ENTYVIO 300mg powder for concentrate infusion solution medication leaflet

Entyvio 300 mg powder for concentrate for solution for infusion

Each vial contains 300 mg of vedolizumab.

After reconstitution, each mL contains 60 mg of vedolizumab.

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.

Powder for concentrate for solution for infusion.

White to off-white lyophilised cake or powder.

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.

Pouchitis

Entyvio is indicated for the treatment of adult patients with moderately to severely active chronicpouchitis, who have undergone proctocolectomy and ileal pouch anal anastomosis for ulcerativecolitis, and have had an inadequate response with or lost response to antibiotic therapy.

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

The recommended dose regimen of intravenous vedolizumab is 300 mg administered by intravenousinfusion at 0, 2 and 6 weeks and then every 8 weeks thereafter.

Therapy for patients with ulcerative colitis should be discontinued if no evidence of therapeutic benefitis observed by week 10 (see section 5.1).

Some patients who have experienced a decrease in their response may benefit from an increase indosing frequency to intravenous vedolizumab 300 mg every 4 weeks.

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

If therapy is interrupted and there is a need to restart treatment with intravenous vedolizumab, dosingat every 4 weeks may be considered (see section 5.1). The treatment interruption period in clinicaltrials extended up to 1 year. Efficacy was regained with no evident increase in adverse reactions orinfusion-related reactions during retreatment with vedolizumab (see section 4.8).

The recommended dose regimen of intravenous vedolizumab is 300 mg administered by intravenousinfusion at 0, 2 and 6 weeks and then every 8 weeks thereafter.

Patients with Crohn’s disease, who have not shown a response may benefit from a dose of intravenousvedolizumab at week 10 (see section 4.4). Therapy should be continued every 8 weeks from week 14in responding patients. Therapy for patients with Crohn’s disease should be discontinued if noevidence of therapeutic benefit is observed by week 14 (see section 5.1).

Some patients who have experienced a decrease in their response may benefit from an increase indosing frequency to intravenous vedolizumab 300 mg every 4 weeks.

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

If therapy is interrupted and there is a need to restart treatment with intravenous vedolizumab, dosingat every 4 weeks may be considered (see section 5.1). The treatment interruption period in clinicaltrials extended up to 1 year. Efficacy was regained with no evident increase in adverse reactions orinfusion-related reactions during retreatment with vedolizumab (see section 4.8).

Pouchitis

The recommended dose regimen of intravenous vedolizumab is 300 mg administered by intravenousinfusion at 0, 2 and 6 weeks and then every 8 weeks thereafter.

Treatment with vedolizumab should be initiated in parallel with standard of care antibiotic (e.g., four-week of ciprofloxacin) (see section 5.1).

Discontinuation of treatment should be considered if no evidence of therapeutic benefit is observed by14 weeks of treatment with vedolizumab.

There are no retreatment data available in patients with pouchitis.

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 300 mg powder for concentrate for solution for infusion is for intravenous use only. It is to bereconstituted and further diluted prior to intravenous administration.

Entyvio 300 mg powder for concentrate for solution for infusion is administered as an intravenousinfusion over 30 minutes. Patients should be monitored during and after infusion (see section 4.4).

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 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).

Intravenous vedolizumab should be administered in a healthcare setting equipped to allowmanagement of acute hypersensitivity reactions including anaphylaxis, if they occur. Appropriatemonitoring and medical support measures should be available for immediate use when administeringintravenous vedolizumab. All patients should be observed continuously during each infusion. For thefirst 2 infusions, they should also be observed for approximately 2 hours following completion of theinfusion 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.

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

Infusion-related reactions and hypersensitivity reactions

In clinical studies and post-marketing surveillance, infusion-related reactions (IRR) andhypersensitivity 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 fromsubcutaneous to intravenous formulation.

If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of Entyvio mustbe 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 appropriatetreatment initiated. Once the mild or moderate IRR subsides, continue the infusion. Physicians shouldconsider pre-treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the nextinfusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize theirrisks (see section 4.8).

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). Vedolizumab treatment is not to be initiated inpatients with active, severe infections until the infections are controlled, and physicians shouldconsider withholding treatment in patients who develop a severe infection while on chronic treatmentwith vedolizumab. Caution should be exercised when considering the use of vedolizumab in patientswith a controlled chronic severe infection or a history of recurring severe infections. Patients should bemonitored closely 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).

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.

In adult patients with pouchitis, vedolizumab has been co-administered with antibiotics (seesection 5.1). The pharmacokinetics of vedolizumab in patients with pouchitis has not been studied (seesection 5.2).

The effect of vedolizumab on the pharmacokinetics of commonly co-administered medicinalcompounds 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.

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 withvedolizumab.

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,

Rectal haemorrhage*

Hepatobiliary disorders Common Liver enzyme increased

Very rare Hepatitis

Skin and subcutaneous tissue Common Rash,disorders Pruritus,

Eczema,

Erythema,

Night sweats,

Acne

Uncommon Folliculitis

Very common Arthralgia

Musculoskeletal and connective Common Muscle spasms,tissue disorders Back pain,

Muscular weakness,

Fatigue,

Pain in the extremity

General disorders and Common Pyrexia,administration site conditions Infusion related reaction (asthenia* and chestdiscomfort*),

Infusion site reaction (including: Infusion sitepain and Infusion site irritation)

Uncommon Chills,

Feeling cold

*Reported in the EARNEST pouchitis study

In GEMINI 1 and 2 controlled studies (ulcerative colitis and Crohn’s disease), 4% of intravenousvedolizumab-treated patients and 3% of placebo-treated patients experienced an adverse reactiondefined by the investigator as infusion-related reaction (IRR) (see section 4.4). No individual Preferred

Term reported as an IRR occurred at a rate above 1%. The majority of IRRs were mild or moderate inintensity and < 1% resulted in discontinuation of study treatment. Observed IRRs generally resolvedwith no or minimal intervention following the infusion. Most infusion related reactions occurredwithin the first 2 hours. Of those patients who had infusion related reactions, those dosed withintravenous vedolizumab had more infusion related reactions with in the first 2 hours as compared toplacebo patients with infusion related reactions. Most infusion related reactions were not serious andoccurred during the infusion or within the first hour after infusion is completed.

One serious adverse reaction of IRR was reported in a Crohn’s disease patient during the secondinfusion (symptoms reported were dyspnoea, bronchospasm, urticaria, flushing, rash, and increasedblood pressure and heart rate) and was successfully managed with discontinuation of infusion andtreatment with antihistamine and intravenous hydrocortisone. In patients who received intravenousvedolizumab at weeks 0 and 2 followed by placebo, no increase in the rate of IRR was seen uponretreatment with intravenous vedolizumab after loss of response.

In EARNEST controlled study (pouchitis) with intravenous vedolizumab, hypersensitivity reactions,including IRRs, were reported in 3 out of 51 subjects (5.9%) in the vedolizumab group and 2 out of 51subjects (3.9%) in the placebo group. The individual Preferred Terms included mouth ulceration,swelling, oedema peripheral, chest discomfort, asthenia, acute kidney injury, obstructive airwaydisorder and flushing. All events were reported as mild to moderate in intensity, none were consideredserious and none resulted in study discontinuation.

In GEMINI 1 and 2 controlled studies (ulcerative colitis and Crohn’s disease) with intravenousvedolizumab, the rate of infections was 0.85 per patient-year in the vedolizumab-treated patientsand 0.70 per patient-year in the placebo-treated patients. The infections consisted primarily ofnasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infections. Most patientscontinued on vedolizumab after the infection 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 the EARNEST controlled study (pouchitis) with intravenous vedolizumab, only 1 out of 51 subjects(2.0%) in the vedolizumab group experienced a serious infection of gastroenteritis. The subject washospitalized for observation, recovered from the event and completed the study.

In controlled and open-label studies (ulcerative colitis and Crohn’s disease) in adults with intravenousvedolizumab, serious infections have been reported, which include tuberculosis, sepsis (some fatal),salmonella sepsis, listeria meningitis, and cytomegaloviral colitis.

In clinical studies with intravenous vedolizumab (ulcerative colitis and Crohn’s disease), the rate ofinfections in vedolizumab-treated patients with BMI of 30 kg/m2 and above was higher than for thosewith BMI less than 30 kg/m2.

In clinical studies with intravenous vedolizumab (ulcerative colitis and Crohn’s disease), a slightlyhigher incidence of serious infections was reported in vedolizumab-treated patients who had priorexposure to TNFα antagonist therapy compared to patients who were naïve to previous TNFαantagonist 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, CDand pouchitis patients. Inhibiting the interaction of α4β7 with MAdCAM-1 with vedolizumab preventstransmigration of gut-homing memory T helper lymphocytes across the vascular endothelium intoparenchymal tissue in nonhuman primates and induced a reversible 3-fold elevation of these cells inperipheral blood. The murine precursor of vedolizumab alleviated gastrointestinal inflammation incolitic cotton-top tamarins, 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.

Infusion related reactions after vedolizumab infusion are reported in subjects with anti-vedolizumabantibodies.

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.

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 one 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 IV

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 one of the followingregimens beginning at week 6: vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every4 weeks, or placebo every 4 weeks. Beginning at week 6, patients who had achieved clinical responseand were receiving corticosteroids were required to begin a corticosteroid-tapering regimen. Primaryendpoint was the proportion of patients in clinical remission at week 52. Table 3 shows the resultsfrom the primary 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 had discontinuedcorticosteroids beginning at week 6 and were in clinical remission at week 52. Patient numbers were n = 72for placebo, n = 70 for vedolizumab every 8 weeks, and n = 73 for vedolizumab every 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).

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 one conventionaltherapy, 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 4).

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 one 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 5).

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

Table 4. 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 to week 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 5. 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.

Pouchitis

The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with chronicpouchitis were demonstrated in a randomised, double-blind, placebo-controlled study evaluatingefficacy at week 14 and week 34 (EARNEST). Enrolled patients had undergone proctocolectomy andileal pouch anal anastomosis (IPAA) for ulcerative colitis at least one year prior to randomisation andhad developed active chronic pouchitis (defined as antibiotic-dependent (recurrent) or antibiotic-refractory), with a baseline modified Pouchitis Disease Activity Index (mPDAI) score ≥ 5 andendoscopic subscore ≥ 2. All patients received concomitant antibiotic treatment with ciprofloxacin500 mg twice daily from the start of treatment through week 4. Patients received additional courses ofantibiotics during the study as needed, including for pouchitis flares.

Patients (n=102) were randomised (1:1) to receive either intravenous vedolizumab 300 mg orintravenous placebo at 0, 2 and 6 weeks, and every 8 weeks thereafter, until week 30. The primaryendpoint was clinical remission (defined as an mPDAI score < 5 and a reduction in total mPDAI scoreof ≥ 2 points from baseline) at week 14. Table 6 shows the results from the primary and secondaryendpoints at week 14 and Table 7 shows the results from secondary endpoints at week 34.

Table 6. Efficacy results for EARNEST at week 14

Difference

Placebo Vedolizumab IV Vedolizumab-Placebo (95% CI)

Endpoint n = 51 n = 51 [percentage points]

Clinical remission* 9.8% 31.4%† 21.6 (4.9, 37.5)

PDAI remission‡ 9.8% 35.3% 25.5 (8.0, 41.4)

Clinical response§ 33.3% 62.7% 29.4 (8.0, 47.6)

*Clinical remission is defined as mPDAI score < 5 and a reduction in total mPDAI score of ≥ 2 points frombaseline†p < 0.05‡PDAI remission is defined as PDAI score < 7 and a reduction in PDAI score of ≥ 3 points from baseline§Clinical response is defined as reduction of mPDAI score of ≥ 2 points from baseline

Table 7. Efficacy results for EARNEST at week 34

Difference

Placebo Vedolizumab IV Vedolizumab-Placebo (95% CI)

Endpoint n = 51 n = 51 [percentage points]

Clinical remission* 17.6% 35.3% 17.6 (0.3, 35.1)

PDAI remission‡ 17.6% 37.3% 19.6 (1.9, 37.0)

Clinical response§ 29.4% 51.0% 21.6 (1.9, 39.8)

*Clinical remission is defined as mPDAI score < 5 and reduction in total mPDAI score of ≥ 2 points frombaseline‡ PDAI remission is defined as PDAI score < 7 and a reduction in PDAI score of ≥ 3 points from baseline§Clinical response is defined as reduction of mPDAI score of ≥ 2 points from baseline

Approximately two-thirds of patients had received prior (for UC or pouchitis) TNF α antagonisttherapy (33 in vedolizumab and 31 in placebo treatment groups). Among these patients, 33.3% in thevedolizumab group achieved clinical remission at W14 compared with 9.7% in the placebo group.

The European Medicines Agency has deferred the obligation to submit the results of studies withvedolizumab in one or more subsets of the paediatric population in ulcerative colitis, Crohn’s diseaseand pouchitis (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. Thepharmacokinetics of vedolizumab has not been studied in patients with pouchitis but is expected to besimilar to that in patients with moderate to severely active ulcerative colitis or Crohn’s disease.

In patients administered 300 mg vedolizumab as a 30 minute intravenous infusion on weeks 0 and 2,mean serum trough concentrations at week 6 were 27.9 mcg/mL (SD ± 15.51) in ulcerative colitisand 26.8 mcg/mL (SD ± 17.45) in Crohn’s disease. In studies with intravenous vedolizumab, startingat week 6, patients received 300 mg intravenous vedolizumab every 8 or 4 weeks. In patients withulcerative colitis, mean steady-state serum trough concentrations were 11.2 mcg/mL (SD ± 7.24)and 38.3 mcg/mL (SD ± 24.43), respectively. In patients with Crohn's disease mean steady-state serumtrough concentrations were 13.0 mcg/mL (SD ± 9.08) and 34.8 mcg/mL (SD ± 22.55), respectively.

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. Age is not expected to impact the vedolizumabclearance in patients with pouchitis. No formal studies have been conducted to examine the effects ofeither 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.

L-histidine

L-histidine monohydrochloride

L-arginine hydrochloride

Sucrose

Polysorbate 80

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

3 years

In-use stability of the reconstituted solution in the vial has been demonstrated for 8 hours at 2°C-8°C.

In-use stability of the diluted solution in sodium chloride 9 mg/mL (0.9%) solution for injection ininfusion bag has been demonstrated for 12 hours at 20°C-25°C or 24 hours at 2°C-8°C.

The combined in-use stability of vedolizumab in the vial and infusion bag with sodium chloride9 mg/mL (0.9%) solution for injection is a total of 12 hours at 20°C-25°C or 24 hours at 2°C-8°C. A24 hour period may include up to 8 hours at 2°C-8°C for reconstituted solution in the vial and up to12 hours at 20°C-25°C for diluted solution in the infusion bag but the infusion bag must be stored inthe refrigerator (2°C-8°C) for the rest of the 24 hour period.

Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag.

Storage condition

Refrigerator (2°C-8°C) 20°C-25°C

Reconstituted solution in the vial 8 hours Do not hold1

Diluted solution in sodium chloride 9 mg/mL24 hours2,3 12 hours2(0.9%) solution for injection1 Up to 30 minutes are allowed for reconstitution2 This time assumes the reconstituted solution is immediately diluted in the sodium chloride 9 mg/mL (0.9%)solution for injection and held in the infusion bag only. Any time that the reconstituted solution was held in thevial should be subtracted from the time the solution may be held in the infusion bag.3 This period may include up to 12 hours at 20 °C-25 °C.

Store in a refrigerator (2 °C-8 °C). Keep the vial in the outer carton in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Powder for concentrate for solution for infusion in Type 1 glass vial (20 mL) fitted with rubberstopper and aluminium crimp protected by a plastic cap.

Each pack contains 1 vial.

Instructions for reconstitution and infusion1. Use aseptic technique when preparing Entyvio solution for intravenous infusion.

2. Remove flip-off cap from the vial and wipe with alcohol swab. Reconstitute vedolizumab with4.8 mL of sterile water for injections at room temperature (20 °C-25 °C), using a syringe with a21-25 gauge needle.

3. Insert the needle into the vial through the centre of the stopper and direct the stream of liquid tothe wall of the vial to avoid excessive foaming.

4. Gently swirl the vial for at least 15 seconds. Do not vigorously shake or invert.

5. Let the vial sit for up to 20 minutes at room temperature (20 °C-25 °C), to allow forreconstitution and for any foam to settle; the vial can be swirled and inspected for dissolutionduring this time. If not fully dissolved after 20 minutes, allow another 10 minutes fordissolution.

6. Inspect the reconstituted solution visually for particulate matter and discolouration prior todilution. Solution should be clear or opalescent, colourless to light yellow and free of visibleparticulates. Reconstituted solution with uncharacteristic colour or containing particulates mustnot be administered.

7. Once dissolved, gently invert vial 3 times.

8. Immediately withdraw 5 mL (300 mg) of reconstituted Entyvio using a syringe with a21-25 gauge needle.

9. Add the 5 mL (300 mg) of reconstituted Entyvio to 250 mL of sterile sodium chloride 9 mg/mL(0.9%) solution for injection, and gently mix the infusion bag (5 mL of sodium chloride9 mg/mL (0.9%) solution for injection does not have to be withdrawn from the infusion bagprior to adding Entyvio). Do not add other medicinal products to the prepared infusion solutionor intravenous infusion set. Administer the infusion solution over 30 minutes (see section 4.2).

Once reconstituted, the infusion solution should be used as soon as possible.

Do not store any unused portion of the reconstituted solution or infusion solution for reuse.

Each vial 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

EU/1/14/923/001

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