Entyvio

Infusion concentrate: Entyvio powder for concentrate for solution for infusion is supplied as white to off-white lyophilized cake or powder.
Each vial contains 300 mg of vedolizumab.
After reconstitution, each mL contains 60 mg of vedolizumab.
Solution for injection: Colourless to yellow solution.
Each pre-filled pen contains 108 mg of vedolizumab in 0.68 mL.
Vedolizumab is a humanised IgG₁ monoclonal antibody produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology.
Excipients/Inactive Ingredients: Infusion concentrate: L-histidine, L-histidine monohydrochloride, L-arginine hydrochloride, sucrose, polysorbate 80.
Solution for injection: Citric acid monohydrate, Sodium citrate dihydrate, L-histidine, L-histidine monohydrochloride, L-arginine hydrochloride, Polysorbate 80, Water for injections.

Pharmacologic class: selective immunosuppressants. Pharmacotherapeutic group: immunosuppressants, monoclonal antibodies. ATC code: Infusion concentrate: L04AA33; Solution for injection: L04AG05.
Pharmacology: 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 non-human 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 Precautions). In contrast, vedolizumab inhibited an immune response to a gastrointestinal antigenic challenge in healthy human volunteers (see Precautions).
Immunogenicity: Solution for injection: 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.
Pharmacodynamics effects: In clinical studies with 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.
Vedolizumab did not affect CD4+ and CD8+ trafficking into the CNS as evidenced by the lack of change in the ratio of CD4+/CD8+ in cerebrospinal fluid pre- and post-vedolizumab administration in healthy human volunteers. These data are consistent with investigations in non-human primates which did not detect effects on immune surveillance of the CNS.
Clinical efficacy and safety: Ulcerative colitis - vedolizumab for intravenous administration: The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥2) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 6 and week 52 (GEMINI I). Enrolled patients had failed at least one conventional therapy, including corticosteroids, immunomodulators, and/or the TNFα antagonist infliximab (including primary non-responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators 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 the proportion 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 1 shows the results from the primary and secondary endpoints evaluated. (See Table 1.)

Click on icon to see table/diagram/image

The beneficial effect of vedolizumab on clinical response, remission and mucosal healing was observed both in patients with no prior TNFα antagonist exposure as well as in those who had failed prior TNFα antagonist therapy.
In GEMINI I, two cohorts of patients received vedolizumab at week 0 and week 2: cohort 1 patients were randomised to receive either vedolizumab 300 mg or placebo in a double-blind fashion, and cohort 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 clinical response at week 6 were randomised in a double-blind fashion (1:1:1) to 1 of the following regimens beginning at week 6: vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, or placebo every 4 weeks. Beginning at week 6, patients who had achieved clinical response and were receiving corticosteroids were required to begin a corticosteroid-tapering regimen. Primary endpoint was the proportion of patients in clinical remission at week 52. Table 2 shows the results from the primary and secondary endpoints evaluated. (See Table 2.)

Click on icon to see table/diagram/image

Exploratory analyses provide additional data on key subpopulations studied. Approximately one-third of patients had failed prior TNFα antagonist therapy. Among these patients, 37% receiving vedolizumab every 8 weeks, 35% receiving vedolizumab every 4 weeks, and 5% receiving placebo achieved 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-free clinical remission (23%, 32%, 4%) were seen in the prior TNFα antagonist failure population treated with 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 received vedolizumab every 4 weeks. Clinical response using partial Mayo scores was achieved at week 10 and week 14 by greater proportions of vedolizumab patients (32% and 39%, respectively) compared with placebo patients (15% and 21%, respectively).
Patients who lost response to vedolizumab when treated every 8 weeks were allowed to enter an open-label extension study and receive vedolizumab every 4 weeks. In these patients, clinical remission 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 then randomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-label extension study and receive vedolizumab every 4 weeks. In these patients, clinical remission was achieved 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 Mayo score, 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 vedolizumab groups, and the improvements were significantly greater as compared with the placebo group at week 6 and week 52 on EQ-5D and EQ-5D VAS scores, all subscales of IBDQ (bowel symptoms, systemic function, emotional function and social function), and all subscales of SF-36 including the Physical Component Summary (PCS) and Mental Component Summary (MCS).
Ulcerative colitis - vedolizumab for subcutaneous administration: The efficacy and safety of subcutaneous vedolizumab for the treatment of adult patients with moderately to severely active ulcerative colitis (Mayo score 6 to 12 with endoscopic sub score ≥2) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 52 (VISIBLE 1).
In VISIBLE 1, enrolled patients (n=383) had failed at least one conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators were permitted.
Patients who achieved clinical response to open-label treatment with intravenous vedolizumab at week 6 were eligible to be randomized. For the evaluation of the week 52 endpoints, 216 (56.4%) patients were randomised and treated in a double-blind fashion (2:1:1) to one of the following regimens: subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo.
The baseline demographics were similar for patients in vedolizumab and placebo groups. The baseline Mayo score was between 9 to 12 (severe ulcerative colitis) in about 62% and 6 to 8 (moderate ulcerative colitis) in about 38% of the overall study population.
Primary study endpoint clinical remission was defined as a complete Mayo score of ≤2 points and no individual subscore >1 point at 52 weeks in patients who had achieved a clinical response at week 6 of intravenous vedolizumab induction treatment. Clinical response was defined as a 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 ≤2 points and no individual subscore >1 point.
Table 3 shows the evaluated results from the primary and secondary endpoints. (See Table 3.)

Click on icon to see table/diagram/image

The primary and secondary endpoints were analysed in subgroups of patients who had failed prior TNFα antagonist therapy (37%; n=80) and patients who were naïve to previous TNFα antagonist therapy (63%; n=136). Results of study patients treated with placebo and subcutaneous vedolizumab in these subgroups are presented in Table 4. (See Table 4.)

Click on icon to see table/diagram/image

Health related quality of life (HRQOL) was assessed by Inflammatory Bowel Disease Questionnaire (IBDQ), a disease specific instrument, and EuroQol-5 Dimension (EQ-5D, including EQ 5D VAS), which is a generic measure. Work productivity was assessed by work productivity and activity impairment questionnaire (WPAI-UC). Patients treated with subcutaneous vedolizumab maintained improvements in IBDQ, EQ-5D and WPAI-UC scores at week 52 to a greater extent than patients who received placebo.
Patients who completed VISIBLE 1 were eligible to enrol in an ongoing, open-label extension study to evaluate long-term safety and efficacy of subcutaneous vedolizumab treatment in patients with ulcerative colitis or Crohn's disease.
Patients in VISIBLE 1 who did not achieve clinical response at week 6 received a third dose of vedolizumab 300 mg by intravenous infusion at week 6. Of patients who received a third dose of vedolizumab 300 mg by intravenous infusion at week 6, 79.7% (114/143) achieved a clinical response at week 14. Patients who achieved a clinical response at week 14 were eligible to enter the open-label extension study and receive subcutaneous vedolizumab 108 mg every 2 weeks. Clinical remission as assessed by the partial Mayo score (a standardised measure that includes 3 of the 4 scored subscales of the complete Mayo score: stool frequency, rectal bleeding, and physician global assessment) was achieved by 39.2% (40/102) of these patients at week 40 after transitioning to subcutaneous vedolizumab in the open-label extension study.
Patients randomised to intravenous vedolizumab treatment group in VISIBLE 1 received vedolizumab 300 mg intravenously at weeks 0, 2, and 6 and every 8 weeks thereafter until week 52.
At week 52, these patients entered the open-label extension study and received subcutaneous vedolizumab 108 mg every 2 weeks. Clinical remission as assessed by the partial Mayo score was maintained in 77% of patients at 24 weeks after transitioning to subcutaneous vedolizumab in the open-label extension study.
Crohn's disease - vedolizumab for intravenous administration: The efficacy and safety of intravenous vedolizumab for the treatment of adult patients with moderately to severely active Crohn's disease (Crohn's Disease Activity Index [CDAI] score of 220 to 450) were evaluated in 2 studies (GEMINI 2 and 3). Enrolled patients have failed at least 1 conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non-responders). Concomitant stable doses of oral corticosteroids, immunomodulators, and antibiotics were permitted.
The GEMINI 2 Study was a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints 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 endpoints were the proportion of patients in clinical remission (defined as CDAI score ≤150 points) at week 6 and the proportion of patients with enhanced clinical response (defined as a ≥100-point decrease in CDAI score from baseline) at week 6 (see Table 5).
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-blind fashion, and cohort 2 patients were treated with open-label vedolizumab 300 mg. To evaluate efficacy at week 52, 461 patients from cohorts 1 and 2, who were treated with vedolizumab and had achieved clinical response (defined as a ≥70-point decrease in CDAI score from baseline) at week 6, were randomised in a double-blind fashion (1:1:1) to 1 of the following regimens beginning at week 6: vedolizumab 300 mg every 8 weeks, vedolizumab 300 mg every 4 weeks, or placebo every 4 weeks. Patients showing clinical response at week 6 were required to begin corticosteroid tapering. Primary endpoint was the proportion of patients in clinical remission at week 52 (see Table 6).
The GEMINI 3 Study was a second randomised, double-blind, placebo-controlled study that evaluated efficacy at week 6 and week 10 in the subgroup of patients defined as having failed at least 1 conventional therapy and failed TNFα antagonist therapy (including primary non-responders) as well as the overall population, which also included patients who failed at least 1 conventional therapy and 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 either vedolizumab 300 mg or placebo at weeks 0, 2, and 6. The primary endpoint was the proportion of patients in clinical remission at week 6 in the TNFα antagonist failure subpopulation. As noted in Table 5, although the primary endpoint was not met, exploratory analyses show that clinically meaningful results were observed. (See Tables 5 and 6.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Exploratory analyses examined the effects of concomitant corticosteroids and immunomodulators on induction of remission with vedolizumab. Combination treatment, most notably with concomitant corticosteroids, appeared to be more effective in inducing remission in Crohn's disease than vedolizumab alone or with concomitant immunomodulators, which showed a smaller difference from placebo in the rate of remission. Clinical remission rate in GEMINI 2 at week 6 was 10% (difference from 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 from placebo 3%, 95% CI: -7, 13) and 22% (difference from placebo 8%, 95% CI: -3, 19) when administered 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 with concomitant corticosteroids. These effects were seen whether or not immunomodulators were also concomitantly 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 in 29%, 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 and received vedolizumab every 4 weeks. Enhanced clinical response was observed at week 10 and week 14 for greater proportions of vedolizumab patients 16% and 22%, respectively, compared with placebo patients 7% and 12%, respectively. There was no clinically meaningful difference in clinical remission between treatment groups at these time points. Analyses of week 52 clinical remission in patients who were non-responders at week 6 but achieved response at week 10 or week 14 indicate that 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 to enter 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 then randomised to placebo (for 6 to 52 weeks) and lost response were allowed to enter the open-label extension study and receive vedolizumab every 4 weeks. In these patients, clinical remission was achieved 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 patients for up to 196 weeks.
Exploratory analysis showed clinically meaningful improvements were observed for the vedolizumab every 4 weeks and every 8 weeks groups in GEMINI 2 and the improvements were significantly greater as compared with the placebo group from baseline to week 52 on EQ-5D and EQ-5D VAS scores, total IBDQ score, and IBDQ subscales of bowel symptoms and systemic function.
Crohn's disease - vedolizumab for subcutaneous administration: The efficacy and safety of subcutaneous vedolizumab for the treatment of adult patients with moderately to severely active Crohn's disease (CDAI score of 220 to 450) was demonstrated in a randomised, double-blind, placebo-controlled study evaluating efficacy endpoints at week 52 (VISIBLE 2).
In VISIBLE 2, enrolled patients (n=644) had inadequate response to, loss of response to, or intolerance to one conventional therapy, including corticosteroids, immunomodulators, and/or TNFα antagonists (including primary non-responders). Concomitant stable doses of oral aminosalicylates, corticosteroids and/or immunomodulators were permitted.
Patients who achieved clinical response to open-label treatment with intravenous vedolizumab at week 6 were eligible to be randomised. For the evaluation of the week 52 endpoints, 409 (64%) patients were randomised and treated in a double-blind fashion (2:1) to receive subcutaneous vedolizumab 108 mg (n=275) or subcutaneous placebo (n=134) every 2 weeks.
The baseline demographics were similar for patients in vedolizumab and placebo groups. The baseline CDAI was >330 (severe Crohn's disease) in about 41% and ≤330 (moderate Crohn's disease) in about 59% of the overall study population.
Beginning at week 6, patients who had achieved clinical response (defined as a ≥70-point decrease in the CDAI score from baseline) and were receiving corticosteroids were required to begin a corticosteroid tapering regimen. Primary endpoint was the proportion of patients with clinical remission (CDAI score ≤150) at week 52. The secondary endpoints were the proportion of patients with enhanced clinical response (≥100 point decrease in CDAI score from baseline) at week 52, the proportion of patients with corticosteroid-free remission (patients using oral corticosteroids at baseline who had discontinued corticosteroids and were in clinical remission) at week 52, and the proportion of TNFα antagonist naïve patients who achieved clinical remission (CDAI score ≤150) at week 52.
Table 7 shows the evaluated results from the primary and secondary endpoints. (See Table 7.)

Click on icon to see table/diagram/image

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 8 and 9. (See Tables 8 and 9.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

HRQOL was assessed by IBDQ, a disease specific instrument, and EQ-5D (including EQ-5D VAS), which is a generic measure. Work productivity was assessed by WPAI-CD. Patients treated with subcutaneous vedolizumab maintained improvements in IBDQ, EQ-5D and WPAI-CD scores at week 52 to a greater extent than patients who received placebo.
Patients who completed VISIBLE 2 were eligible to enrol in an ongoing, open-label extension study to evaluate long-term safety and efficacy of subcutaneous vedolizumab treatment in patients with ulcerative colitis or Crohn's disease.
Paediatric population: Solution for injection: The safety and efficacy of vedolizumab in children aged 0 to 17 years old have not been established. No data are available. (see Dosage & Administration).
Pharmacokinetics: 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 clinical 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 (t_max) was 7 days (range 3 to 14 days), and the mean maximum serum concentration (C_max) was 15.4 mcg/mL (SD ±3.2).
Distribution: Population pharmacokinetic analyses indicate that the distribution volume of vedolizumab is approximately 5 liters. 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: Population pharmacokinetic analyses based on intravenous and subcutaneous data indicate that the clearance of vedolizumab is approximately 0.162 L/day (through linear elimination pathway) and the serum half-life is 26 days. The exact elimination route of vedolizumab is not known. Population pharmacokinetic analyses suggest that while low albumin, higher body weight and prior treatment with anti-TNF drugs may increase vedolizumab clearance, the magnitude of their effects is not considered to be clinically relevant.
Linearity: Vedolizumab exhibited linear pharmacokinetics at serum concentrations greater than 1 mcg/mL.
Special Populations: Age does not impact the vedolizumab clearance in ulcerative colitis and Crohn's disease patients based on the population pharmacokinetic analyses. No formal studies have been conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of vedolizumab.
Toxicology: Preclinical safety data: Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.
Long-term animal studies with vedolizumab to assess its carcinogenic potential have not been conducted because pharmacologically responsive models to monoclonal antibodies do not exist. In a pharmacologically responsive species (cynomolgus monkeys), there was no evidence of cellular hyperplasia or systemic immunomodulation that could potentially be associated with oncogenesis in 13- and 26-week toxicology studies. Furthermore, no effects were found of vedolizumab on the proliferative 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 definitive conclusion can be drawn on the male reproductive organs in cynomolgus monkey repeated dose toxicity study. Given the lack of binding of vedolizumab to male reproductive tissue in monkey and human, and the intact male fertility observed in β7 integrin-knockout mice, it is not expected that vedolizumab will affect male fertility.
Administration of vedolizumab to pregnant cynomolgus monkeys during most of gestation resulted in no evidence of effects on teratogenicity, prenatal or postnatal development in infants up to 6 months of age. Low levels (<300 mcg/L) of vedolizumab were detected on post-partum day 28 in the milk of 3 of 11 cynomolgus monkeys treated 100 mg/kg of vedolizumab dosed every 2 weeks and not in any animals that received 10 mg/kg.

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.

Posology: Infusion concentrate: Ulcerative colitis: The recommended dose regimen of 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 14. Some patients who have experienced a decrease in their response may benefit from an increase in dosing frequency to Vedolizumab 300 mg every four weeks.
In patients who have responded to treatment with Vedolizumab, corticosteroids may be reduced and/or discontinued in accordance with standard of care.
Crohn's disease: The recommended dose regimen of Vedolizumab is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter. Patients with Crohn's disease, who have not shown a response may benefit from a dose of Vedolizumab 300 mg at Week 10. Continue therapy every eight weeks from Week 14 in responding patients. Therapy for patients should be discontinued if no evidence of therapeutic benefit is observed by Week 14. Some patients who have experienced a decrease in their response may benefit from an increase in dosing frequency to Vedolizumab 300 mg every four weeks.
Corticosteroids: 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 Vedolizumab, dosing at every 4 weeks may be considered. The treatment interruption period in clinical trials extended up to one year. Efficacy was regained with no evident increase in adverse events or infusion-related reactions during retreatment with Vedolizumab.
Solution for injection: Entyvio treatment should be initiated and supervised by specialist healthcare professionals experienced in the diagnosis and treatment of ulcerative colitis or Crohn's disease (see Precautions).
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 maintenance dose should be administered in place of the next scheduled intravenous dose and every 2 weeks thereafter.
For the intravenous dose regimen, see previously mentioned Dosage & Administration of the Entyvio 300 mg powder for concentrate for solution for infusion.
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 studies extended up to 46 weeks with no evident increase in adverse reactions or injection site reactions during re-initiation of treatment with subcutaneous vedolizumab (see Adverse Reactions).
Method of administration: Infusion concentrate: Vedolizumab is for intravenous infusion only. It is to be reconstituted and further diluted prior to intravenous administration. Vedolizumab is administered as an intravenous infusion over 30 minutes. Do not administer as an intravenous push or bolus. Vedolizumab lyophilized powder must be reconstituted with sterile water for injection and diluted in 250 mL of sterile 0.9% sodium chloride injection solution or 250 mL of sterile Lactated Ringer's solution prior to administration. After the infusion is complete, flush with 30 mL of sterile 0.9% sodium chloride injection solution or 30 mL of sterile Lactated Ringer's solution. Observe patients during infusion and until the infusion is complete.
Solution for injection: Entyvio solution for injection (in 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 pen are given in the respective package leaflet.
For further instructions on preparation and special precautions for handling, see Special precautions for disposal and other handling under Cautions for Usage.
Special Patient Populations: Pediatric patients: The safety and efficacy of Vedolizumab in children aged 0 to 17 years old have not been established.
Solution for injection: No data are available.
Elderly patients: No dose adjustment is required in elderly patients. Population pharmacokinetic analyses showed no effect on age (see Pharmacology: Pharmacokinetics under Actions).
Impaired renal or hepatic function: Vedolizumab has not been studied in patients with renal or hepatic impairment. No dose recommendations can be made.

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

Hypersensitivity to the active substance or to any of the excipients listed in Description.
Solution for injection: Active severe infections such as tuberculosis (TB), sepsis, cytomegalovirus, listeriosis, and opportunistic infections such as Progressive Multifocal Leukoencephalopathy (PML) (see Precautions).

Infusion concentrate: Vedolizumab should be administered by a healthcare professional prepared to manage hypersensitivity reactions including anaphylaxis, if they occur. Appropriate monitoring and medical support measures should be available for immediate use when administering Vedolizumab. Observe patients during infusion and until the infusion is complete.
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/Hypersensitivity reactions: In clinical studies, infusion-related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity (see Adverse Reactions).
If a severe IRR, anaphylactic reaction, or other severe reaction occurs, administration of Vedolizumab must be discontinued immediately and appropriate treatment initiated (e.g., epinephrine and antihistamines) (see Contraindications).
Infusion concentrate: If a mild to moderate IRR occurs, the infusion rate can be slowed or interrupted and appropriate treatment initiated (e.g., epinephrine and antihistamines). 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.
Infections: Vedolizumab is a gut-selective integrin antagonist with no identified systemic immunosuppressive activity. Physicians should be aware of the potential increased risk of opportunistic infections or infections for which the gut is a defensive barrier. Vedolizumab treatment is not to be initiated in patients with active, severe infections such as tuberculosis, sepsis, cytomegalovirus, listeriosis, and opportunistic 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.
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. No systemic immunosuppressive effect was noted in healthy subjects. 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.
Infusion concentrate: Typical signs and symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body, clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months.
Solution for injection: Vedolizumab is contraindicated in patients with active tuberculosis (see Contraindications). 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.
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.
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 (see Adverse Reactions).
Prior and concurrent use of biological products: No Vedolizumab clinical trial data are available for patients previously treated with natalizumab or rituximab (solution for injection). 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.
Solution for injection: 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.
Vaccinations: Infusion concentrate: Prior to initiating treatment with Vedolizumab all patients should be brought up to date with all recommended immunizations. Patients receiving Vedolizumab receive non-live vaccines (e.g., subunit or inactivated vaccines) and may receive live vaccines only if the benefits outweigh the risks. 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 three 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 injectable, oral and nasal vaccines is unknown.
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 three 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 injectable (infusion concentrate), oral and nasal vaccines is unknown.
Solution for injection: 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: Solution for injection: 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 Pharmacology: Pharmacodynamics under Actions).
Exploratory subgroup analyses from the clinical studies 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 Pharmacology: Pharmacodynamics under Actions).
Sodium content: Solution for injection: This medicine contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially 'sodium-free'.
Effects on Ability to Drive and Use Machines: Vedolizumab may have a minor influence on the ability to drive or operate machines, as dizziness has been reported in a small percentage of patients.

Pregnancy: There are limited amount of data from the use of vedolizumab in pregnant women.
Infusion concentrate: Vedolizumab should be used during pregnancy only if the benefits to the mother are considered to outweigh the risk to the unborn child.
Solution for injection: 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 Pharmacology: Toxicology: Preclinical safety data under Actions).
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.
Lactation: Vedolizumab has been detected in human milk. The effect of Vedolizumab on infants is 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: Solution for injection: 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 Pharmacology: Toxicology: Preclinical safety data under Actions).

Summary of the safety profile: Infusion concentrate: Vedolizumab has been studied in three placebo-controlled clinical trials in patients with ulcerative colitis (GEMINI I) or Crohn's disease (GEMINI II and III). In two 52-Week controlled studies (GEMINI I and II) involving 1434 patients receiving Vedolizumab 300 mg at Week 0, Week 2 and then every eight weeks or every four weeks for up to 52 weeks, and 297 patients receiving placebo for up to 52 weeks, adverse events were reported in 84% of Vedolizumab-treated patients and 78% of placebo-treated patients. Over 52 weeks, 19% of Vedolizumab-treated patients experienced serious adverse events compared to 13% of placebo-treated patients. Similar rates of adverse events were seen in the every eight week and every four week dosing groups in the Phase 3 clinical trials. The proportion of patients who discontinued treatment due to adverse events was 9% for Vedolizumab-treated patients and 10% for placebo-treated patients. In the combined 52-Week studies the adverse reactions that occurred in ≥5% of patients were nausea, nasopharyngitis, upper respiratory tract infection, arthralgia, pyrexia, fatigue, headache and cough.
Infusion-related reactions were reported in 4% of patients receiving Vedolizumab.
In the shorter (10-week) placebo controlled induction trial the types of adverse reactions reported were similar but occurred at lower frequency than the longer 52-Week trials. A further 279 patients were treated with Vedolizumab at Week 0 and Week 2 and then with placebo for up to 52 weeks. Of these patients, 84% experienced adverse events and 15% experienced serious adverse events. Patients (n=1822) previously enrolled in Phase 2 or 3 Vedolizumab studies were eligible to enroll in an ongoing open-label study and received Vedolizumab 300 mg every four weeks.
The following convention is used for the classification of the frequency of an adverse drug reaction (ADR) and is based on the Council for International Organizations of Medical Sciences (CIOMS) guidelines: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). (See Table 10.)

Click on icon to see table/diagram/image

Solution for injection: 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: Solution for injection: The following listing of adverse reactions is based on clinical study 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. (See Table 11.)

Click on icon to see table/diagram/image

Postmarketing Experience: Infusion concentrate: In the post-marketing setting reports of anaphylaxis have been identified. The frequency of anaphylaxis in this setting is unknown.
Description of selected adverse reactions: Infusion-related reactions: Infusion concentrate: In the 52-Week controlled studies, 4% of Vedolizumab-treated patients and 3% of placebo-treated patients experienced an adverse event defined by the investigator as IRR. 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 IRRs, those dosed with Vedolizumab had more IRRs within the first two hours as compared to placebo patients with IRRs. Most IRRs were not serious and occurred during the infusion or within the first hour after infusion is completed.
One serious adverse event of IRR was reported in a Crohn's disease patient during the second infusion (symptoms reported were dyspnea, 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 Vedolizumab at Weeks 0 and 2 followed by placebo, no increase in the rate of IRR was seen upon retreatment with Vedolizumab after loss of response.
Injection site reactions: Solution for injection: 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: Infusion concentrate: In the 52-Week controlled studies, 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 the 52-Week controlled studies, 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 treated with 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, 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.
Solution for injection: In GEMINI I and II 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 I and II 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.
Immunogenicity: Infusion concentrate: An acid dissociation electrochemiluminescence (ECL) method for detecting antibodies to vedolizumab was developed and validated. The incidence of anti-vedolizumab antibodies to intravenous vedolizumab with the drug-tolerant ECL method for patients in GEMINI 1 and GEMINI 2 studies who had continuous treatment for 52 weeks was 6% (86 out of 1427). Of the 86 patients who tested positive for anti-vedolizumab antibodies, 20 patients were persistently positive and 56 developed neutralizing antibodies to vedolizumab. Overall, there was no apparent correlation of anti-vedolizumab antibody development to adverse events following administration of vedolizumab.
Malignancy: Overall, results from the clinical program to date do not suggest an increased risk for malignancy with Vedolizumab treatment; however, the number of malignancies was small and long-term exposure was limited. Long-term safety evaluations are ongoing.
Reporting of suspected adverse reactions: Solution for injection: 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.

No interaction studies have been performed.
Solution for injection: 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 thatco-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 Precautions).

Incompatibilities: Solution for injection: In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
Infusion concentrate: Instructions for use and handling and disposal: Vedolizumab does not contain preservatives. Once reconstituted, the infusion solution should be used as soon as possible.
Instructions for reconstitution and infusion: 1. Use aseptic technique when preparing Entyvio solution for intravenous infusion.
2. Remove flip-off cap from the vial and wipe with alcohol swab. Reconstitute Entyvio with 4.8 mL of sterile water for injection at room temperature (20°C-25°C), using a syringe with a 21-25 gauge needle.
3. Insert the syringe needle into the vial through the center of the stopper and direct the stream of sterile water for injection to the 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 for reconstitution and for any foam to settle; the vial can be swirled and inspected for dissolution during this time. If not fully dissolved after 20 minutes, allow another 10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 30 minutes.
6. Inspect the reconstituted solution visually for particulate matter and discoloration prior to dilution. Solution should be clear or opalescent, colorless to light yellow and free of visible particulates. Reconstituted solution with uncharacteristic color or containing particulates must not be administered.
7. Once dissolved, gently invert vial 3 times.
8. Immediately withdraw 5 mL (300 mg) of reconstituted Entyvio using a syringe with a 21-25 gauge needle.
9. Add the 5 mL (300 mg) of reconstituted Entyvio to 250 mL of sterile 0.9% sodium chloride solution or 250 mL of Lactated Ringer's solution, and gently mix the infusion bag (5 mL of solution does not have to be withdrawn from the infusion bag prior to adding Entyvio). Do not add other medicinal products to the prepared infusion solution or intravenous infusion set. Administer the infusion solution over 30 minutes.
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 local requirements.
Solution for injection: Special precautions for disposal and other handling: Instructions for administration: After removing the pre-filled pen from the refrigerator, wait 30 minutes before injecting to allow the solution to reach room temperature.
Do not leave the pre-filled pen in direct sunlight.
Each pre-filled pen is for single use only.
Do not freeze.
Do not use if it has been frozen.
Inspect the solution visually for particulate matter and discoloration prior to administration. The solution should be colourless to yellow. Do not use pre-filled pen with visible particulate matter or discoloration.
Any unused product or waste material should be disposed of in accordance with local requirements.

Store in a refrigerator (2°C-8°C). Keep the vial/prefilled pen in the outer carton in order to protect from light. Do not freeze.
Solution for injection: If needed, the pre-filled pen can be left out of the refrigerator in its original carton up to 25°C for up to 7 days. Do not use the pre-filled pen if left out of the refrigerator for more than 7 days.
Shelf life: Infusion concentrate: 3 years (up to 36 months).
Stability of reconstituted vedolizumab solution in vial: In-use stability of the reconstituted solution in the vial has been demonstrated for 8 hours at 2°C-8°C.
Stability of diluted vedolizumab solution in 0.9% sodium chloride solution: In-use stability of the diluted solution in 0.9% sodium chloride solution in infusion 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 0.9% sodium chloride is a total of 12 hours at 20°C-25°C or 24 hours at 2°C-8°C. This hold time may include up to 8 hours at 2°C-8°C in the vial. Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag.
Stability of the diluted vedolizumab solution in Lactated Ringer's solution: In-use stability of the diluted solution in Lactated Ringer's solution in the infusion bag has been demonstrated for 8 hours at 2°C-8°C.
The combined in-use stability of vedolizumab in the vial and infusion bag diluted with Lactated Ringer's solution is a total of 8 hours at 2°C-8°C. Do not freeze the reconstituted solution in the vial or the diluted solution in the infusion bag. (See Table 12.)

Click on icon to see table/diagram/image

Solution for injection: Instructions for Use: Important Information: Read and follow these Instructions for Use before you inject. A healthcare provider should show you how to use the ENTYVIO pre-filled pen before you use it for the first time.
Do not put or press thumb, fingers or hand over the yellow needle shield.
If you have any questions or concerns about ENTYVIO prefilled pen, call a healthcare provider.
Storage: Refrigerate at 2°C to 8°C.
If needed, for example when you are traveling, the prefilled pen/autoinjector can be left in its box at room temperature up to 25°C for up to 7 days.
Do not freeze.
Do not leave in direct sunlight.
1) Place what you need for the injection on a clean, flat surface: Take the pre-filled pen carton out of the refrigerator.
If you are opening the carton for the first time, check to make sure the carton is properly sealed. Do not use the pre-filled pen(s) if any of the seals on the carton are broken or missing.
Check the expiry date (EXP) on the box. Do not use if the expiration date on the carton has passed.
Remove one pre-filled pen from the carton. Keep any remaining pre-filled pens in the carton in the refrigerator.
Wait 30 minutes to let the pre-filled pen come to room temperature.
Do not warm the pre-filled pen in any other way.
Do not let it sit in direct sunlight.
Do not take the pre-filled pen out of its tray until you are ready to inject.
You will also need: Alcohol pad, Cotton ball or gauze, Sharps disposal container.
2) Open and check the pre-filled pen: Wash your hands.
Peel back the paper on the tray and lift the pre-filled pen out.
Inspect the pre-filled pen for damage.
Do not use the pre-filled pen if any part of it is damaged.
Check the expiry date on the pre-filled pen.
Do not use if the expiry date on the pre-filled pen has passed.
Check the medicine. It should be colorless to yellow.
Do not use the pre-filled pen if the medicine is cloudy or has particles floating in it.
You may see air bubbles in the pre-filled pen. This is normal.
Do not shake.
3) Prepare the injection site: Choose an injection site on your bare skin from one of the following: Front of the thighs, or Stomach area (abdomen) except for the area 2 inches (5 cm) around the belly button (navel), or Back of the upper arm (only if a caregiver gives the injection).
Use a new injection site or a different area within the same injection site for each injection.
Do not inject into moles, scars, bruises, or skin that is tender, hard, red, or damaged.
Wipe the chosen site with an alcohol pad. Let the skin dry.
Do not touch this area again before you inject.
Pull the purple cap straight off and throw it away.
Do not put or press thumb, fingers or hand over the yellow needle shield.
Do not re-cap the pre-filled pen.
Do not use a dropped pre-filled pen.
4) Inject ENTYVIO: Hold the pre-filled pen so you can see the viewing window.
Place the pre-filled pen at 90 degrees to the injection site.
Be sure the yellow end is toward the injection site.
Do not push down until you are ready to inject.
Push down on the pre-filled pen as far as it will go to begin the injection.
Hold and count to 10 while pushing down with constant pressure. This will allow all of the medicine to be injected.
You may hear two clicks, one at the start and one near the end of the injection.
Confirm that the viewing window is filled with purple before you stop pushing.
You will see a small amount of grey in the window. This is normal.
Lift the pre-filled pen from the injection site.
The yellow needle shield will drop down and lock over the needle.
If the viewing window did not fill completely, call your healthcare provider. You may not have received the full dose of medicine.
You may see a small amount of blood at the injection site. If you do, press on the skin with a cotton ball or gauze.
5) Throw away used material: Put the used pre-filled pen in a a puncture-resistant container, like a sharps container, immediately after use.
Dispose of your sharps container according to your local regulations.
The rest of the material can be thrown away in your household rubbish.

GIT Regulators, Antiflatulents & Anti-Inflammatories / Immunosuppressants

L04AG05 - vedolizumab ; Belongs to the class of monoclonal antibodies. Used as immunosuppressants.

B