vedolizumab: prescribing information – dosing, contraindications, interactions, side effects

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.

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.

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.

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

Posology

Ulcerative colitis and Crohn’s disease

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

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

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

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

In patients who have responded to treatment with vedolizumab, corticosteroids may be reduced and/or discontinued 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) of subcutaneous vedolizumab, patient should be advised to inject the next subcutaneous dose as soon as possible and then every 2 weeks thereafter.

The treatment interruption period in clinical trials extended up to 46 weeks. Efficacy was regained with no evident increase in adverse reactions or injection site reactions after re-initiation of treatment with subcutaneous vedolizumab (see section 4.8).

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

After proper training on correct subcutaneous injection technique, a patient or caregiver may inject with subcutaneous vedolizumab if their physician determines it is appropriate. Comprehensive instructions for administration using the pre-filled syringe or the pre-filled pen are given in the respective 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, and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) (see section 4.4).

p = 0.591‡‡
*Endpoints are presented in the order that fixed-sequence testing was performed for control of Type 1 error at 5% †The placebo group includes those subjects who received intravenous vedolizumab at week 0 and week 2, and were 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-Haenszel method §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 discontinued corticosteroids and were in clinical remission at week 52. Patient numbers using oral corticosteroids at baseline 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 not experience treatment failure (7%; n = 29). Results of study patients treated with placebo and subcutaneous 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 Endpoint Placebo n = 63 Vedolizumab SC 108 mg every 2 weeks n = 107 Treatment difference (95% CI) Vedolizumab SC vs.
Placebo
Clinical remission
42.9%
48.6%

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

System organ class
Frequency
Adverse reactions
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 national reporting system listed in Appendix V.

Summary of the safety profile

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

No clinically relevant differences in the overall safety profile and adverse reactions were observed in patients who received subcutaneous vedolizumab compared to the safety profile observed in clinical studies with intravenous vedolizumab with the exception of injection site reactions (with subcutaneous administration).

Tabulated list of adverse reactions

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

Table 1. Adverse reactions
System organ class
Frequency
Adverse reactions
Infections and infestations
Very common
Nasopharyngitis
Common
Pneumonia,
Clostridium difficile infection,
Bronchitis,
Gastroenteritis,
Upper respiratory tract infection,
Influenza,
Sinusitis,
Pharyngitis,
Herpes zoster
Uncommon
Respiratory tract infection,
Vulvovaginal candidiasis,
Oral candidiasis
Immune system disorders
Very rare
Anaphylactic reaction,
Anaphylactic shock
Nervous system disorders
Very common
Headache
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

System organ class
Frequency
Adverse reactions
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,
Injection site reactions
Uncommon
Chills,
Feeling cold

Description of selected adverse reactions

Injection site reactions

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

Infections

In GEMINI 1 and 2 controlled studies 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 controlled and open-label studies 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 subcutaneous vedolizumab, the rate of infections was 0.26 per patient year in vedolizumab-treated patients. The most frequent infections were nasopharyngitis, upper respiratory tract infection, bronchitis and influenza.

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

In clinical studies with intravenous and subcutaneous vedolizumab, 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 and subcutaneous vedolizumab, 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 national reporting system listed in Appendix V.

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.

Traceability

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

Hypersensitivity reactions

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

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

Infections

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

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

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

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

Healthcare professionals should monitor patients on 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).

Sodium content

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

Polysorbate 80 content

This medicinal product contains 1.48 mg of polysorbate 80 in each Entyvio 108 mg pre-filled pen or pre-filled syringe.

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).

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. 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).

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).

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

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.

5.
PHARMACOLOGICAL PROPERTIES

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

Mechanism of action

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

The α4β7 integrin is expressed on a discrete subset of memory T helper lymphocytes which preferentially migrate into the gastrointestinal (GI) tract and cause inflammation that is characteristic of ulcerative colitis and Crohn’s disease, both of which are chronic inflammatory immunologically mediated conditions of the GI tract. Vedolizumab reduces gastrointestinal inflammation in UC, CD and pouchitis patients. Inhibiting the interaction of α4β7 with MAdCAM-1 with vedolizumab prevents transmigration of gut-homing memory T helper lymphocytes across the vascular endothelium into parenchymal tissue in nonhuman primates and induced a reversible 3-fold elevation of these cells in peripheral blood. The murine precursor of vedolizumab alleviated gastrointestinal inflammation in colitic cotton-top tamarins, a model of ulcerative colitis.

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

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 (see section 4.4). In contrast, vedolizumab inhibited an immune response to a gastrointestinal antigenic challenge in healthy human volunteers (see section 4.4).

Immunogenicity

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 vedolizumab and lower rates of clinical remission.

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

Pharmacodynamic effects

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 surveillance was observed in patients.

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

Mechanism of action

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

The α4β7 integrin is expressed on a discrete subset of memory T helper lymphocytes which preferentially migrate into the gastrointestinal (GI) tract and cause inflammation that is characteristic of ulcerative colitis and Crohn’s disease, both of which are chronic inflammatory immunologically mediated conditions of the GI tract. Vedolizumab reduces gastrointestinal inflammation in UC and CD patients. Inhibiting the interaction of α4β7 with MAdCAM-1 with vedolizumab prevents transmigration of gut-homing memory T helper lymphocytes across the vascular endothelium into parenchymal tissue in nonhuman primates and induced a reversible 3-fold elevation of these cells in peripheral blood. The murine precursor of vedolizumab alleviated gastrointestinal inflammation in colitic cotton-top tamarins, a model of ulcerative colitis.

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

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 (see section 4.4). In contrast, vedolizumab inhibited an immune response to a gastrointestinal antigenic challenge in healthy human volunteers (see section 4.4).

Immunogenicity

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 vedolizumab and lower rates of clinical remission.

Pharmacodynamic effects

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 surveillance was observed in patients.

The single and multiple dose pharmacokinetics of vedolizumab have been studied in healthy subjects and in patients with moderate to severely active ulcerative colitis or Crohn’s disease. The pharmacokinetics of vedolizumab has not been studied in patients with pouchitis but is expected to be similar 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 colitis and 26.8 mcg/mL (SD ± 17.45) in Crohn’s disease. In studies with intravenous vedolizumab, starting at week 6, patients received 300 mg intravenous vedolizumab every 8 or 4 weeks. In patients with ulcerative 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 serum trough concentrations were 13.0 mcg/mL (SD ± 9.08) and 34.8 mcg/mL (SD ± 22.55), respectively.

Distribution

Population pharmacokinetic analyses indicate that the distribution volume of vedolizumab is approximately 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. Vedolizumab 450 mg administered intravenously was not detected in the cerebrospinal fluid of healthy subjects.

Elimination

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

Absorption

In patients administered 300 mg intravenous 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 colitis and 26.8 mcg/mL (SD ± 17.45) in Crohn’s disease. In studies with intravenous vedolizumab, starting at week 6, patients received 300 mg intravenous vedolizumab every 8 or 4 weeks. In patients with ulcerative 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 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 mean steady state serum trough concentrations were 35.8 mcg/mL (SD ± 15.2) in patients with ulcerative colitis and 31.4 mcg/mL (SD ± 14.7) in patients with Crohn’s disease. The bioavailability of vedolizumab following single-dose subcutaneous administration of 108 mg relative to single-dose intravenous administration was approximately 75%. The median time to reach maximum serum concentration (tmax) was 7 days (range 3 to 14 days), and the mean maximum serum concentration (Cmax) was 15.4 mcg/mL (SD ± 3.2).

Distribution

Population pharmacokinetic analyses indicate that the distribution volume of vedolizumab is approximately 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.