A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Remicade Side Effects, and Drug Interactions - Infliximab
Remicade Side Effects, and Drug Interactions - Infliximab
SIDE EFFECTS
The data described herein reflect exposure to REMICADE in 1678
patients, including 842 patients exposed beyond 30 weeks and 295 exposed beyond
one year. The most common reason for discontinuation of treatment was infusion-related
reactions (e.g. dyspnea, flushing, headache and rash). Adverse events have been
reported in a higher proportion of rheumatoid arthritis patients receiving the
10 mg/kg dose than the 3 mg/kg dose, however, no differences were observed in
the frequency of adverse events between the 5 mg/kg dose and 10 mg/kg dose in
patients with Crohn’s disease.
Infusion-related Reactions
Acute infusion reactions
An infusion reaction was defined in clinical trials as any
adverse event occurring during an infusion or within 1 to 2 hours after an infusion.
Approximately 20% of REMICADE-treated patients in all clinical studies experienced
an infusion reaction compared to approximately 10% of placebo-treated patients.
Among all REMICADE infusions, 3% were accompanied by nonspecific symptoms such
as fever or chills, 1% were accompanied by cardiopulmonary reactions (primarily
chest pain, hypotension, hypertension or dyspnea), and <1% were accompanied
by pruritus, urticaria, or the combined symptoms of pruritus/urticaria and cardiopulmonary
reactions. Serious infusion reactions occurred in <1% of patients and included
anaphylaxis, convulsions, erythematous rash and hypotension. Approximately 3%
of patients discontinued REMICADE because of infusion reactions, and all patients
recovered with treatment and/or discontinuation of the infusion. REMICADE infusions
beyond the initial infusion were not associated with a higher incidence of reactions.
Patients who became positive for antibodies to infliximab were
more likely (approximately 2- to 3-fold) to have an infusion reaction than were
those who were negative. Use of concomitant immunosuppressant agents appeared
to reduce the frequency of antibodies to infliximab and infusion reactions (see
ADVERSE REACTIONS, Immunogenicity
and PRECAUTIONS, Drug
Interactions).
In post-marketing experience, cases of anaphylactic-like reactions,
including laryngeal/pharyngeal edema and severe bronchospasm, and seizure have
been associated with REMICADE administration.
Reactions following readministration
In a study where 37 of 41 patients with Crohn’s period without
infliximab treatment, 10 patients experienced adverse events manifesting 3 to
12 days following infusion of which 6 were considered serious. Signs and symptoms
included myalgia and/or arthralgia with fever and/or rash, with some patients
also experiencing pruritus, facial, hand or lip edema, dysphagia, urticaria,
sore throat, and headache. Patients experiencing these adverse events had not
experienced infusion-related adverse events associated with their initial infliximab
therapy. These adverse events occurred in 39% (9/23) of patients who had received
liquid formulation which is no longer in use and 7% (1/14) of patients who received
lyophilized formulation. The clinical data are not adequate to determine if
occurrence of these reactions is due to differences in formulation. Patients’
signs and in all cases. There are insufficient data on the incidence of these
events after drug-free intervals of 1 to 2 years. These events have been observed
only infrequently in clinical studies and post-marketing surveillance with retreatment
intervals up to 1 year.
Infections
In REMICADE clinical studies, treated infections were reported
in 35% of REMICADE-treated patients (average of 53 weeks of follow-up) and in
26% of placebo-treated patients (average of 41 weeks of follow-up). When longer
observation of patients on REMICADE was accounted for, the event rate was similar
for both groups. The infec-ortions most frequently reported were respiratory
tract infections (including sinusitis, pharyngitis, and bronchitis)rheumatoid
arthritis and chronic exposure to immuno-and urinary tract infections. No increased
risk of serious infections or sepsis was observed with REMICADE compared with
placebo in clinical studies. Among REMICADE-treated patients, serious infections
included pneumonia, cellulitis, abscess, skin ulceration, sepsis, and bacterial
infection. Three opportunistic infections were reported; coccidioidomycosis
(which resulted in death), nocardiosis and cytomegalovirus. Tuberculosis was
reported in two patients, one of whom died due to miliary tuberculosis. Other
cases of tuberculosis, including disseminated tuberculosis, also have been reported
post-marketing. Most of the cases of tuberculosis occurred within the first
two months after initiation of therapy with infliximab and may reflect recrudescence
of latent disease (see WARNINGS, RISK
OF INFECTIONS). During the 54 week ACCENT II trial, 15% of patients
with fistulizing Crohn’s disease developed a new fistula- overall health be
assessed In post-marketing experience, infections have been observed with various
pathogens including viral, bacterial, reading of the Patient Information Sheet
fungal, and protozoal organisms. Infections have been noted in all organ systems
and have been reported in patients receiving REMICADE alone or in combination
with immunosuppressive agents.
Autoantibodies/Lupus-like Syndrome
Approximately 52% of 1261 infliximab-treated patients in clinical
trials who were antinuclear antibody (ANA) clinical studies received one or
more concomitant medi-negative at baseline developed a positive ANA during the
trial compared with approximately 19% of 129 placebo-treated patients. Anti-dsDNA
antibodies were newly detected in approximately 17% of 1507 infliximab- disease
medications were antibiotics, treated patients compared with 0% of 162 placebo-treated
patients. Reports of lupus and lupus-like syndromes, disease who received immu-however,
remain uncommon.
Malignancies/Lymphoproliferative Disease
In completed clinical studies of REMICADE for up to 102 weeks,
18 of 1678 patients developed 19 new or recurrent malignancies of various types,
such as non-Hodgkin’s (metronidazole or ciprofloxacin) and aminosalicylates.
rectal and basal cell. There are insufficient data to determine whether REMICADE
contributed to the development of these malignancies. The observed rates and
incidences were similar to those expected for the populations studied11,12
(see PRECAUTIONS, Malignancy).
Immunogenicity
Treatment with REMICADE can be associated with the development
of antibodies to infliximab. The incidence disease. Results indi-of antibodies
to infliximab in patients given a 3-dose induction regimen followed by maintenance
dosing was approximately 10% as assessed through one to two years of REMICADE
treatment. A higher incidence of antibodies to infliximab was observed in Crohn’s
>16 weeks. The majority of antibody-positive patients had low titers. Patients
who were antibody-positive were more likely to experience an infusion reaction
(see ADVERSE REACTIONS, Infusion-related
Reactions). Antibody development was lower among rheumatoid arthritis and
Crohn’s therapies such as 6-MP/AZA or MTX.
The data reflect the percentage of patients whose test results
were positive for antibodies to infliximab in an ELISA assay, and are highly
dependent on the sensitivity and specificity of the assay. Additionally, the
observed incidence of antibody positivity in an assay may be influenced by several
factors including sample handling, timing of sample collection, concomitant
medication, and underlying disease. For these reasons, comparison of the incidence
of antibodies to infliximab with the incidence of antibodies to other products
may be misleading.
Congestive Heart Failure
In a phase II study evaluating REMICADE in NYHA Class III/IV
CHF patients (left ventricular ejection fraction £35%),
higher incidences of mortality and hospitalization due to worsening heart failure
were seen in REMICADE-treated patients, especially those treated with 10 mg/kg.
One hundred and fifty patients were treated with 3 infusions of REMICADE 5 mg/kg,
10 mg/kg, or placebo over 6 weeks. At 28 weeks, 4 of 101 patients treated with
REMICADE (1 at 5 mg/kg and 3 at 10 mg/kg) died compared with no deaths among
the 49 placebo-treated patients. In follow-up, at 38 weeks, 9 patients treated
with REMICADE (2 at 5 mg/kg and 7 at 10 mg/kg) died compared with one death
among the placebo-treated patients. At 28 weeks, 14 of 101 patients treated
with REMICADE (3 at 5 mg/kg and 11 at 10 mg/kg) were hospitalized for worsening
CHF compared with 5 of the 49 placebo-treated patients (see CONTRAINDICATIONS
and WARNINGS, Congestive
Heart Failure).
Other Adverse Reactions
Safety data are available from 1678 REMICADE-treated patients,
including 555 with rheumatoid arthritis, 1106 with Crohn’s disease and 17 with
conditions other reported in ³5% of all patients
with rheumatoid arthritis receiving 4 or more infusions are in Table 5. The
types disease and frequencies of adverse reactions observed were similar in
REMICADE-treated rheumatoid arthritis andstudies, there were insufficient numbers
of patients Crohn’s disease patients except for abdominal pain Crohn’s disease.
In the patients who never received REMICADE to provide meaningful comparisons.
|
Table 5 ADVERSE EVENTS OCCURRING IN 5% OR MORE OF PATIENTS
RECEIVING 4 OR MORE INFUSIONS FOR RHEUMATOID ARTHRITIS
|
| |
Placebo(n=81)
|
REMICADE(n=430)
|
|
Average weeks of follow-up
|
73
|
82
|
|
Gastrointestinal
|
|
|
|
Abdominal pain
|
12%
|
17%
|
|
Nausea
|
23%
|
24%
|
|
Diarrhea
|
19%
|
19%
|
|
Dyspepsia
|
9%
|
10%
|
|
Respiratory
|
|
Upper respiratory tract infection
|
35%
|
40%
|
|
Pharyngitis
|
12%
|
17%
|
|
Sinusitis
|
7%
|
20%
|
|
Coughing
|
9%
|
18%
|
|
Rhinitis
|
14%
|
14%
|
|
Dyspnea
|
2%
|
6%
|
|
Skin and appendages disorders
|
|
Rash
|
7%
|
18%
|
|
Pruritis
|
2%
|
9%
|
|
Body as a whole–general disorders
|
|
Fatigue
|
9%
|
13%
|
|
Chest pain
|
6%
|
7%
|
|
Resistance mechanism disorders
|
|
Fever
|
11%
|
13%
|
|
Abscess
|
5%
|
6%
|
|
Moniliasis
|
2%
|
8%
|
|
Central and peripheral nervous system disorders
|
|
Headache
|
21%
|
29%
|
|
Musculoskeletal system disorders
|
|
Arthralgia
|
7%
|
13%
|
|
Back pain
|
5%
|
13%
|
|
Psychiatric disorders
|
|
Insomnia
|
4%
|
6%
|
|
Depression
|
2%
|
8%
|
|
Urinary system disorders
|
|
Urinary tract infection
|
12%
|
14%
|
|
Cardiovascular disorders, general
|
|
Hypertension
|
6%
|
10%
|
Because clinical trials are conducted under widely varying
conditions, adverse reaction rates observed in clinical trials of a drug cannot
be directly compared to rates in clinical trials of another drug and may not
predict the rates observed in broader patient populations in clinical practice.
The most common serious adverse events observed in clinical
trials were infections (see ADVERSE REACTIONS,
Infections). Other serious, medically relevant adverse events ³0.2%
or clinically significant adverse events by body system were as follows:
Body as a whole: allergic reaction, diaphragmatic hernia,
edema, surgical/procedural sequela
Blood: pancytopenia Cardiovascular: circulatory
failure, hypotension, syncope
Gastrointestinal: constipation, gastrointestinal hemorrhage,
ileus, intestinal obstruction, intestinal perforation, intestinal stenosis,
pancreatitis, peritonitis, proctalgia
Central & Peripheral Nervous: meningitis, neuritis,
peripheral neuropathy, dizziness
Heart Rate and Rhythm: arrhythmia, bradycardia, cardiac
arrest, tachycardia
Liver and Biliary: biliary pain, cholecystitis, cholelithiasis,
hepatitis
Metabolic and Nutritional: dehydration
Musculoskeletal: intervertebral disk herniation, tendon
disorder
Myo-, Endo-, Pericardial and Coronary Valve: myocardial
infarction
Platelet, Bleeding and Clotting: thrombocytopenia
Neoplasms: basal cell, breast, lymphoma
Psychiatric: confusion, suicide attempt
Red Blood Cell: anemia, hemolytic anemia
Reproductive: menstrual irregularity
Resistance Mechanism: cellulitis, sepsis, serum sickness
Respiratory: adult respiratory distress syndrome, lower
respiratory tract infection, pleural effusion, pleurisy, pulmonary edema, respiratory
insufficiency
Skin and Appendages: increased sweating, ulceration
Urinary: renal calculus, renal failure
Vascular (Extracardiac): brain infarction, pulmonary
embolism, thrombophlebitis
White Cell and Reticuloendothelial: leukopenia, lymphadenopathy
A greater proportion of patients enrolled into the ATTRACT
study who received REMICADE + MTX experienced transient mild (<2 times the
upper limit of normal) or moderate (³2 but <3
times the upper limit of normal) elevations in AST or ALT (49% and 47%, respectively)
compared to patients treated with placebo + MTX (27% and 35%, respectively).
Six (1.8%) patients treated with REMICADE + MTX experienced more prolonged elevations
in their ALT.
The following adverse events have been reported during post-approval
use of REMICADE: demyelinating disorders (see WARNINGS,
Neurologic Events) (such as multiple sclerosis and optic neuritis), Guillain-Barré
syndrome, hemolytic anemia, idiopathic thrombocytic purpura, interstitial pneumonitis/fibrosis,
neuropathies, thrombotic thrombocytopenic purpura, and transverse myelitis.
Because these events 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 REMICADE exposure.
DRUG INTERACTIONS
Specific drug interaction studies, including interactions with
MTX, have not been conducted. The majority of patients in rheumatoid arthritis
or Crohn’s cations. In rheumatoid arthritis, concomitant medications besides
MTX were nonsteroidal anti-inflammatory agents, folic acid, corticosteroids
and/or narcotics. Concomitant antivirals, corticosteroids, 6-MP/AZA and aminosalicylates.
Patients with nosuppressants tended to experience fewer infusion reactions compared
to patients on no immunosuppressants (see ADVERSE
REACTIONS, Immunogenicity and Infusion-related Reactions).
Serum infliximab concentrations appeared to be unaffected by
baseline use of medications for the treatment of Crohn’s disease including corticosteroids,
antibiotics (metronidazole or ciprofloxacin) and aminosalicylates.
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