4.1. Therapeutic indications

Ulcerative colitis

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

Crohn's disease

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

Pouchitis

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

4.2. Posology and method of administration

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

Posology

Ulcerative colitis

The recommended dose regimen of intravenous vedolizumab is 300 mg administered by intravenous infusion 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 benefit is observed by week 10 (see section 5.1).

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

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

Retreatment

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

Crohn's disease

The recommended dose regimen of intravenous vedolizumab is 300 mg administered by intravenous infusion 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 intravenous vedolizumab at week 10 (see section 4.4). Therapy should be continued every 8 weeks from week 14 in responding patients. Therapy for patients with Crohn's disease should be discontinued if no evidence 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 in dosing frequency to intravenous vedolizumab 300 mg every 4 weeks.

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

Retreatment

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

Pouchitis

The recommended dose regimen of intravenous vedolizumab is 300 mg administered by intravenous infusion 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 by 14 weeks of treatment with vedolizumab.

Retreatment

There are no retreatment data available in patients with pouchitis.

Special populations

Elderly patients

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

Patients with renal or hepatic impairment

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

Paediatric population

The safety and efficacy of vedolizumab in children aged 0 to 17 years old have not been established. No data are available.

Method of administration

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

Entyvio 300 mg powder for concentrate for solution for infusion is administered as an intravenous infusion 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, see section 6.6.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Active severe infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis, and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) (see section 4.4).

4.4. Special warnings and precautions for use

Intravenous vedolizumab should be administered in a healthcare setting equipped to allow management of acute hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering intravenous vedolizumab. All patients should be observed continuously during each infusion. For the first 2 infusions, they should also be observed for approximately 2 hours following completion of the infusion for signs and symptoms of acute hypersensitivity reactions. For all subsequent infusions, patients should be observed for approximately 1 hour following completion of the infusion.

Traceability

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

Infusion‑related reactions and hypersensitivity reactions

In clinical studies and post-marketing surveillance, infusion‑related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity (see section 4.8). Hypersensitivity reactions were also reported in patients switching from subcutaneous to intravenous formulation.

If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of Entyvio must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines) (see section 4.3).

If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated. Once the mild or moderate IRR subsides, continue the infusion. Physicians should consider pre‑treatment (e.g., with antihistamine, hydrocortisone and/or paracetamol) prior to the next infusion for patients with a history of mild to moderate IRR to vedolizumab, in order to minimize their risks (see section 4.8).

Infections

Vedolizumab is a gut‑selective integrin antagonist with no identified systemic immunosuppressive activity (see section 5.1).

Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier (see section 4.8). Vedolizumab treatment is not to be initiated in patients with active, severe infections until the infections are controlled, and physicians should consider withholding treatment in patients who develop a severe infection while on chronic treatment with vedolizumab. Caution should be exercised when considering the use of vedolizumab in patients with a controlled chronic severe infection or a history of recurring severe infections. Patients should be monitored closely for infections before, during and after treatment.

Vedolizumab is contraindicated in patients with active tuberculosis (see section 4.3). Before starting treatment with vedolizumab, patients must be screened for tuberculosis according to the local practice. If latent tuberculosis is diagnosed, appropriate treatment must be started with anti‑tuberculosis treatment in accordance with local recommendations, before beginning vedolizumab. In patients diagnosed with TB whilst receiving vedolizumab therapy, then vedolizumab therapy should be discontinued until the TB infection has been resolved.

Some integrin antagonists and some systemic immunosuppressive agents have been associated with progressive multifocal leukoencephalopathy (PML), which is a rare and often fatal opportunistic infection caused by the John Cunningham (JC) virus. By binding to the α4β7 integrin expressed on gut‑homing lymphocytes, vedolizumab exerts an immunosuppressive effect specific to the gut. Although no systemic immunosuppressive effect was noted in healthy subjects the effects on systemic immune system function in patients with inflammatory bowel disease is not known.

Healthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological 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 permanently discontinued.

Malignancies

The risk of malignancy is increased in patients with ulcerative colitis and Crohn's disease. Immunomodulatory medicinal products may increase the risk of malignancy.

Prior and concurrent use of biological products

No vedolizumab clinical trial data are available for patients previously treated with natalizumab or rituximab. 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 to initiating therapy with vedolizumab, unless otherwise indicated by the patient's clinical condition.

No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants are available. 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 not lower rates of protective immunity to hepatitis B virus in subjects who were vaccinated intramuscularly with 3 doses of recombinant hepatitis B surface antigen. Vedolizumab‑exposed subjects had lower seroconversion rates after receiving a killed, oral cholera vaccine. The impact on other oral and nasal vaccines is unknown. It is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating vedolizumab therapy. Patients receiving vedolizumab treatment may continue to receive non‑live vaccines. There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab. Administration of the influenza vaccine should be by injection in line with routine clinical practice. Other live vaccines may be administered concurrently with vedolizumab only if 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 for this are not fully known and are possibly related to the mechanism of action. This should be taken into consideration, 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 vedolizumab administered in patients without concomitant corticosteroid treatment may be less effective for induction of remission in Crohn's disease than in those patients already receiving concomitant corticosteroids (regardless of use of concomitant immunomodulators; see section 5.1).

Polysorbate 80 content

This medicinal product contains 3.31 mg of polysorbate 80 in each Entyvio 300 mg vial.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Vedolizumab has been studied in adult ulcerative colitis and Crohn's disease patients with concomitant administration of corticosteroids, immunomodulators (azathioprine, 6‑mercaptopurine, and methotrexate), and aminosalicylates. Population pharmacokinetic analyses suggest that co‑administration of such agents did not have a clinically meaningful effect on vedolizumab pharmacokinetics.

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

The effect of vedolizumab on the pharmacokinetics of commonly co‑administered medicinal compounds has not been studied.

Vaccinations

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

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

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

Pregnancy

There are limited amount of data from the use of vedolizumab in pregnant women.

In a small prospective observational study the rate of major birth defects was 7.4% in 99 women with ulcerative colitis or Crohn's disease treated with vedolizumab and 5.6% in 76 women with ulcerative colitis or Crohn's disease treated with other biologic agents (adjusted relative risk (RR) 1.07, 95% Confidence Interval (CI): 0.33, 3.52).

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of vedolizumab during pregnancy unless the benefits clearly outweigh any potential risk to both the mother and foetus.

Breast‑feeding

Vedolizumab has been detected in human milk. The effect of vedolizumab on breast-fed infants, and the effects on milk production are unknown. In a milk-only lactation study assessing the concentration of vedolizumab in breast milk of lactating women with active ulcerative colitis or Crohn's disease receiving vedolizumab, the concentration of vedolizumab in human breast milk was approximately 0.4% to 2.2% of the maternal serum concentration obtained from historical studies of vedolizumab. The estimated average daily dose of vedolizumab ingested by the infant was 0.02 mg/kg/day, which is approximately 21% of the body weight-adjusted average maternal daily dose.

The use of vedolizumab in lactating women should take into account the benefit of therapy to the mother and potential risks to the infant.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions are infections (such as nasopharyngitis, upper respiratory tract infection, bronchitis, influenza and sinusitis), headache, nausea, pyrexia, fatigue, cough, arthralgia.

Infusion related reactions (with symptoms such as dyspnoea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) have also been reported in patients treated with vedolizumab.

Tabulated list of adverse reactions

The following listing of adverse reactions is based on clinical trial and post marketing experience and is displayed by system organ class. Within the system organ classes, adverse reactions are listed under headings of the following frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), very rare (< 1/10 000) and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions

System organ class

Frequency

Adverse reactions

Infections and infestations

Very common

Nasopharyngitis

Common

Pneumonia,

Clostridium difficile infection,

Bronchitis,

Gastroenteritis,

Upper respiratory tract infection,

Influenza,

Sinusitis,

Pharyngitis,

Herpes zoster

Uncommon

Respiratory tract infection,

Vulvovaginal candidiasis,

Oral candidiasis

Immune system disorders

Very rare

Anaphylactic reaction,

Anaphylactic shock

Nervous system disorders

Very common

Headache

Common

Paraesthesia

Eye disorders

Uncommon

Blurred vision

Vascular disorders

Common

Hypertension

Respiratory, thoracic and mediastinal disorders

Common

Oropharyngeal pain,

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 disorders

Common

Rash,

Pruritus,

Eczema,

Erythema,

Night sweats,

Acne

Uncommon

Folliculitis

Musculoskeletal and connective tissue disorders

Very common

Arthralgia

Common

Muscle spasms,

Back pain,

Muscular weakness,

Pain in the extremity

General disorders and administration site conditions

Common

Pyrexia,

Fatigue,

Infusion related reaction (asthenia* and chest discomfort*),

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

Uncommon

Chills,

Feeling cold

*Reported in the EARNEST pouchitis study

Description of selected adverse reactions

Infusion‑related reactions

In GEMINI 1 and 2 controlled studies (ulcerative colitis and Crohn's disease), 4% of intravenous vedolizumab‑treated patients and 3% of placebo‑treated patients experienced an adverse reaction defined 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 in intensity and < 1% resulted in discontinuation of study treatment. Observed IRRs generally resolved with no or minimal intervention following the infusion. Most infusion related reactions occurred within the first 2 hours. Of those patients who had infusion related reactions, those dosed with intravenous vedolizumab had more infusion related reactions with in the first 2 hours as compared to placebo patients with infusion related reactions. Most infusion related reactions were not serious and occurred 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 second infusion (symptoms reported were dyspnoea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) and was successfully managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In patients who received intravenous vedolizumab at weeks 0 and 2 followed by placebo, no increase in the rate of IRR was seen upon retreatment 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 51 subjects (3.9%) in the placebo group. The individual Preferred Terms included mouth ulceration, swelling, oedema peripheral, chest discomfort, asthenia, acute kidney injury, obstructive airway disorder and flushing. All events were reported as mild to moderate in intensity, none were considered serious and none resulted in study discontinuation.

Infections

In GEMINI 1 and 2 controlled studies (ulcerative colitis and Crohn's disease) with intravenous vedolizumab, the rate of infections was 0.85 per patient‑year in the vedolizumab‑treated patients and 0.70 per patient‑year in the placebo‑treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infections. Most patients continued on vedolizumab after the infection resolved.

In GEMINI 1 and 2 controlled studies with intravenous vedolizumab, the rate of serious infections was 0.07 per patient year in vedolizumab‑treated patients and 0.06 per patient year in placebo‑treated patients. 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 was hospitalized 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 intravenous vedolizumab, 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 of infections in vedolizumab‑treated patients with BMI of 30 kg/m2 and above was higher than for those with BMI less than 30 kg/m2.

In clinical studies with intravenous vedolizumab (ulcerative colitis and Crohn's disease), a slightly higher incidence of serious infections was reported in vedolizumab‑treated patients who had prior exposure to TNFα antagonist therapy compared to patients who were naïve to previous TNFα antagonist therapy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme. Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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