

Entyvio 108 mg solution for injection in pre-filled syringe

Solution for injection in a Type I glass 1 mL syringe with a fixed 27 gauge thin wall, 1.27 cm needle.

The syringe has a rubber needle cover encased in a plastic shell and rubber stopper.

The subcutaneous vedolizumab pre-filled syringe is a single dose, disposable drug delivery systemwith manual injection operation. Each pre-filled syringe is equipped with a safety device that activatesto extend and lock a guard over the needle once the injection is completed.

Packs of 1 or 2 pre-filled syringes, and multipacks of 6 (6 packs of 1) pre-filled syringes.

Entyvio 108 mg solution for injection in pre-filled pen

Solution for injection in a pre-filled pen in a Type I glass 1 mL syringe and a fixed 27 gauge thin wall,1.27 cm needle. The syringe has a rubber needle cover encased in a plastic shell and rubber stopper.

The subcutaneous vedolizumab pre-filled pen is a single dose, disposable drug delivery system withmechanical injection operation. Each pre-filled pen is equipped with an automated needle shield toextend and lock over the needle once the device is removed from the injection site.

Packs of 1 or 2 pre-filled pens, and multipacks of 6 (6 packs of 1) pre-filled pens.

Not all pack sizes may be marketed.

Instructions for administration

After removing the pre-filled syringe or pre-filled pen from the refrigerator, wait 30 minutes beforeinjecting to allow the solution to reach room temperature.

Do not leave the pre-filled syringe or pre-filled pen in direct sunlight.

Do not freeze. Do not use if it has been frozen.

Inspect the solution visually for particulate matter and discoloration prior to administration. Thesolution should be colourless to yellow. Do not use pre-filled syringe or pre-filled pen with visibleparticulate matter or discoloration.

Each pre-filled syringe or pre-filled pen is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Takeda Pharma A/S

Delta Park 452665 Vallensbaek Strand

DenmarkmedinfoEMEA@takeda.com

Entyvio 108 mg solution for injection in pre-filled syringe

EU/1/14/923/002: 1 pre-filled syringe

EU/1/14/923/003: 2 pre-filled syringes

EU/1/14/923/004 Multipack: 6 (6 packs of 1) pre-filled syringes

Entyvio 108 mg solution for injection in pre-filled pen

EU/1/14/923/005: 1 pre-filled pen

EU/1/14/923/006: 2 pre-filled pens

EU/1/14/923/007 Multipack: 6 (6 packs of 1) pre-filled pens

Date of first authorisation: 22 May 2014

Date of latest renewal: 12 December 2018

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu