6.1 Clinical Trials Experience
(Additions
and/or revisions underlined)
Because
clinical trials are conducted under widely varying conditions, adverse reaction
rates observed in the clinical trials of a drug cannot be directly compared
to rates in the clinical trials of another drug and may not
reflect the rates observed in practice.
The data described below reflect exposure to intravenous ENTYVIO
in 3,326 patients and healthy volunteers in clinical trials, including 1,396 exposed for greater than one year, and
835 exposed for greater than two years.
Intravenous Infusion
The safety
data described in Table 2
are derived from four controlled Phase 3 trials
(UC Trials I and II, and CD
Trials I and III); data from adult patients receiving open-label
intravenous ENTYVIO treatment at Weeks 0 and 2 (prior to entry into UC Trial II and CD Trial III) and from
Weeks 6 to 52 (non-responders at Week 6 of UC Trial I and CD Trial I) are
included [see Clinical Studies (14.1, 14.2)].
In these trials, 1,434
patients
received ENTYVIO 300 mg intravenously for
up to 52 weeks, and 297 patients received placebo for up
to 52 weeks. Of these, 769 patients had ulcerative colitis and 962 patients had Crohn’s disease. Patients were exposed for a
mean duration of 259
days (UC Trials I and II) and 247 days (CD Trials I and III). Adverse reactions were reported in 52% of
patients treated with intravenous ENTYVIO and 45% of patients treated
with placebo (UC Trials I and II: 49% with ENTYVIO and 37% with placebo; CD
Trials I
and III: 55% with ENTYVIO and 47% with placebo). Serious adverse reactions were reported in 7% of patients treated
with intravenous ENTYVIO
compared to 4% of patients treated with placebo (UC
Trials I and II: 8% with ENTYVIO and 7% with placebo; CD Trials I and III: 12% with
ENTYVIO and 9% with placebo).
The most common adverse
reactions (reported by greater than or
equal to 3% of patients treated with intravenous ENTYVIO in the UC Trials I and II
and CD Trials I and III
combined group
and greater than or equal to 1% higher than
in
combined placebo group) were
nasopharyngitis, headache, arthralgia,
nausea,
pyrexia,
upper
respiratory tract infection, fatigue, cough, bronchitis,
influenza, back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in
extremities (Table 2).
Safety
data
for
patients
(n=279)
in
UC
Trials
I
and
II
and
CD
Trials
I
and
III
who
received intravenous ENTYVIO at Weeks 0 and 2 and were then randomized to placebo at Week 6 for
up to 52 weeks, and for patients (n=416) in CD Trial II, a 10 week Crohn’s
disease trial, are similar to those listed in Table 2.
Infusion-Related Reactions and Hypersensitivity Reactions
Serious infusion-related reactions and
hypersensitivity reactions including anaphylaxis have been reported following intravenous
ENTYVIO administration in clinical trials [see Warnings and Precautions (5.1)]. In UC Trials I and II and Crohn’s Trials I and III, one case of
anaphylaxis [one out of 1,434 patients treated with intravenous ENTYVIO
(0.07%)] was reported by 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 managed with discontinuation of infusion and treatment with antihistamine and intravenous hydrocortisone.
In UC Trials I and II
and CD Trials I and III, 4% of patients treated with intravenous ENTYVIO
and 3% of patients treated with placebo experienced an infusion-related
reaction (IRR). The most frequently observed IRR in the patients treated with intravenous
ENTYVIO (reported more than twice)
were nausea, headache,
pruritus, dizziness, fatigue,
infusion-related reaction,
pyrexia, urticaria and vomiting (each of these adverse reactions occurred in
<1% in all patients treated with intravenous ENTYVIO) and no
individual adverse reaction reported occurred at a rate above 1%. These
reactions generally occurred within the first two hours after the infusion and
resolved with no treatment or following antihistamine and/or IV hydrocortisone
treatment. Less than 1% of patients treated with intravenous ENTYVIO had
IRRs assessed by the investigator as severe, and IRRs requiring discontinuation
of study treatment occurred in <1%.
In clinical trials, for
patients with mild IRRs or hypersensitivity reactions, physicians were allowed to pretreat with standard medical
treatment (e.g., antihistamine, hydrocortisone and/or
acetaminophen) prior to next infusion.
Infections
In UC Trials I and II
and CD Trials I and III, the rate of infections was 0.85 per patient-year in
the patients treated with intravenous ENTYVIO and 0.7 per patient-year in the patients
treated with placebo [see Warnings and Precautions (5.2)]. The
infections consisted primarily of nasopharyngitis, upper respiratory tract
infection, sinusitis, and urinary tract infection. Two percent of patients
discontinued intravenous ENTYVIO due to infections.
In UC Trials I and II and CD Trials I and III, the rate of serious
infections was 0.07 per
patient-
year in patients treated with intravenous ENTYVIO and 0.06 per
patient-year in patients treated with placebo. Serious infections were more
common in Crohn’s disease patients than ulcerative colitis patients, and anal
abscesses were the most frequently reported serious adverse reaction in Crohn’s
disease patients. Over 48 months, there was no increase in the rate of serious
infections.
In controlled- and
open-label long-term extension trials in adults treated with intravenous
ENTYVIO, serious infections have been reported,
including anal abscess,
sepsis (some fatal), tuberculosis, salmonella sepsis,
Listeria meningitis, giardiasis and cytomegaloviral colitis.
In UC Trials I and II and CD Trials I and III, sepsis, including bacterial sepsis and septic shock,was
reported in four of 1,434 (0.3%) patients
treated with intravenous ENTYVIO and in two of 297
patients treated with placebo (0.7%). During these trials, two
Crohn’s disease patients treated with intravenous ENTYVIO died due to
reported sepsis or septic shock; both patients had significant comorbidities and a complicated hospital course that contributed to the deaths. In an open label, long-term
extension trial, additional cases of sepsis (some fatal), including bacterial
sepsis and septic shock, were
reported. The rate of sepsis in patients with ulcerative colitis or Crohn’s
disease receiving intravenous ENTYVIO was two per 1,000 patient-years.
In clinical trials, all
patients were screened for tuberculosis. One case of latent, pulmonary
tuberculosis was diagnosed
during the controlled trials with intravenous ENTYVIO. Additional
cases of pulmonary tuberculosis were diagnosed during the open-label trial. All
of these observed cases occurred outside the United States (U.S.), and none of
the patients had extrapulmonary manifestations.
Liver Injury
There have been reports of elevations of
transaminase and/or bilirubin in patients receiving intravenous ENTYVIO [see Warnings
and Precautions (5.4)]. In UC Trials I and II and CD Trials I and III, three patients reported serious
adverse reactions of hepatitis, manifested as elevated transaminases with or
without elevated bilirubin and symptoms consistent with hepatitis (e.g., malaise, nausea, vomiting, abdominal pain, anorexia). These adverse reactions occurred following two to five
intravenous ENTYVIO doses; however, based on case report information it is
unclear if the reactions indicated drug-induced or autoimmune etiology. All
patients recovered following discontinuation of therapy with some requiring
corticosteroid treatment. In controlled trials, the incidence of ALT and AST
elevations ?3x ULN was <2% in patients treated with intravenous ENTYVIO
and in patients treated with placebo. In the open- label trial, one additional
case of
serious hepatitis was observed.
Malignancies
In
UC
Trials
I
and
II
and
CD
Trials
I
and
III,
malignancies (excluding dysplasia
and
basal
cell carcinoma) were reported in six of 1,434 (0.4%) patients
treated with intravenous ENTYVIO, including
colon cancer
(n=2), transitional cell carcinoma (n=1), breast cancer
(n=1),
carcinoid
tumor of the appendix (n=1) and squamous cell carcinoma (n=1). Malignancy was reported in one of 297 (0.3%)
patients treated with placebo (squamous cell carcinoma).
Malignancies
(excluding dysplasia and basal cell carcinoma) observed during the ongoing
open-label long-term extension trial included B-cell lymphoma, breast cancer,
colon cancer, malignant hepatic neoplasm,
malignant lung neoplasm, malignant melanoma, lung cancer of primary
neuroendocrine carcinoma, renal cancer and
squamous cell carcinoma. Overall, the number of
malignancies in the clinical trials was small; however, long-term exposure was limited.
Subcutaneous Injection
for UC after Two Intravenous Doses of ENTYVIO
ENTYVIO was administered as a subcutaneous injection in adult patients
with ulcerative colitis in a double-blind, placebo-controlled clinical trial.
Patients who achieved clinical response following two doses of ENTYVIO administered as an intravenous infusion at Week 0 and Week
2 were randomized 2:1 at Week 6 to ENTYVIO as a subcutaneous injection (N=106)
or placebo (N=56) (SC UC Trial) [see Clinical Studies (14.1)].
The safety profile was similar between patients who were
switched to ENTYVIO as a subcutaneous injection in SC UC Trial and patients in
UC and CD clinical trials who received ENTYVIO as an intravenous infusion (Table
2) except for injection site reactions, which were reported with subcutaneous ENTYVIO.
Injection site reactions
with subcutaneous ENTYVIO
in SC UC Trial
were reported in 9% (10/106)
of patients, including
injection site erythema, rash, swelling, bruising, and hematoma.
Live and Oral Vaccines
There are no data on the secondary transmission of infection by live vaccines
in patients receiving
ENTYVIO.
In a placebo-controlled
study of healthy volunteers, 61 subjects were given a single intravenous
ENTYVIO 750 mg dose (2.5 times the recommended dose), and 62 subjects received
placebo followed by intramuscular vaccination with Hepatitis B surface antigen
and oral cholera vaccine. After intramuscular vaccination with three doses of
recombinant Hepatitis B surface
antigen, those treated with intravenous ENTYVIO did not have lower rates
of protective immunity to Hepatitis B virus.
However,
those
exposed
to intravenous ENTYVIO did
have
lower
seroconversion rates and
anti-cholera titers relative to placebo after receiving the two doses of a killed, oral cholera vaccine. The impact on other oral vaccines and on nasal vaccines in
patients is unknown.
8.1 Pregnancy
(Additions
and/or revisions underlined)
Risk Summary
Available data from the
Organization of Teratology Information Specialists (OTIS)/MotherToBaby
ENTYVIO Pregnancy Registry, published literature and pharmacovigilance in
pregnant women have not reliably identified an ENTYVIO-associated risk of major birth defects, miscarriage or adverse maternal or
fetal outcomes (see Data). There
are risks to the mother and the fetus associated with inflammatory bowel
disease in pregnancy (see Clinical Considerations).
No fetal harm was
observed in animal reproduction studies with intravenous administration of
vedolizumab to rabbits
and monkeys at dose levels
20 times the recommended human dosage (see Data).
The background risk of major birth defects and miscarriage for the indicated populations is unknown. All
pregnancies have a background risk of birth defect, loss, or other adverse…
…
Data
Human Data
The vedolizumab
pregnancy exposure registry conducted by OTIS/MotherToBaby study in the United States and Canada collected prospective observational data between
2015 and 2022 to
assess the risk of major birth defects in live-born infants of women with
ulcerative colitis (UC) or Crohn’s disease (CD) treated with vedolizumab during
pregnancy. The study compared pregnant patients with UC or CD exposed to
vedolizumab with pregnant patients with UC or CD treated with other biological products. The registry included
99 women (58 with UC, 41 with CD) treated with vedolizumab during
pregnancy, and 76 women (27 with UC, 49 with CD) exposed to other biological
products during pregnancy.
The proportion of major
birth defects among live-born infants in patients with UC or CD treated with vedolizumab and patients with UC or
CD treated with other biological products was 7.4% (7/94) and 5.6% (4/71),
respectively. Overall, there was no evidence of increased risk for major structural birth defects (adjusted
RR 1.07, 95% CI: 0.33, 3.52).
The methodological
limitations of the registry, including small sample size and the non-
randomized design, resulted
in a limited ability to estimate the risk of major birth defects and other maternal and infant outcomes.
The conclusions from the pregnancy registry were consistent with the published
literature and pharmacovigilance.
8.4 Geriatric Use
(Additions
and/or revisions underlined)
Clinical trials of ENTYVIO did not include sufficient numbers of subjects aged 65 and over (56 Crohn’s
and ulcerative colitis patients aged 65 and over were treated with ENTYVIO during controlled
Phase
3
trials)
to
determine
whether
they
respond
differently
from younger
subjects. However, no overall differences in safety or
effectiveness were observed between these patients and younger patients, and
other reported clinical experience has not identified differences
in responses between the elderly and younger patients.
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