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Various  Format Changes

• To highlight intravenous vedolizumab (in light of subcutaneous vedolizumab being licensed).
• Changing Entyvio to vedolizumab.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

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Vedolizumab is a humanised IgG1 monoclonal antibody that binds to the human α4β7 integrin and is produced using recombinant DNA technology in Chinese hamster ovary (CHO) cells by recombinant DNA technology.

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4.4  Special warnings and precautions for use

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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, infusion‑related reactions (IRR) and hypersensitivity reactions have been reported, with the majority being mild to moderate in severity (see section 4.8).

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4.8 Undesirable effects

Summary of the safety profile

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

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

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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 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.

In clinical studies with intravenous 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.

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10. Date of revision of the text

Updated text in red:

28 April 2020

Change to section

Details of change

4.2

Posology and method of administration

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Posology

Ulcerative colitis

The recommended dose regimen of Entyvio is 300 mg administered by intravenous infusion at zero, two and six weeks and then every eight weeks thereafter.

Continued tTherapy for patients with ulcerative colitis should be carefully reconsidered 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 Entyvio 300 mg every four weeks.

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

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Crohn's disease

The recommended dose regimen of Entyvio 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 Entyvio at week 10 (see section 4.4). Therapy should be continued every eight weeks from week 14 in responding patients. Therapy for patients with Crohn's disease should not 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 Entyvio 300 mg every four weeks.

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4.4

Special warnings and precautions for use

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Infections

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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 on 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.

No cases of PML were reported in clinical studies of vedolizumab however, hHealthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological signs and symptoms as outlined in physician education materials, and consider neurological referral if they occur. The patient is to be given a Patient Alert Card (see section 4.2). If PML is suspected, treatment with vedolizumab must be withheld; if confirmed, treatment must be permanently discontinued.

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4.6

Fertility, pregnancy and lactation

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Breast-feeding

Vedolizumab has been detected in human milk. The effect of vedolizumab on infants is unknown. The use of vedolizumab in lactating women should take into account the benefit of therapy to the mother and potential risks to the infant.

It is unknown whether vedolizumab is excreted in human milk or absorbed systemically after ingestion.

Available pharmacodynamic/toxicological data in animals have shown excretion of vedolizumab in milk (see section 5.3).

A risk to the infants cannot be excluded.

Because maternal antibodies (IgG) are excreted in breast milk, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Entyvio therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

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4.8

Undesirable effects

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Herpes zoster added to the Infections and infestations section of Table 1 (Adverse Reactions) as an Uncommon side effect.

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Immunogenicity

In GEMINI I and II controlled studies, vedolizumab showed an immunogenicity rate of 4% (56 of 1,434 patients who received continuous treatment with vedolizumab were anti-vedolizumab antibody-positive at any time during treatment). Nine out of 56 patients were persistently positive (anti-vedolizumab antibody-positive at two or more study visits) and 33 patients developed neutralizing anti-vedolizumab antibodies.

The frequency of anti-vedolizumab antibody detected in patients 16 weeks after the last dose of vedolizumab (approximately five half-lives after the last dose) was approximately 10% in GEMINI I and II.

In GEMINI I and II controlled studies, 5% (3 of 61) of the patients who had an adverse reaction assessed by the investigator as an IRR were persistently anti-vedolizumab antibody-positive.

Overall, there was no apparent correlation of anti-vedolizumab antibody development to clinical response or adverse reactions. However, the number of patients that developed anti-vedolizumab antibodies was too limited to make a definitive assessment.

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5.1

Pharmacodynamic properties

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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 α_Eβ₇ 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.

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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.

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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 four 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 124 196 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 general 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).

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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 four 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 124 196 weeks.

Exploratory analysis showed clinically meaningful improvements were observed for the vedolizumab every four weeks and every eight weeks groups in GEMINI II 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.

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5.2

Pharmacokinetic properties

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Elimination

Population pharmacokinetic analyses indicate that vedolizumab has a total body clearance of approximately 0.157 L/day and a serum half-life of 25 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 and presence of anti-vedolizumab antibody may increase vedolizumab clearance, the magnitude of their effects is not considered to be clinically relevant.

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5.3

Preclinical safety data

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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. It is not known whether vedolizumab is excreted in human milk.

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10. Date of revision of the text

Updated text in red:

20^th February 2019

Change to section

Details of change

10. Date of revision of the text

Updated text in red:

14 December 2017 09 February 2018

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Details of change

4.8 Undesirable effects

Text in blue removed and text in red added:

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Tabulated list of adverse reactions

The following listing of adverse reactions is based on the clinical trial and post marketing experience and isare 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), and uncommon (≥1/1,000 to <1/100) and very rare (< 1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

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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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

10. Date of revision of the text

Updated text in red:

14 December 2017