Adverse reactions : תופעות לוואי

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.

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

Tabulated list of adverse reactions

The following listing of adverse reactions is based on clinical trial and post marketing experience and is displayed by system organ class. Within the system organ classes, adverse reactions are listed under headings of the following frequency categories: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1,000 to < 1/100), very rare (< 1/10,000) and not known (cannot be estimated from 
the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions
System organ class                 Frequency           Adverse reaction(s) Infections and infestations        Very common         Nasopharyngitis Common              Pneumonia,
Clostridium difficile infection,
Bronchitis,
Gastroenteritis,
Upper respiratory tract infection,
Influenza,
Sinusitis,
Pharyngitis,
Herpes zoster
Uncommon            Respiratory tract infection,
Vulvovaginal candidiasis,
Oral candidiasis
Immune system disorders            Very rare           Anaphylactic reaction, Anaphylactic shock
Nervous system disorders           Very common         Headache
Common              Paraesthesia
Eye disorders                      Uncommon            Blurred vision 
Vascular disorders                  Common              Hypertension
Respiratory, thoracic and           Common              Oropharyngeal pain, mediastinal disorders                                   Nasal congestion, Cough
Not known           Interstitial lung disease
Gastrointestinal disorders          Common              Anal Abscess, Anal fissure,
Nausea,
Dyspepsia,
Constipation,
Abdominal distension,
Flatulence,
Haemorrhoids,
Rectal haemorrhage*
Skin and subcutaneous tissue        Common              Rash,
disorders                                               Pruritus,
Eczema,
Erythema,
Night sweats,
Acne
Uncommon            Folliculitis
Very common         Arthralgia
Musculoskeletal and connective      Common              Muscle spasms, tissue disorders                                        Back pain,
Muscular weakness,
Fatigue,
Pain in the extremity
General disorders and               Common              Pyrexia,
administration site conditions                          Infusion related reaction (asthenia* and chest discomfort*),
Infusion site reaction (including: Infusion site pain and Infusion site irritation)

Uncommon              Chills,
Feeling cold
*Reported in the EARNEST pouchitis study

Description of selected adverse reactions
Infusion-related reactions

In GEMINI 1 and 2 controlled studies (ulcerative colitis and Crohn’s disease), 4% of intravenous vedolizumab-treated patients and 3% of placebo-treated patients experienced an adverse reaction defined by the investigator as infusion-related reaction (IRR) (see section 4.4). No individual Preferred Term reported as an IRR occurred at a rate above 1%. The majority of IRRs were mild or moderate in intensity and < 1% resulted in discontinuation of study treatment. Observed IRRs generally resolved with no or minimal intervention following the infusion. Most infusion related reactions occurred within the first 2 hours. Of those patients who had infusion related reactions, those dosed with intravenous vedolizumab had more infusion related reactions with in the first 2 hours as compared to placebo patients with infusion related reactions. Most infusion related reactions were not serious and occurred during the infusion or within the first hour after infusion is completed.

One serious adverse reaction of IRR was reported in a Crohn’s disease patient during the second infusion (symptoms reported were dyspnoea, bronchospasm, urticaria, flushing, rash, and increased blood pressure and heart rate) and was successfully managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone. In patients who received intravenous vedolizumab at weeks 0 and 2 followed by placebo, no increase in the rate of IRR was seen upon retreatment with intravenous vedolizumab after loss of response.

In EARNEST controlled study (pouchitis) with intravenous vedolizumab, hypersensitivity reactions, including IRRs, were reported in 3 out of 51 subjects (5.9%) in the vedolizumab group and 2 out of 51 subjects (3.9%) in the placebo group. The individual Preferred Terms included mouth ulceration, swelling, oedema peripheral, chest discomfort, asthenia, acute kidney injury, obstructive airway disorder and flushing. All events were reported as mild to moderate in intensity, none were considered serious and none resulted in study discontinuation.

Infections

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

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

In the EARNEST controlled study (pouchitis) with intravenous vedolizumab, only 1 out of 51 subjects (2.0%) in the vedolizumab group experienced a serious infection of gastroenteritis. The subject was hospitalized for observation, recovered from the event and completed the study.

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

In clinical studies with intravenous vedolizumab (ulcerative colitis and Crohn’s disease), the rate of infections in vedolizumab-treated patients with BMI of 30 kg/m2 and above was higher than for those with BMI less than 30 kg/m2.

In clinical studies with intravenous vedolizumab (ulcerative colitis and Crohn’s disease), a slightly higher incidence of serious infections was reported in vedolizumab-treated patients who had prior exposure to TNFα antagonist therapy compared to patients who were naïve to previous TNFα antagonist therapy.

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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il