Approved Drug Label (PDF)
4
Contraindications
Additions and revisions underlined:
The use of IXIFI
at doses >5 mg/kg is contraindicated in
patients with moderate
or severe heart failure [see Warnings and Precautions (5.5) and Adverse
Reactions (6.1)].
IXIFI is contraindicated in patients with
a previous severe hypersensitivity reaction to infliximab products or
any of the inactive ingredients of IXIFI or any murine
proteins [severe hypersensitivity reactions have included anaphylaxis, hypotension, and
serum sickness] [see Warnings and
Precautions (5.7) and Adverse Reactions (6.1)].
5
Warnings and Precautions
5.13 Vaccinations and Use of Live Vaccines/Therapeutic Infectious Agents
Newly added information:
Subsection title revised
Vaccinations
Prior to initiating IXIFI in pediatric and adult patients, update vaccinations in accordance with current
vaccination guidelines.
5.5 Heart Failure
Additions and revisions underlined:
The use of IXIFI at doses >5 mg/kg is
contraindicated in patients with moderate or severe heart failure. A
randomized, double-blind, placebo-controlled study evaluated the use
of infliximab (5 mg/kg or 10 mg/kg at Weeks 0, 2, and 6) in patients with
moderate or severe heart failure [New York Heart Association (NYHA)
Functional Class III/IV].
Compared to patients
who received placebo,
there was a higher rate of mortality and a higher risk
of hospitalization at Week 28 due to heart failure in patients who received
the 10 mg/kg infliximab dose, and higher rates of cardiovascular adverse
events in patients who received infliximab doses of 5 mg/kg and 10
mg/kg.
There have been post-marketing reports
of new onset and worsening heart failure, with and without
identifiable precipitating factors (e.g., pre-existing cardiovascular
disease), in patients treated with infliximab products.
Some of these patients
have been under
50 years of age.
If a decision is made to administer IXIFI (< or = 5
mg/kg) to patients with moderate or severe heart failure or to
administer IXIFI (any approved dose) to patients with mild heart failure,
they should be closely monitored during therapy, and IXIFI should be discontinued if new or worsening symptoms
of heart failure
appear [see Contraindications (4) and Adverse Reactions (6.1)].
6
Adverse Reactions
6.1 Clinical Trials Experience
Extensive changes; please refer to label
6.2 Immunogenicity
Newly added information:
Newly added subsection:
The observed incidence of anti-drug antibodies is
highly dependent on the sensitivity and specificity of the assay. Differences in assay methods
preclude meaningful comparisons of the incidence
of anti-drug antibodies in the studies described below
with the incidence of anti-drug antibodies in other studies, including those of
infliximab or of other infliximab products.
6.3 Postmarketing Experience
Additions and revisions underlined:
Adverse reactions, some with fatal outcomes, have
been identified during post approval use of infliximab products in adult and pediatric
patients. Because these reactions are reported voluntarily from a population of
uncertain size, it is not always possible
to reliably estimate
their frequency or establish a causal relationship to drug exposure.
Postmarketing Adverse
Reactions in Adults
and Pediatric Patients
Neutropenia [see Warnings and Precautions (5.6)], agranulocytosis (including infants
exposed in utero to infliximab products), idiopathic
thrombocytopenic purpura, thrombotic thrombocytopenic purpura.
Interstitial lung disease
(including pulmonary fibrosis/interstitial pneumonitis and rapidly progressive disease).
Pericardial effusion, systemic
and cutaneous vasculitis.
Erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal
necrolysis, linear IgA bullous dermatosis
(LABD), acute generalized exanthematous pustulosis (AGEP),
new onset and worsening
psoriasis (all subtypes including pustular, primarily palmoplantar), lichenoid
reactions.
Peripheral demyelinating disorders
(such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and multifocal motor neuropathy) transverse
myelitis, and neuropathies (additional neurologic reactions have also been observed)
[see Warnings and Precautions (5.9)].
Acute liver failure,
jaundice, hepatitis, and cholestasis [see Warnings
and Precautions (5.4)].
Serious infections [see Warnings and
Precautions (5.1)] and vaccine breakthrough infection including bovine tuberculosis (disseminated BCG infection) following vaccination in an infant
exposed in utero to infliximab products [see Warnings and Precautions (5.13)].
Malignancies, including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer [see Warnings
and Precautions (5.2)].
Anaphylactic reactions, including anaphylactic shock, laryngeal/pharyngeal edema
and severe bronchospasm, and seizure
have been associated with administration of infliximab products.
Transient visual loss have been reported in association with infliximab products
during or within
2 hours of infusion. Cerebrovascular accidents, myocardial ischemia/infarction (some fatal),
and arrhythmia occurring within 24 hours of initiation of
infusion have also been reported [see
Warnings and Precautions (5.8)].
Postmarketing Serious
Adverse Reactions in Pediatric Patients
The following serious adverse reactions have been
reported in the postmarketing experience in
pediatric patients:
infections (some fatal) including opportunistic infections and tuberculosis,
infusion reactions, hypersensitivity reactions.
7
Drug Interactions
7.1 Other Biological Products
Newly added information:
The combination of IXIFI with other biological products used to treat the same conditions as IXIFI is not
recommended [see Warnings and Precautions
(5.10)].
8
Use in Specific Populations
8.1 Pregnancy
Extensive changes; please refer to label
8.2 Lactation
Additions and revisions underlined:
Risk Summary
Published literature show that infliximab is
present at low levels in human milk. Systemic exposure in a breastfed
infant is expected to be low because infliximab products are largely
degraded in the gastrointestinal tract. A U.S. multi-center study of 168 women
treated with infliximab for inflammatory bowel disease (breast milk samples
obtained, n=29) showed
that infants exposed
to infliximab through
breast milk had no increase
in rates of infections and developed normally. There are no data on the
effects of infliximab products on milk production. The developmental and health
benefits of breastfeeding should be considered along with the mother’s clinical
need for IXIFI and any potential
adverse effects on the breastfed child from IXIFI or from the underlying maternal condition.
8.4 Pediatric Use
Extensive changes; please refer to label
8.5 Geriatric Use
Additions and revisions underlined:
Of the total number of infliximab-treated patients
in RA and Ps clinical
studies, 256 (9.6%) were 65 years old and over, while 17 (0.6%) were 75
years old and over. In these trials, no overall differences in safety or
effectiveness were observed between geriatric patients (patients > or =65
years old) and younger adult patients (patients 18 to 65 years old). However,
the incidence of serious adverse reactions in geriatric patients was
higher in both infliximab and control groups compared to younger adult patients.
Of the total number of infliximab-treated patients
in CD, UC, AS, and PsA clinical studies, 76 (3.2%) were 65 years old and over, while 9 (0.4%) were 75 years old and over. In the CD, UC, AS, and PsA studies,
there were insufficient numbers of geriatric patients to
determine whether they respond differently from younger adults.
The incidence of serious
infections in infliximab-treated geriatric patients was greater than in infliximab-treated younger adult
patients; therefore close
monitoring of geriatric patients for the development of serious infections is recommended [see Warnings and Precautions (5.1), and Adverse
Reactions (6.1)].
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Extensive changes; please refer to label
Approved Drug Label (PDF)
5
Warnings and Precautions
5.1 Serious Infections
(additions
underlined)
…
Opportunistic
infections due to bacterial, mycobacterial, invasive fungal, viral, or
parasitic organisms including aspergillosis, blastomycosis, candidiasis,
coccidioidomycosis, cryptococcosis, histoplasmosis, legionellosis,
listeriosis, pneumocystosis, salmonellosis and tuberculosis have been
reported with TNF-blockers. Patients have frequently presented with
disseminated rather than localized disease.
…
5.9 Neurologic Reactions
(additions
underlined)
Infliximab
products and other
agents that inhibit TNF have been associated with CNS manifestation of systemic
vasculitis, seizure and new onset or exacerbation of clinical symptoms and/or
radiographic evidence of central nervous system demyelinating disorders,
including multiple sclerosis and optic neuritis, and peripheral demyelinating
disorders, including Guillain-Barré syndrome. Prescribers should exercise
caution in considering the use of IXIFI in patients with these neurologic
disorders and should consider discontinuation of IXIFI if these disorders
develop.
6
Adverse Reactions
6.1 Clinical Trials Experience
(additions and
revisions underlined)
…
Immunogenicity
As
with all therapeutic proteins, there is potential for immunogenicity. The
detection of antibody formation is highly dependent on the sensitivity and
specificity of the assay. Additionally, the observed incidence of antibody
(including neutralizing antibody) positivity in an assay may be influenced by
several factors including assay methodology, sample handling, timing of sample
collection, concomitant medications, and underlying disease. For these reasons,
comparison of the incidence of antibodies in the studies described below with
the incidence of antibodies in other studies or to other infliximab products may
be misleading.
…
The
incidence of antibodies to infliximab was based on the original EIA method in
all clinical studies of infliximab except for the Phase 3 study in pediatric
patients with ulcerative colitis where the incidence of antibodies to infliximab
was detected using both the EIA and ECLIA methods.
…
Pediatric
Ulcerative Colitis
Overall,
the adverse reactions reported in the pediatric ulcerative colitis trial and
adult ulcerative colitis (Study UC I and Study UC II) studies were generally
consistent. In a pediatric UC trial, the most common adverse reactions were
upper respiratory tract infection, pharyngitis, abdominal pain, fever, and
headache.
Infections
were reported in 31 (52%) of 60 treated patients in the pediatric UC trial and
22 (37%) required oral or parenteral antimicrobial treatment. The proportion of
patients with infections in the pediatric UC trial was similar to that in the
pediatric Crohn’s disease study (Study Peds Crohn’s) but higher than the
proportion in the adults’ ulcerative colitis studies (Study UC I and Study UC
II). The overall incidence of infections in the pediatric UC trial was 13/22
(59%) in the every 8 week maintenance treatment group. Upper respiratory tract
infection (7/60 [12%]) and pharyngitis (5/60 [8%]) were the most frequently
reported respiratory system infections. Serious infections were reported in 12%
(7/60) of all treated patients.
In
the pediatric UC trial, 58 patients were evaluated for antibodies to infliximab
using the EIA as well as the drug-tolerant ECLIA. With the EIA, 4 of 58 (7%)
patients had antibodies to infliximab. With the ECLIA, 30 of 58 (52%) patients
had antibodies to infliximab. The higher incidence of antibodies to infliximab
by the ECLIA method was due to the 60-fold higher sensitivity compared to the
EIA method. While EIA-positive patients generally had undetectable trough
infliximab concentrations, ECLIA- positive patients could have detectable
trough concentrations of infliximab because the ECLIA assay is more sensitive
and drug-tolerant.
Elevations
of ALT up to 3 times the upper limit of normal (ULN) were seen in 17% (10/60)
of pediatric patients in the pediatric UC trial; 7% (4/60) had ALT elevations greater than or equal to3 x ULN, and 2% (1/60)
had elevations greater than or equal to5
x ULN (median follow-up was 49 weeks).
In
the pediatric UC trial, 45 patients were in the 12 to 17 year age group and 15
in the 6 to 11 year age group. The numbers of patients in each subgroup are too
small to make any definitive conclusions about the effect of age on safety
events. There were higher proportions of patients with serious adverse events
(40% vs. 18%) and discontinuation due to adverse events (40% vs. 16%) in the
younger age group than in the older age group.
While
the proportion of patients with infections was also higher in the younger age
group (60% vs. 49%), for serious infections, the proportions were similar in
the two age groups (13% in the 6 to 11 year age group vs. 11% in the 12 to 17
year age group). Overall proportions of adverse reactions, including infusion
reactions, were similar between the 6 to 11 and 12 to 17 year age groups (13%).
6.2 Postmarketing Experience
(additions
underlined)
… malignancies,
including leukemia, melanoma, Merkel cell carcinoma, and cervical cancer
and vaccine breakthrough infection including bovine tuberculosis (disseminated
BCG infection) following vaccination in an infant exposed in utero to infliximab products.
Infusion-related
Reactions
In
postmarketing experience, cases of anaphylactic reactions, including anaphylactic
shock, laryngeal/pharyngeal edema and severe bronchospasm, and seizure have
been associated with administration of infliximab products.
…
8
Use in Specific Populations
8.4 Pediatric Use
(additions
underlind)
The
safety and effectiveness of infliximab products have been established in
pediatric patients 6 to 17 years of age for induction and maintenance treatment
of Crohn’s disease or ulcerative colitis. However, infliximab products
have not been studied in children with Crohn’s disease or ulcerative colitis
<6 years of age.
…
Pediatric
Ulcerative Colitis
The
safety and effectiveness of infliximab products for reducing signs and symptoms
and inducing and maintaining clinical remission in pediatric patients aged 6
years and older with moderately to severely active ulcerative colitis who have
had an inadequate response to conventional therapy are supported by evidence
from adequate and well-controlled studies of infliximab in adults. Additional
safety and pharmacokinetic data were collected in 60 pediatric patients aged 6
years and older. The effectiveness of
infliximab in inducing and maintaining mucosal healing could not be
established. Although 41 patients had a Mayo endoscopy subscore of 0 or 1 at
the Week 8 endoscopy, the induction phase was open-label and lacked a control
group. Only 9 patients had an optional endoscopy at Week 54.
In
the pediatric UC trial, approximately half of the patients were on concomitant
immunomodulators (AZA, 6- MP, MTX) at study start. Due to the risk of HSTCL, a
careful risk-benefit assessment should be made when infliximab is used in
combination with other immunosuppressants.
The
longer term (greater than 1 year) safety and effectiveness of infliximab
products in pediatric ulcerative colitis patients have not been established in
clinical trials.
…
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
MEDICATION GUIDE
(additions underlined)
…
What is IXIFI?
…
…
The most common
side effects of infliximab products include:
…
Among
patients who received infliximab for ulcerative colitis in clinical studies,
more children had infections as compared with adults.
…
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