ENTYVIO 108 mg Solution for injection Ref.[109634] Active ingredients: Vedolizumab

Traceability

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

Hypersensitivity reactions

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

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

Infections

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

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

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

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

Healthcare professionals should monitor patients on vedolizumab for any new onset or worsening of neurological signs and symptoms and consider neurological referral if they occur. If PML is suspected, treatment with vedolizumab must be withheld; if confirmed, treatment must be permanently discontinued.

Malignancies

The risk of malignancy is increased in patients with ulcerative colitis and Crohn’s disease. Immunomodulatory medicinal products may increase the risk of malignancy (see section 4.8).

Prior and concurrent use of biological products

No vedolizumab clinical trial data are available for patients previously treated with natalizumab or rituximab. Caution should be exercised when considering the use of vedolizumab in these patients.

Patients previously exposed to natalizumab should normally wait a minimum of 12 weeks prior to initiating therapy with vedolizumab, unless otherwise indicated by the patient’s clinical condition. No clinical trial data for concomitant use of vedolizumab with biologic immunosuppressants are available. Therefore, the use of vedolizumab in such patients is not recommended.

Live and oral vaccines

In a placebo-controlled study of healthy volunteers, a single 750 mg dose of vedolizumab did not lower rates of protective immunity to hepatitis B virus in subjects who were vaccinated intramuscularly with 3 doses of recombinant hepatitis B surface antigen. Vedolizumab-exposed subjects had lower seroconversion rates after receiving a killed, oral cholera vaccine. The impact on other oral and nasal vaccines is unknown. It is recommended that all patients be brought up to date with all immunisations in agreement with current immunisation guidelines prior to initiating vedolizumab therapy. Patients receiving vedolizumab treatment may continue to receive non-live vaccines. There are no data on the secondary transmission of infection by live vaccines in patients receiving vedolizumab. Administration of the influenza vaccine should be by injection in line with routine clinical practice. Other live vaccines may be administered concurrently with vedolizumab only if the benefits clearly outweigh the risks.

Induction of remission in Crohn’s disease

Induction of remission in Crohn’s disease may take up to 14 weeks in some patients. The reasons for this are not fully known and are possibly related to the mechanism of action. This should be taken into consideration, particularly in patients with severe active disease at baseline not previously treated with TNFα antagonists (see also section 5.1).

Exploratory subgroup analyses from the clinical trials in Crohn’s disease suggested that vedolizumab administered in patients without concomitant corticosteroid treatment may be less effective for induction of remission in Crohn’s disease than in those patients already receiving concomitant corticosteroids (regardless of use of concomitant immunomodulators; see section 5.1).

Sodium content

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

No interaction studies have been performed.

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

Vaccinations

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

Women of childbearing potential

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

Pregnancy

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

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

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

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

Breast-feeding

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

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

Fertility

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

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

Summary of the safety profile

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

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

Tabulated list of adverse reactions

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

Table 1. Adverse reactions:

^# Subcutaneous administration only.

Description of selected adverse reactions

Injection site reactions

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

Infections

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

In GEMINI 1 and 2 controlled studies with intravenous vedolizumab, the rate of serious infections was 0.07 per patient year in vedolizumab-treated patients and 0.06 per patient year in placebo-treated patients. Over time, there was no significant increase in the rate of serious infections.

In controlled and open-label studies in adults with intravenous vedolizumab, serious infections have been reported, which include tuberculosis, sepsis (some fatal), salmonella sepsis, listeria meningitis, and cytomegaloviral colitis.

In clinical studies with subcutaneous vedolizumab, the rate of infections was 0.26 per patient year in vedolizumab-treated patients. The most frequent infections were nasopharyngitis, upper respiratory tract infection, bronchitis and influenza.

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

In clinical studies with intravenous and subcutaneous vedolizumab, the rate of infections in vedolizumab-treated patients with BMI of 30 kg/m² and above was higher than for those with BMI less than 30 kg/m².

In clinical studies with intravenous and subcutaneous vedolizumab, a slightly higher incidence of serious infections was reported in vedolizumab-treated patients who had prior exposure to TNFα antagonist therapy compared to patients who were naïve to previous TNFα antagonist therapy.

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.