Entyvio 300 mg powder for concentrate for solution for infusion

  • Name:

    Entyvio 300 mg powder for concentrate for solution for infusion

  • Company:
    info
  • Active Ingredients:

    Vedolizumab

  • Legal Category:

    Product subject to medical prescription which may not be renewed (A)

Patient Information Leaflet Patient Information Leaflet last updated on medicines.ie: 06/03/19

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Summary of Product Characteristics last updated on medicines.ie: 6/3/2019

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Takeda Products Ireland Ltd

Takeda Products Ireland Ltd

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When a pharmaceutical company changes any document, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.

Updated on 6 March 2019 PIL

Reasons for updating

  • Change to section 2 - pregnancy, breast feeding and fertility
  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 6 March 2019 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.1 - Pharmacodynamic properties
  • Change to section 5.2 - Pharmacokinetic properties
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to section

Details of change

4.2

Posology and method of administration

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.

 …

 

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.

4.4

Special warnings and precautions for use

 

Infections

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.

 

4.6

Fertility, pregnancy and lactation

 

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.

4.8

Undesirable effects

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

 

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.

5.1

Pharmacodynamic properties

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.

 

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.

 

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).

 

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.

5.2

Pharmacokinetic properties

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.

5.3

Preclinical safety data

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.

10. Date of revision of the text

Updated text in red:

 

20th February 2019

Updated on 21 December 2018 PIL

Reasons for updating

  • Change to section 3 - how to take/use
  • Removal of Black Inverted Triangle
  • Improved presentation of PIL

Updated on 21 December 2018 SmPC

Reasons for updating

  • Change to section 2 - Qualitative and quantitative composition
  • Change to section 4.6 - Pregnancy and lactation
  • Change to section 4.7 - Effects on ability to drive and use machines
  • Change to section 4.8 - Undesirable effects
  • Change to section 5.3 - Preclinical safety data
  • Change to section 10 - Date of revision of the text
  • Improved presentation of SmPC
  • Removal of Black Inverted Triangle

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 6 September 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision

Updated on 6 September 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

In section 4.8 (undesirable effects), anaphylactic reaction and anaphylactice shock have been added as a very rare adverse reaction.

In section 10, date of revision is 23 August 2018

Updated on 11 June 2018 SmPC

Reasons for updating

  • Change to section 6.3 - Shelf life
  • Change to section 6.6 - Special precautions for disposal and other handling
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 11 June 2018 PIL

Reasons for updating

  • Change to section 5 - how to store or dispose

Updated on 16 February 2018 SmPC

Reasons for updating

  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to section

Details of change

10. Date of revision of the text

Updated text in red:

 

14 December 2017 09 February 2018

Updated on 16 February 2018 SmPC

Reasons for updating

  • New SmPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Updated on 15 February 2018 PIL

Reasons for updating

  • New PIL for new product

Updated on 15 February 2018 PIL

Reasons for updating

  • Change to section 6 - date of revision

Updated on 8 January 2018 SmPC

Reasons for updating

  • Change to section 4.8 - Undesirable effects
  • Change to Section 4.8 – Undesirable effects - how to report a side effect
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to section

Details of change

4.8 Undesirable effects

Text in blue removed and text in red added:

 

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.

 

Table 1. Adverse Reactions

System Organ Class

Frequency

Adverse Reaction(s)

Infection and infestation

Very Common

Nasopharyngitis

Common

Bronchitis, Gastroenteritis, Upper respiratory tract infection, Influenza, Sinusitis, Pharyngitis

Uncommon

Respiratory tract infection, Vulvovaginal candidiasis, Oral Candidiasis

Very rare

Pneumonia

Nervous system disorders

Very Common

Headache

Common

Paraesthesia

Eye disorders

Very rare

Blurred vision

Vascular disorders

Common

Hypertension

Respiratory, thoracic and mediastinal disorders

Common

Oropharyngeal pain, Nasal congestion, Cough

 

 

 

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

 

Updated on 4 January 2018 PIL

Reasons for updating

  • Change to section 4 - possible side effects
  • Change to section 6 - date of revision
  • Change to section 4 - how to report a side effect

Updated on 10 November 2016 PIL

Reasons for updating

  • Change to section 6 - manufacturer

Updated on 13 January 2016 PIL

Reasons for updating

  • Addition of manufacturer

Updated on 3 September 2015 SmPC

Reasons for updating

  • Change to section 4.2 - Posology and method of administration
  • Change to section 4.4 - Special warnings and precautions for use
  • Change to section 4.8 - Undesirable effects
  • Change to section 10 - Date of revision of the text

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

Change to section

Details of change

4.2           Posology and method of administration

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 section 4.4). Patients should be given the package leaflet and the Patient Alert Card.

 

4.4.  Special warnings and precautions for use

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 vedolizumab.

 

4.8. Undesirable Effects

Summary of safety profile

 

“……eight weeks or every four weeks from Week 6 for up to 52 weeks, and 297 patients receiving placebo for up to 52 weeks, adverse events….”

 

Muscle spasms,  Back pain, Muscular weakness, Fatigue, Pain in the extremity – has been added as “common” under “Musculoskeletal and connective tissue disorders”

10. DATE OF REVISION OF THE TEXT

 

Changed to:

20th August 2015

Updated on 26 August 2015 PIL

Reasons for updating

  • Change to side-effects
  • Change to date of revision
  • Addition of information on reporting a side effect.

Updated on 3 August 2015 PIL

Reasons for updating

  • Change to dosage and administration

Updated on 1 June 2015 PIL

Reasons for updating

  • Change to name of manufacturer

Updated on 12 September 2014 SmPC

Reasons for updating

  • New SPC for new product

Legal category: Product subject to medical prescription which may not be renewed (A)

Free text change information supplied by the pharmaceutical company

None provided

Updated on 4 September 2014 PIL

Reasons for updating

  • New PIL for new product