SERIOUS INFECTIONS
Patients treated with REMICADE® (infliximab) are at increased risk for developing
serious infections that may lead to hospitalization or death. Most patients who
developed these infections were taking concomitant immunosuppressants such as
methotrexate or corticosteroids. Discontinue REMICADE® if a patient develops a serious
infection or sepsis.
Reported infections include:
- Active tuberculosis (TB), including reactivation of latent TB. Patients
frequently presented with disseminated or extrapulmonary disease. Patients should be
tested for latent TB before and during treatment with REMICADE®.1,2
Treatment for latent infection should be initiated prior to treatment with
REMICADE®.
- Invasive fungal infections, including histoplasmosis, coccidioidomycosis,
candidiasis, aspergillosis, blastomycosis, pneumocystosis, and cryptococcosis.
Patients may present with disseminated, rather than localized, disease. Empiric
anti-fungal therapy should be considered in patients at risk for invasive fungal
infections who develop severe systemic illness.
- Bacterial, viral, and other infections due to opportunistic pathogens,
including Legionella, Listeria, and Salmonella.
The risks and benefits of treatment with REMICADE® should be
carefully considered prior to initiating therapy in patients with chronic or
recurrent infection. Closely monitor patients for the development of signs and
symptoms of infection during and after treatment with REMICADE®, including the
possible development of TB in patients who tested negative for latent TB infection
prior to initiating therapy, who are on treatment for latent TB, or who were
previously treated for TB infection.
MALIGNANCIES
Lymphoma and other malignancies, some fatal, have been reported
in children and adolescent patients treated with TNF blockers, including
REMICADE®. Approximately half of these cases were lymphomas, including
Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of
malignancies, including rare malignancies that are usually associated with
immunosuppression and malignancies that are not usually observed in children and
adolescents. The malignancies occurred after a median of 30 months after the first
dose of therapy. Most of the patients were receiving concomitant immunosuppressants.
Postmarketing cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma,
have been reported in patients treated with TNF blockers, including REMICADE®. These
cases have had a very aggressive disease course and have been fatal. The majority of
reported REMICADE® cases have occurred in patients with Crohn’s disease or ulcerative
colitis and most were in adolescent and young adult males. Almost all of these
patients had received treatment with azathioprine or 6-mercaptopurine concomitantly
with REMICADE® at or prior to diagnosis. Carefully assess the risks and benefits of
treatment with REMICADE®, especially in these patient types.
In clinical trials of all TNF blockers, more cases of lymphoma were observed compared
with controls and the expected rate in the general population. However, patients with
Crohn’s disease, rheumatoid arthritis, or plaque psoriasis may be at higher risk for
developing lymphoma. In clinical trials of some TNF blockers, including REMICADE®,
more cases of other malignancies were observed compared with controls. The rate of
these malignancies among patients treated with REMICADE® was similar to that expected
in the general population whereas the rate in control patients was lower than
expected. Cases of acute and chronic leukemia have been reported with postmarketing
TNF-blocker use. As the potential role of TNF blockers in the development of
malignancies is not known, caution should be exercised when considering treatment of
patients with a current or a past history of malignancy or other risk factors such as
chronic obstructive pulmonary disease (COPD).
Melanoma and Merkel cell carcinoma have been reported in patients treated with
TNF-blocker therapy, including REMICADE®. Periodic skin examination is recommended for
all patients, particularly those with risk factors for skin cancer.
A population-based retrospective cohort study found a 2- to 3-fold increase in the
incidence of invasive cervical cancer in women with rheumatoid arthritis treated with
REMICADE® compared to biologics-naïve patients or the general population, particularly
those over 60 years of age. A causal relationship between REMICADE® and cervical
cancer cannot be excluded. Periodic screening should continue in women treated with
REMICADE®.
CONTRAINDICATIONS
The use of REMICADE® at doses >5 mg/kg is contraindicated in patients with moderate
or severe heart failure. REMICADE® is contraindicated in patients with a previous
severe hypersensitivity reaction to infliximab or any of the inactive ingredients of
REMICADE® or any murine proteins (severe hypersensitivity reactions have included
anaphylaxis, hypotension, and serum sickness).
HEPATITIS B REACTIVATION
TNF blockers, including REMICADE®, have been associated with reactivation of hepatitis
B virus (HBV) in patients who are chronic carriers. Some cases were fatal. Patients
should be tested for HBV infection before initiating REMICADE®. For patients who test
positive, consult a physician with expertise in the treatment of hepatitis B. Exercise
caution when prescribing REMICADE® for patients identified as carriers of HBV and
monitor closely for active HBV infection during and following termination of therapy
with REMICADE®. Discontinue REMICADE® in patients who develop HBV reactivation and
initiate antiviral therapy with appropriate supportive treatment. Exercise caution
when considering resumption of REMICADE® and monitor patients closely.
HEPATOTOXICITY
Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and
cholestasis have been reported in patients receiving REMICADE® postmarketing. Some
cases were fatal or required liver transplant. Aminotransferase elevations were not
noted prior to discovery of liver injury in many cases. Patients with symptoms or
signs of liver dysfunction should be evaluated for evidence of liver injury. If
jaundice and/or marked liver enzyme elevations (eg, ≥5 times the upper limit of
normal) develop, REMICADE® should be discontinued, and a thorough investigation of the
abnormality should be undertaken.
HEART FAILURE
In a randomized, placebo-controlled study in patients with moderate or severe heart
failure (NYHA Functional className III/IV), higher mortality rates and a higher risk
of hospitalization were observed at Week 28 at a dose of 10 mg/kg and higher rates of
cardiovascular events were observed at both 5 mg/kg and 10 mg/kg. There have been
postmarketing reports of new onset and worsening heart failure, with and without
identifiable precipitating factors. Patients with moderate or severe heart failure
taking REMICADE® (≤5 mg/kg) or patients with mild heart failure should be closely
monitored and treatment should be discontinued if new or worsening symptoms appear.
HEMATOLOGIC EVENTS
Cases of leukopenia, neutropenia, thrombocytopenia, and pancytopenia (some fatal) have
been reported. The causal relationship to REMICADE® therapy remains unclear. Exercise
caution in patients who have ongoing or a history of significant hematologic
abnormalities. Advise patients to seek immediate medical attention if they develop
signs and symptoms of blood dyscrasias or infection. Consider discontinuation of
REMICADE® in patients who develop significant hematologic abnormalities.
HYPERSENSITIVITY
REMICADE® has been associated with hypersensitivity reactions that differ in their
time of onset. Anaphylaxis, acute urticaria, dyspnea, and hypotension have occurred in
association with infusions of REMICADE®. Medications for the treatment of
hypersensitivity reactions should be available.
CARDIOVASCULAR AND CEREBROVASCULAR REACTIONS DURING AND AFTER INFUSION
Serious cerebrovascular accidents, myocardial ischemia/infarction (some fatal),
hypotension, hypertension, and arrhythmias have been reported during and within 24
hours of initiation of REMICADE® infusion. Cases of transient visual loss have been
reported during or within 2 hours of REMICADE® infusion. Monitor patients during
infusion and if a serious reaction occurs, discontinue infusion. Manage reactions
according to signs and symptoms.
NEUROLOGIC EVENTS
TNF blockers, including REMICADE®, have been associated with CNS manifestation of
systemic vasculitis, seizure, and new onset or exacerbation of CNS demyelinating
disorders, including multiple sclerosis and optic neuritis, and peripheral
demyelinating disorders, including Guillain-Barré syndrome. Exercise caution when
considering REMICADE® in patients with these disorders and consider discontinuation if
these disorders develop.
CONCURRENT ADMINISTRATION WITH OTHER BIOLOGICS
Concurrent use of REMICADE® with anakinra, abatacept, tocilizumab, or other biologics
used to treat the same conditions as REMICADE® is not recommended because of the
possibility of an increased risk of infection. Care should be taken when switching
from one biologic to another, since overlapping biological activity may further
increase the risk of infection.
AUTOIMMUNITY
Treatment with REMICADE® may result in the formation of autoantibodies and in the
development of a lupus-like syndrome. Discontinue treatment if symptoms of a
lupus-like syndrome develop.
VACCINATIONS AND USE OF LIVE VACCINES/THERAPEUTIC INFECTIOUS AGENTS
Prior to initiating REMICADE®, update vaccinations in accordance with current
vaccination guidelines. Live vaccines or therapeutic infectious agents should not be
given with REMICADE® due to the possibility of clinical infections, including
disseminated infections.
At least a 6-month waiting period following birth is recommended before the
administration of any live vaccine to infants exposed in utero to REMICADE®.
ADVERSE REACTIONS
In clinical trials, the most common adverse reactions occurring in >10% of
REMICADE®-treated patients included infections (eg, upper respiratory, sinusitis, and
pharyngitis), infusion-related reactions, headache, and abdominal pain.
For more information, please see the full Prescribing Information and Medication Guide for REMICADE®. Provide the Medication Guide to your patients and encourage discussion.
References: 1. American Thoracic Society, Centers for Disease Control
and Prevention. Targeted tuberculin testing and treatment of latent tuberculosis
infection. Am J Respir Crit Care Med. 2000;161:S221-S247. 2.
See latest Centers for Disease Control guidelines and recommendations for tuberculosis
testing in immunocompromised patients.
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