InFLIXimab
Pronunciation
(in FLIKS
e mab)
Index Terms
AvakineInfliximab, RecombinantInfliximab-abdaInfliximab-dyybInfliximab-qbtxIxifi
Dosage Forms
Excipient
information presented when available (limited, particularly for generics);
consult specific product labeling.
Solution
Reconstituted, Intravenous:
Inflectra:
100 mg (1 ea) [contains polysorbate 80]
Solution
Reconstituted, Intravenous [preservative free]:
Remicade:
100 mg (1 ea) [contains polysorbate 80]
Renflexis:
100 mg (1 ea) [contains polysorbate 80]
Brand Names:U.S.
InflectraRemicadeRenflexis
Pharmacologic Category
Antirheumatic, Disease ModifyingGastrointestinal Agent, MiscellaneousImmunosuppressant AgentMonoclonal AntibodyTumor Necrosis Factor (TNF) Blocking Agent
Pharmacology
Infliximab
is a chimeric monoclonal antibody that binds to human tumor necrosis factor
alpha (TNFα), thereby interfering with endogenous TNFα activity. Elevated TNFα
levels have been found in involved tissues/fluids of patients with rheumatoid
arthritis, ankylosing spondylitis, psoriatic arthritis, plaque psoriasis, Crohn
disease and ulcerative colitis. Biological activities of TNFα include the
induction of proinflammatory cytokines (interleukins), enhancement of leukocyte
migration, activation of neutrophils and eosinophils, and the induction of
acute phase reactants and tissue degrading enzymes. Animal models have shown
TNFα expression causes polyarthritis, and
infliximab can prevent disease as well as allow diseased joints to heal.
Distribution
Within
the vascular compartment; Vd: 3 to 6 L (Klotz 2007)
Onset of Action
Crohn
disease: 1 to 2 weeks; Rheumatoid arthritis: 3 to 7 days
Duration of Action
Crohn disease:
8 to 48 weeks; Rheumatoid arthritis: 6 to 12 weeks
Half-Life Elimination
7 to 12
days (Klotz 2007)
Use: Labeled Indications
Ankylosing
spondylitis: Treatment of
adults with active ankylosing spondylitis (to reduce signs/symptoms)
Crohn
disease: Treatment of adults and
pediatric patients ≥6 years with moderately to severely active Crohn disease
who have had inadequate responses to conventional therapy (to reduce
signs/symptoms and induce and maintain clinical remission) or to reduce the
number of draining enterocutaneous and rectovaginal fistulas and maintain
fistula closure in adults
Plaque
psoriasis: Treatment of adults with
chronic, severe (extensive and/or disabling) plaque psoriasis as an alternative
to other systemic therapy
Psoriatic
arthritis: Treatment of adults with
psoriatic arthritis (to reduce signs/symptoms of active arthritis and inhibit
progression of structural damage and improve physical function)
Rheumatoid
arthritis: Treatment of adults with
moderately to severely active rheumatoid arthritis (with methotrexate) (to
reduce signs/symptoms of active arthritis and inhibit progression of structural
damage and improve physical function)
Ulcerative
colitis: Treatment of adults and
pediatric patients ≥6 years (Remicade only) with moderately to severely active
ulcerative colitis with inadequate response to conventional therapy (to reduce
signs/symptoms and induce and maintain clinical remission and mucosal healing
and eliminate corticosteroid use)
Note: Renflexis, Inflectra, and Remsima [Canadian
product] are approved as biosimilar to Remicade; approved uses may vary (see
product labeling).
Off Label Uses
Juvenile idiopathic arthritis
Data from
randomized, placebo-controlled trials support the use of infliximab in the
treatment of juvenile idiopathic arthritis (JIA) [Ruperto 2007], [Ruperto
2010], [ Visvanathan 2010]. Additional trials may be
necessary to further define the role of infliximab in this condition.
Based on
the American College of Rheumatology
guidelines for the treatment of JIA, infliximab is effective and is recommended in the management
of patients with systemic JIA who require additional therapy due to continued
disease activity following initial therapy.
Behçet syndrome uveitis
Initial
data from 3 case series suggest that IV infliximab may play a beneficial role
in the management of uveitis associated with Behçet syndrome. Additional
controlled trials are needed to verify these results.
Pustular psoriasis
Data from
noncontrolled studies and case series/reports in a limited number of patients
support the use of infliximab in the treatment of pustular psoriasis.
Additional trials may be necessary to further define the role of infliximab in
this condition.
Based on
the National Psoriasis Foundation (NPF) Medical Board consensus statement,
infliximab is recommended as a first-line treatment option for some adults with
pustular psoriasis, particularly those with severe, acute generalized forms of
disease.
Pyoderma gangrenosum
Initial
data suggest that infliximab may be beneficial in the treatment of refractory
pyoderma gangrenosum. Larger, controlled trials are needed to fully assess the
efficacy of infliximab for the treatment of pyoderma gangrenosum.
Contraindications
Hypersensitivity
to infliximab, murine proteins, or any component of the formulation; doses
>5 mg/kg in patients with moderate or severe heart failure (NYHA Class
III/IV)
Canadian
labeling: Additional
contraindications (not in US labeling): Severe infections (eg, sepsis,
abscesses, tuberculosis, and opportunistic infections); use in patients with
moderate or severe heart failure (NYHA Class III/IV)
Dosing: Adult
Note: Premedication with antihistamines (H1-antagonist
+/- H2-antagonist), acetaminophen, and/or corticosteroids may be
considered to prevent and/or manage infusion-related reactions. Renflexis,
Inflectra, and Remsima [Canadian product] are approved as biosimilar to
Remicade. Approved uses for biosimilar agents may vary (consult product
labeling).
Ankylosing
spondylitis: IV: 5 mg/kg at
0, 2, and 6 weeks, followed by 5 mg/kg every 6 weeks thereafter
Crohn
disease: IV: 5 mg/kg at 0, 2, and 6
weeks, followed by 5 mg/kg every 8 weeks thereafter; dose may be increased to
10 mg/kg in patients who respond but then lose their response. If no response
by week 14, consider discontinuing therapy.
Plaque
psoriasis: IV: 5 mg/kg at 0, 2, and 6
weeks, followed by 5 mg/kg every 8 weeks thereafter.
Psoriatic
arthritis (with or without methotrexate): IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg
every 8 weeks thereafter.
Rheumatoid
arthritis (in combination with methotrexate therapy): IV 3 mg/kg at 0, 2, and 6 weeks, followed by 3
mg/kg every 8 weeks thereafter; Remicade doses have ranged from 3 to 10 mg/kg
repeated at 4- to 8-week intervals
Ulcerative
colitis: IV: 5 mg/kg at 0, 2, and 6
weeks, followed by 5 mg/kg every 8 weeks thereafter. Doses up to 10 mg/kg were
studied in clinical trials with similar efficacy observed with both doses
(Rutgeerts 2005).
Pustular
psoriasis (off-label use): IV:
5 mg/kg at week 0, 2, and 6, followed by 5 mg/kg every 8 weeks for up to 46
weeks (Suguira 2014; Torii 2011)
Dosage
adjustment with heart failure (HF): Weigh risk versus benefits for individual patient:
Mild HF
(NYHA Class I/II): No dosage
adjustment necessary; use with caution and monitor closely for worsening of HF
Moderate
to severe (NYHA Class III or IV): ≤5
mg/kg
Dosing: Geriatric
Refer to
adult dosing.
Dosing: Pediatric
Note: Premedication with antihistamines (H1-antagonist
+/- H2-antagonist), acetaminophen, and/or corticosteroids may be
considered to prevent and/or manage infusion-related reactions. Renflexis,
Inflectra, and Remsima [Canadian product] are approved as biosimilar to
Remicade. Approved uses for biosimilar agents may vary (consult product
labeling).
Crohn
disease: Children ≥6 years and
Adolescents: IV: 5 mg/kg at 0, 2, and 6 weeks, followed by 5 mg/kg every 8
weeks thereafter; in adult patients with Crohn disease, it has been observed
that patients who do not respond by week 14 are unlikely to respond with
continued dosing; consider discontinuing therapy.
Ulcerative
colitis: Children ≥6 years and
Adolescents: IV (Remicade only): 5 mg/kg at 0, 2, and 6 weeks, followed by 5
mg/kg every 8 weeks thereafter
Juvenile
idiopathic arthritis (off-label use): Children ≥4 years and Adolescents: IV: Initial: 3 mg/kg at
0, 2, and 6 weeks; then 3 to 6 mg/kg/dose every 8 weeks thereafter, in
combination with methotrexate during induction and maintenance (Ruperto 2010).
Alternatively, some studies used 6 mg/kg starting at week 14 of a methotrexate
induction regimen (weeks 0 to 13); repeat dose (6 mg/kg) at week 16 and 20,
then every 8 weeks thereafter (Ruperto 2007; Visvanathan 2012).
Dosing: Renal Impairment
There are
no dosage adjustments provided in the manufacturer's labeling.
Dosing: Hepatic Impairment
There are
no dosage adjustments provided in the manufacturer's labeling.
Reconstitution
Reconstitute
vials with 10 mL sterile water for injection (SWFI) with a 21-gauge or smaller
needle, directing the SWFI towards the wall of the vial. Swirl vial gently to
dissolve powder; do not shake. Allow solution to stand for 5 minutes. Total
dose of reconstituted product should be further diluted to 250 mL of NS
injection (add reconstituted infliximab slowly) to a final concentration of 0.4
to 4 mg/mL. Do not dilute reconstituted infliximab solution with any other
diluent. Infusion should begin within 3 hours of preparation (see
Storage/Stability for additional information).
Administration
IV: The
infusion should begin within 3 hours of reconstitution and dilution. Infuse
over at least 2 hours; do not infuse with other agents; use in-line low protein
binding filter (≤1.2 micron). Temporarily discontinue or decrease infusion rate
with infusion-related reactions. Antihistamines (H1-antagonist +/- H2-antagonist),
acetaminophen and/or corticosteroids may be used to manage reactions. Infusion
may be reinitiated at a lower rate upon resolution of mild to moderate
symptoms.
Guidelines
for the treatment and prophylaxis of infusion reactions: (Note: Limited to adult patients
and dosages used in Crohn disease; prospective data for other populations
[pediatrics, other indications/dosing] are not available).
A
protocol for the treatment of infusion reactions, as well as prophylactic
therapy for repeat infusions, has been published (Mayer, 2006).
Treatment
of infusion reactions: Medications
for the treatment of hypersensitivity reactions should be available for
immediate use. For mild reactions, the rate of infusion should be decreased to
10 mL/hour. Initiate a normal saline infusion (500 to 1,000 mL/hour) and appropriate
symptomatic treatment (eg, acetaminophen and diphenhydramine); monitor vital
signs every 10 minutes until normal. After 20 minutes, the infusion may be
increased at 15-minute intervals, as tolerated, to completion (initial increase
to 20 mL/hour, then 40 mL/hour, then 80 mL/hour, etc [maximum of 125 mL/hour]).
For moderate reactions, the infusion should be stopped or slowed. Initiate a
normal saline infusion (500 to 1,000 mL/hour) and appropriate symptomatic
treatment. Monitor vital signs every 5 minutes until normal. After 20 minutes,
the infusion may be reinstituted at 10 mL/hour; then increased at 15-minute
intervals, as tolerated, to completion (initial increase 20 mL/hour, then 40
mL/hour, then 80 mL/hour, etc [maximum of 125 mL/hour]). For severe reactions,
the infusion should be stopped with administration of appropriate symptomatic
treatment (eg, hydrocortisone/methylprednisolone, diphenhydramine and
epinephrine) and frequent monitoring of vitals (consult institutional policies,
if available). Re-treatment after a severe reaction should only be done if the
benefits outweigh the risks and with appropriate prophylaxis. Delayed infusion
reactions typically occur 1 to 7 days after an infusion. Treatment should
consist of appropriate symptomatic treatment (eg, acetaminophen, antihistamine,
methylprednisolone).
Prophylaxis
of infusion reactions: Premedication
with acetaminophen and diphenhydramine 90 minutes prior to infusion may be
considered in all patients with prior infusion reactions, and in patients with
severe reactions corticosteroid administration is recommended. Steroid dosing
may be oral (prednisone 50 mg orally every 12 hours for 3 doses prior to
infusion) or intravenous (a single dose of hydrocortisone 100 mg or
methylprednisolone 20 to 40 mg administered 20 minutes prior to the infusion).
On initiation of the infusion, begin with a test dose at 10 mL/hour for 15
minutes. Thereafter, the infusion may be increased at 15-minute intervals, as
tolerated, to completion (initial increase 20 mL/hour, then 40 mL/hour, then 80
mL/hour, etc). A maximum rate of 125 mL/hour is recommended in patients who
experienced prior mild to moderate reactions and 100 mL/hour is recommended in
patients who experienced prior severe reactions. In patients with cutaneous
flushing, aspirin may be considered (Becker, 2004). For delayed infusion
reactions, premedicate with acetaminophen and diphenhydramine 90 minutes prior
to infusion. On initiation of the infusion, begin with a test dose at 10
mL/hour for 15 minutes. Thereafter, the infusion may be increased to infuse
over 3 hours. Postinfusion therapy with acetaminophen for 3 days and an
antihistamine for 7 days is recommended.
Storage
Store
intact vials at 2°C to 8°C (36°F to 46°F); may be stored at room temperature
(maximum of 30°C [86°F]) for up to 6 months (not to exceed the original
expiration date); do not return to refrigerated storage. The manufacturer
recommends that solutions diluted in NS for infusion should be used within 3
hours of preparation. However, a stability study of infliximab 0.4 mg/mL
prepared in NS in polyvinyl chloride (PVC) bags found no loss of biological
activity when stored refrigerated at 4°C for up to 14 days (Ikeda 2012).
Drug Interactions
Abatacept:
Anti-TNF Agents may enhance the adverse/toxic effect of Abatacept. An increased
risk of serious infection during concomitant use has been reported. Avoid
combination
Adalimumab:
May enhance the immunosuppressive effect of InFLIXimab. Avoid
combination
Anakinra:
Anti-TNF Agents may enhance the adverse/toxic effect of Anakinra. An increased
risk of serious infection during concomitant use has been reported. Avoid
combination
BCG
(Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG
(Intravesical). Avoid combination
Belimumab:
Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid
combination
Canakinumab:
Anti-TNF Agents may enhance the adverse/toxic effect of Canakinumab.
Specifically, the risk for serious infections and/or neutropenia may be
increased. Avoid combination
Certolizumab
Pegol: Anti-TNF Agents may enhance the immunosuppressive effect of Certolizumab
Pegol. Avoid combination
Coccidioides
immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of
Coccidioides immitis Skin Test. Monitor therapy
Denosumab:
May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the
risk for serious infections may be increased. Monitor therapy
Echinacea:
May diminish the therapeutic effect of Immunosuppressants. Consider
therapy modification
Etanercept:
May enhance the immunosuppressive effect of InFLIXimab. Avoid
combination
Fingolimod:
Immunosuppressants may enhance the immunosuppressive effect of Fingolimod.
Management: Avoid the concomitant use of fingolimod and other immunosuppressants
when possible. If combined, monitor patients closely for additive
immunosuppressant effects (eg, infections). Consider therapy
modification
Golimumab:
May enhance the immunosuppressive effect of InFLIXimab. Avoid
combination
Leflunomide:
Immunosuppressants may enhance the adverse/toxic effect of Leflunomide.
Specifically, the risk for hematologic toxicity such as pancytopenia,
agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider
not using a leflunomide loading dose in patients receiving other
immunosuppressants. Patients receiving both leflunomide and another
immunosuppressant should be monitored for bone marrow suppression at least
monthly. Consider therapy modification
Natalizumab:
Immunosuppressants may enhance the adverse/toxic effect of Natalizumab.
Specifically, the risk of concurrent infection may be increased. Avoid
combination
Nivolumab:
Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider
therapy modification
Ocrelizumab:
May enhance the immunosuppressive effect of Immunosuppressants. Monitor
therapy
Pidotimod:
Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor
therapy
Pimecrolimus:
May enhance the adverse/toxic effect of Immunosuppressants. Avoid
combination
Rilonacept:
Anti-TNF Agents may enhance the adverse/toxic effect of Rilonacept. Avoid
combination
Roflumilast:
May enhance the immunosuppressive effect of Immunosuppressants. Consider
therapy modification
Sipuleucel-T:
Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor
therapy
Tacrolimus
(Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid
combination
Tertomotide:
Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor
therapy
Tocilizumab:
May enhance the immunosuppressive effect of Anti-TNF Agents. Avoid
combination
Tofacitinib:
Anti-TNF Agents may enhance the adverse/toxic effect of Tofacitinib. Avoid
combination
Trastuzumab:
May enhance the neutropenic effect of Immunosuppressants. Monitor
therapy
Ustekinumab:
May enhance the immunosuppressive effect of InFLIXimab. Avoid
combination
Vaccines
(Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines
(Inactivated). Management: Vaccine efficacy may be reduced. Complete all
age-appropriate vaccinations at least 2 weeks prior to starting an
immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate
at least 3 months after immunosuppressant discontinuation.Consider therapy
modification
Vaccines
(Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines
(Live). Immunosuppressants may diminish the therapeutic effect of Vaccines
(Live). Management: Avoid use of live organism vaccines with
immunosuppressants; live-attenuated vaccines should not be given for at least 3
months after immunosuppressants. Avoid combination
Vedolizumab:
Anti-TNF Agents may enhance the adverse/toxic effect of Vedolizumab. Avoid
combination
Adverse Reactions
>10%:
Central
nervous system: Headache (18%)
Gastrointestinal:
Abdominal pain (Crohn disease: 26%; rheumatoid arthritis: 12%), nausea (21%)
Hematologic
& oncologic: Anemia (adults: <1%; children and adolescents with Crohn
disease: 11%)
Hepatic:
Increased serum ALT (<3 x ULN: 17% to 51%; ≥3 x ULN: 2% to 10%; ≥ 5x ULN: 1%
to 4%)
Immunologic:
Increased ANA titer (~50%), antibody development (double-stranded DNA, ~20%),
antibody development (6% to 15%; more immunogenic when given as a single induction
dose, episodic treatment, and monotherapy; Mayer 2006)
Infection:
Infection (adults with Crohn disease: 50% ; children and adolescents with Crohn
disease: 38% to 74%; other indications: 27% to 59%), serious infection (5%;
children and adolescents: 12% to 60%), abscess (Crohn disease patients with
fistulizing disease: 15%)
Respiratory:
Upper respiratory tract infection (rheumatoid arthritis: 32%; children and
adolescents with ulcerative colitis: 12%), sinusitis (14%), cough (12%),
pharyngitis (8% to 12%)
Miscellaneous:
Infusion related reaction (≤18%; severe: <1%)
1% to
10%:
Cardiovascular:Flushing(children and adolescents with Crohn
disease: 9%), hypertension (7%)
Central
nervous system: Fatigue (9%), pain (8%)
Dermatologic:
Skin rash (10%), pruritus (7%)
Gastrointestinal:
Dyspepsia (10%)
Genitourinary:
Urinary tract infection (8%)
Hematologic
& oncologic: Leukopenia (children and adolescents with Crohn disease: 9%;
other indications: <1%), neutropenia (children and adolescents with Crohn
disease: 7%)
Hypersensitivity:
Hypersensitivity reaction (children and adolescents with Crohn disease: 6%;
other indications: <1%), delayed hypersensitivity (plaque psoriasis: 1%),
serum sickness (≤1%)
Infection:
Viral infection (children and adolescents with Crohn disease: 8%), bacterial
infection (children and adolescents with Crohn disease: 6%), candidiasis (5%)
Neuromuscular
& skeletal: Arthralgia (8%), bone fracture (children and adolescents with
Crohn disease: 7%)
Respiratory:
Bronchitis (10%), pneumonia (≤2%)
Miscellaneous:
Fever (7%)
<1%,
postmarketing, and/or case reports: Acute hepatic failure, agranulocytosis,
anaphylaxis, autoimmune hepatitis, bradycardia, bronchospasm, cardiac
arrhythmia, cellulitis, cerebrovascular accident, cholestasis, chronic inflammatory
demyelinating polyneuropathy, coccidioidomycosis, constipation, cytomegalovirus
disease, dehydration, demyelinating disease of the central nervous system,
demyelinating disease (peripheral), dermal ulcer, diaphoresis, dizziness,
edema, erythema multiforme, erythematous rash, exacerbation of psoriasis,
Guillain-Barre syndrome, hemolytic anemia, hepatic failure, hepatic injury,
hepatitis, hepatotoxicity (idiosyncratic) (Chalasani 2014), hepatosplenic
T-cell lymphomas (mainly young adult or adolescent males), herpes zoster,
histoplasmosis, Hodgkin lymphoma, hypotension, immune thrombocytopenia,
increased serum AST, interstitial pulmonary disease, intestinal obstruction,
ischemic heart disease, jaundice, laryngeal edema, leukemia, liver enzyme disorder
(transient), lower respiratory tract infection, lupus-like syndrome,
lymphadenopathy, malignant lymphoma, malignant melanoma, malignant neoplasm,
malignant neoplasm of breast, malignant neoplasm of cervix, malignant neoplasm
of colon or rectum, Merkel cell carcinoma, multiple sclerosis, myocardial
infarction, neuropathy (includes multifocal motor), nocardiosis, non-Hodgkin
lymphoma, opportunistic infection, optic neuritis, pancytopenia, pericardial
effusion, pharyngeal edema, pleurisy, pneumocystosis, psoriasis (including new
onset, palmoplantar, pustular), pulmonary edema, pulmonary fibrosis,
reactivated tuberculosis, reactivation of HBV, sarcoidosis, seizure, sepsis,
Stevens-Johnson syndrome, thrombocytopenia, thrombophlebitis, thrombotic
thrombocytopenic purpura, toxic epidermal necrolysis, transverse myelitis,
tuberculosis, urticaria, vasculitis (systemic and cutaneous), temporary vision
loss
ALERT:U.S.Boxed Warning
Serious
infections:
Patients
treated with infliximab are at an increased risk of 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
infliximab if a patient develops a serious infection or sepsis.
Reported
infections include the following:
Active
tuberculosis (TB), including reactivation of latent TB. Patients with TB have
frequently presented with disseminated or extrapulmonary disease. Patients
should be tested for latent TB before infliximab use and during therapy.
Treatment for latent infection should be initiated prior to infliximab use.
Invasive
fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis,
aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis
or other invasive fungal infections may present with disseminated, rather than
localized, disease. Antigen and antibody testing for histoplasmosis may be
negative in some patients with active infection. Empiric antifungal therapy
should be considered in patients at risk of invasive fungal infections who
develop severe systemic illness.
Bacterial,
viral, and other infections caused by opportunistic pathogens, including Legionella and Listeria.
The risks
and benefits of treatment with infliximab should be carefully considered prior
to initiating therapy in patients with long-term or recurrent infection.
Patients
should be closely monitored for the development of signs and symptoms of
infection during and after treatment with infliximab, including the possible
development of TB in patients who tested negative for latent TB infection prior
to initiating therapy.
Malignancy:
Lymphoma
and other malignancies, some fatal, have been reported in children and
adolescent patients treated with tumor necrosis factor (TNF) blockers,
including infliximab.
Postmarketing
cases of hepatosplenic T-cell lymphoma, a rare type of T-cell lymphoma, have
been reported in patients treated with TNF blockers, including infliximab.
These cases have had a very aggressive disease course and have been fatal.
Almost all patients had received treatment with azathioprine or
6-mercaptopurine concomitantly with a TNF-blocker at or prior to diagnosis. The
majority of reported infliximab cases have occurred in patients with Crohn
disease or ulcerative colitis, and most were in adolescent and young adult
males.
Warnings/Precautions
Concerns
related to adverse effects:
•
Autoimmune disorder: Positive antinuclear antibody titers have been detected in
patients (with negative baselines). Rare cases of autoimmune disorder,
including lupus-like syndrome, have been reported; monitor and discontinue if
symptoms develop.
•
Cardiovascular effects: Cerebrovascular accidents, MI (some fatal),
hypotension, hypertension, and arrhythmias have been reported within 24 hours
of infusion. Transient vision loss has also been reported during or within 2
hours of infusion. Discontinue therapy if serious reaction occurs.
•
Hematologic disorders: Hematologic toxicities (eg, leukopenia, neutropenia,
thrombocytopenia, pancytopenia) have been reported (may be fatal). Patients
must be advised to seek medical attention if they develop signs and symptoms
suggestive of blood dyscrasias (eg, persistent fevers); discontinue if
significant hematologic abnormalities are confirmed. Use with caution in
patients with history of hematologic abnormalities.
• Hepatic
reactions: Severe hepatic reactions (including hepatitis, jaundice, acute
hepatic failure, and cholestasis) have been reported during treatment;
reactions occurred between 2 weeks to >1 year after initiation of therapy
and some cases were fatal or necessitated liver transplantation; discontinue with
jaundice and/or marked increase in liver enzymes (≥5 times ULN).
•
Hepatitis B: Reactivation of hepatitis B virus (HBV) has occurred in chronic
carriers of the virus, usually in patients receiving concomitant
immunosuppressants (may be fatal); evaluate for HBV prior to initiation in all
patients. Monitor during and for several months following discontinuation of
treatment in HBV carriers; interrupt therapy if reactivation occurs and treat
appropriately with antiviral therapy; if resumption of therapy is deemed
necessary, exercise caution and monitor patient closely.
•
Hypersensitivity or infusion reactions: Acute infusion reactions may occur.
Hypersensitivity reactions, including anaphylaxis, may occur within 2 hours of
infusion. Medication and equipment for management of hypersensitivity reaction
should be available for immediate use. Interruptions and/or reinstitution at a
slower rate may be required (consult protocols). Pretreatment may be
considered, and may be warranted in all patients with prior infusion reactions.
Serum sickness-like reactions have occurred; may be associated with a decreased
response to treatment. The development of antibodies to infliximab may increase
the risk of hypersensitivity and/or infusion reactions; concomitant use of immunosuppressants
may lessen the development of anti-infliximab antibodies. The risk of infusion
reactions may be increased with re-treatment after an interruption or
discontinuation of prior maintenance therapy. Re-treatment in psoriasis
patients should be resumed as a scheduled maintenance regimen without any
induction doses; use of an induction regimen should be used cautiously for
re-treatment of all other patients.
•
Infections: [US Boxed Warning]: Patients receiving infliximab are at
increased risk for serious infections which may result in hospitalization
and/or fatality; infections usually developed in patients receiving concomitant
immunosuppressive agents (eg, methotrexate or corticosteroids) and may present
as disseminated (rather than local) disease. Active tuberculosis (or
reactivation of latent tuberculosis), invasive fungal (including aspergillosis,
blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, and
pneumocystosis) and bacterial, viral or other opportunistic infections (including
legionellosis and listeriosis) have been reported. Monitor closely for
signs/symptoms of infection. Discontinue for serious infection or sepsis.
Consider risks versus benefits prior to use in patients with a history of
chronic or recurrent infection. Consider empiric antifungal therapy in patients
who are at risk for invasive fungal infection and develop severe systemic
illness. Caution should be exercised when considering use in the
elderly or in patients with conditions that predispose them to infections (eg,
diabetes) or residence/travel from areas of endemic mycoses (blastomycosis,
coccidioidomycosis, histoplasmosis), or with latent or localized infections. Do
not initiate infliximab therapy in patients with an active infection, including
clinically important localized infection. Patients who develop a new infection
while undergoing treatment should be monitored closely.
•
Malignancy: [US Boxed Warning]: Lymphoma and other malignancies (may be
fatal) have been reported in children and adolescent patients receiving
TNF-blocking agents including infliximab.Half the cases are lymphomas
(Hodgkin's and non-Hodgkin's) and the other cases are varied but include
malignancies not typically observed in this population. [USBoxed
Warning]: Postmarketing cases of hepatosplenic T-cell lymphoma have been
reported in patients treated with infliximab. Almost all patients had received
concurrent or prior treatment with azathioprine or mercaptopurine at or prior
to diagnosis and the majority of reported cases occurred in adolescent and
young adult males with Crohn disease or ulcerative colitis. Malignancies
occurred after a median of 30 months (range: 1 to 84 months) after the first
dose of TNF blocker therapy; most patients were receiving concomitant
immunosuppressants. The impact of infliximab on the development and course of
malignancies is not fully defined. As compared to the general population, an
increased risk of lymphoma has been noted in clinical trials; however,
rheumatoid arthritis alone has been previously associated with an increased
rate of lymphoma. Use caution in patients with a history of COPD, higher rates
of malignancy were reported in COPD patients treated with infliximab. Psoriasis
patients with a history of phototherapy had a higher incidence of nonmelanoma
skin cancers. Melanoma and Merkel cell carcinoma have been reported in patients
receiving TNF-blocking agents including infliximab. Perform periodic skin
examinations in all patients during therapy, particularly those at increased
risk for skin cancer. Women with rheumatoid arthritis had a higher incidence of
invasive cervical cancer; periodic screening should be continued in women
treated with infliximab.
•
Tuberculosis: [US Boxed Warning]: Infliximab treatment has been
associated with active tuberculosis (may be disseminated or extrapulmonary) or
reactivation of latent infections. Evaluate patients for tuberculosis risk
factors and latent tuberculosis infection (with a tuberculin skin test) prior
to and during therapy. Treatment of latent tuberculosis should be initiated
before use. Patients with initial negative tuberculin skin tests should receive
continued monitoring for tuberculosis throughout treatment. Most cases
of reactivation have been reported within the first couple months of treatment.
Caution should be exercised when considering the use in patients who have been
exposed to tuberculosis.
Disease-related
concerns:
•
Demyelinating CNS disease: Use with caution in patients with preexisting or
recent onset CNS demyelinating disorders; rare cases of optic neuritis and
demyelinating disease (including multiple sclerosis, systemic vasculitis, and
Guillain-Barré syndrome) have been reported; consider discontinuation of
therapy if patient develops significant CNS reactions.
• Heart
failure (HF): Use with caution in patients with mild HF (NYHA Class I, II) or
decreased left ventricular function; worsening and new-onset HF has been
reported; doses >5 mg/kg should not be administered in patients with
moderate to severe HF (NYHA Class III/IV); discontinue therapy with onset of
new or worsening symptoms. In a scientific statement from the American Heart
Association, TNF blockers have been determined to be agents that may either
cause direct myocardial toxicity or exacerbate underlying myocardial
dysfunction (magnitude: major) (AHA [Page 2016]).
• Seizure
disorders: Use with caution in patients with a history of seizures; discontinue
if significant CNS adverse reactions develop.
Concurrent
drug therapy issues:
• Drug-drug
interactions: Potentially significant interactions may exist, requiring dose or
frequency adjustment, additional monitoring, and/or selection of alternative
therapy. Consult drug interactions database for more detailed information.
Special
populations:
•
Pediatric: Malignancies have been reported among children and adolescents
receiving TNF-blocking agents. Efficacy was not established in a study to
evaluate infliximab use in juvenile idiopathic arthritis (JIA).
Dosage
form specific issues:
•
Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as
Tweens). Hypersensitivity reactions, usually a delayed reaction, have been
reported following exposure to pharmaceutical products containing polysorbate
80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995).
Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic
failure have been reported in premature neonates after receiving parenteral
products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer's
labeling.
Other
warnings/precautions:
•
Immunizations: Patients should be brought up to date with all immunizations
before initiating therapy. Live vaccines should not be given concurrently;
there is no data available concerning secondary transmission of live vaccines
in patients receiving therapy. A fatal outcome has been reported in an infant
who received a live vaccine (BCG) after in utero exposure to infliximab;
infliximab crosses the placenta and has been detected in infants’ serum for up
to 6 months. It is recommended to wait ≥6 months following birth before
administering any live vaccine to infants exposed to infliximab in utero.
Monitoring Parameters
Monitor
improvement of symptoms and physical function assessments. During infusion, if
reaction is noted, monitor vital signs every 2 to 10 minutes, depending on
reaction severity, until normal. Active and latent TB screening prior to
initiating and during therapy; signs/symptoms of infection (prior to, during,
and following therapy); CBC with differential; signs/symptoms/worsening of
heart failure; HBV screening prior to initiating (all patients), HBV carriers
(during and for several months following therapy); signs and symptoms of
hypersensitivity reaction; symptoms of lupus-like syndrome; LFTs (discontinue
if >5 times ULN); signs and symptoms of malignancy (eg, splenomegaly,
hepatomegaly, abdominal pain, persistent fever, night sweats, weight loss).
Psoriasis
patients with history of phototherapy should be monitored for nonmelanoma skin
cancer.
The American
Gastroenterological Association suggests reactive therapeutic drug monitoring
to guide treatment changes in adult patients treated with infliximab for active
inflammatory bowel disease (Feuerstein 2017).
Pregnancy Risk Factor
B
Pregnancy Considerations
Animal
reproduction studies have not been conducted. Infliximab crosses the placenta
and can be detected in the serum of infants for up to 6 months following in
utero exposure. Agranulocytosis has been reported in infants exposed to
infliximab in utero. A fatal outcome has been reported in an infant who
received a live vaccine (BCG) after in utero exposure to infliximab; it is
recommended to wait ≥6 months following birth before administering any live
vaccine to infants exposed to infliximab in utero. If a biologic agent such as
infliximab is needed to treat inflammatory bowel disease during pregnancy, it
is recommended to hold therapy after 30 weeks gestation (Habal 2012).
Health
care providers are also encouraged to enroll women exposed to infliximab during
pregnancy in the MotherToBaby Autoimmune Diseases Study by contacting the
Organization of Teratology Information Specialists (OTIS) (877-311-8972).
Patient Education
• Discuss
specific use of drug and side effects with patient as it relates to treatment.
(HCAHPS: During this hospital stay, were you given any medicine that you had
not taken before? Before giving you any new medicine, how often did hospital
staff tell you what the medicine was for? How often did hospital staff describe
possible side effects in a way you could understand?)
• Patient
may experience nausea, vomiting, abdominal pain, common cold symptoms,
flushing, or injection site irritation. Have patient report immediately to
prescriber signs of infection; signs of lupus (rash on the cheeks or other body
parts, sunburn easy, muscle or joint pain, angina or shortness of breath, or
swelling in the arms or legs); signs of severe cerebrovascular disease (change
in strength on one side is greater than the other, difficulty speaking or thinking,
change in balance, or vision changes); angina; signs of liver problems (dark
urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools,
vomiting, or jaundice); signs of heart problems (cough or shortness of breath
that is new or worse, swelling of the ankles or legs, abnormal heartbeat,
weight gain of more than five pounds in 24 hours, dizziness, or passing out);
infusion reactions; skin eczema; excessive weight loss; burning or numbness
feeling; severe back pain; severe headache; difficulty swallowing; pale skin;
swollen glands; night sweats; vision changes; blindness; black, tarry, or
bloody stools; mole changes; skin growths; dizziness; passing out; bradycardia;
tachycardia; seizures; extremity weakness; bruising; bleeding; severe loss of
strength and energy; or signs of Stevens-Johnson syndrome/toxic epidermal
necrolysis (red, swollen, blistered, or peeling skin [with or without fever];
red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).
• Educate
patient about signs of a significant reaction (eg, wheezing; chest tightness;
fever; itching; bad cough; blue skin color; seizures; or swelling of face,
lips, tongue, or throat). Note: This is not a comprehensive
list of all side effects. Patient should consult prescriber for additional
questions.
Intended
Use and Disclaimer: Should not be printed and given to patients. This
information is intended to serve as a concise initial reference for health care
professionals to use when discussing medications with a patient. You must
ultimately rely on your own discretion, experience, and judgment in diagnosing,
treating, and advising patients.
