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
Humira Side Effects, and Drug Interactions - Adalimumab
Humira Side Effects, and Drug Interactions - Adalimumab
SIDE EFFECTS
General
The most serious adverse reactions were (see WARNINGS):
• Serious Infections
• Neurologic Events
• Malignancies
The most common adverse reaction with HUMIRA was injection
site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA
developed injection site reactions (erythema and/or itching, hemorrhage, pain
or swelling), compared to 14% of patients receiving placebo. Most injection
site reactions were described as mild and generally did not necessitate drug
discontinuation.
The proportion of patients who discontinued treatment due to
adverse events during the double-blind, placebo-controlled portion of Studies
I, n, III and IV was 7% for patients taking HUMIRA and 4% for placebo-treated
patients. The most common adverse events leading to discontinuation of HUMIRA
were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).
Because clinical trials are conducted under widely varying
and controlled conditions, adverse reaction rates observed in clinical trials
of a drug cannot be directly compared to rates in the clinical trials of another
drug and may not predict the rates observed in a broader patient population
in clinical practice.
Infections
In placebo-controlled trials, the rate of infection was 1 per
patient year in the HUMIRA treated patients and 0.9 per patient year in the
placebo-treated patients. The infections consisted primarily of upper respiratory
tract infections, bronchitis and urinary tract infections. Most patients continued
on HUMIRA after the infection resolved. The incidence of serious infections
was 0.04 per patient year in HUMIRA treated patients and 0.02 per patient year
in placebo-treated patients. Serious infections observed included pneumonia,
septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis,
diverticulitis, and pyelonephritis (see WARNINGS)
Thirteen cases of tuberculosis, including Tniliary, lymphatic,
peritoneal, and pulmonary were reported in clinical trials. Most of the cases
of tuberculosis occurred within the first eight months after initiation of therapy
and may reflect recrudescence of latent disease. Six cases of invasive opportunistic
infections caused by histoplasma, aspergillus, and nocardia were also reported
in clinical trials (see WARNINGS).
Malignancies
Among 2468 rheumatoid arthritis patients with moderately to
severely active disease treated with HUMIRA in clinical trials for a mean of
24 months (4870 patient-years of therapy), 10 lymphomas were observed for a
rate of 0.21 cases per 100 patient-years. This is approximately 5-fold higher
than expected in an age and sex matched general population based on the Surveillance,
Epidemiology, and End Results Database7..The adverse reaction rates
observed in clinical trials of a drug cannot be directly compared to rates in
other clinical trials and may not predict the rates observed in a broader patient
population (see WARNINGS; Malignancies). An
increased rate of lymphoma has been reported in the rheumatoid arthritis patient
population. 5,6 Patients with rheumatoid arthritis are at a higher risk for
the development of lymphoma The potential role of TNF-blocking therapy in the
development of malignancies is not known. Thirty-eight malignancies, other than
lymphoma, were observed. Of these, the most common malignancies were breast,
colon, prostate, and uterine, which were similar in type and number to what
would be expected in the general population.7
Autoantibodies
In the controlled trials, 12% of patients treated with HUMIRA
and 1% of placebo-treated patients that had negative baseline ANA liters
developed positive tilers at week 24. One patient out of 2334 treated with HUMIRA
developed clinical signs suggestive of new-onset lupus-like syndrome. The patient
improved following discontinualion of therapy. No patients developed lupus nephritis
or central nervous system symptoms. The impact of long-term treatment with HUMIRA
on the development of autoimmune diseases is unknown.
Immunogenicity
Patients in Studies I, II, and III were tested at multiple
time points for antibodies to adalimumab during the 6 to 12 month period. Approximately
5% (58 of 1,062) of adult rheumatoid arthritis patients receiving HUMIRA developed
low-liter antibodies to adalimumab at least once during treatmenr, which were
neutralizing in vitro. Patients treated with concomitant MTX had a lower
rate of antibody development than patients on HUMIRA monotherapy (1%
versus 12%). No apparent correlation of antibody development to adverse events
was observed. With monotherapy, patients receiving every other week dosing may
develop antibodies more frequently than those receiving weekly dosing. In patients
receiving the recommended dosage of 40 mg every other week as monotherapy, the
ACR 20 response was lower among antibody-positive patients than among antibody-negative
patients. The long-term immunogenicity of HUMIRA is unknown.
The data reflect the percentage of patients whose test results
were considered positive for antibodies to adalimumab 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
medications, and underlying disease. For these reasons, comparison of the incidence
of antibodies to adalimumab with the incidence of antibodies to other products
may be misleading.
Other Adverse Reactions
The data described below reflect exposure to HUMIRA in 2334
patients, including 2073 exposed for 6 months, 1497 exposed for greater than
one year and 1380 in adequate and well-controlled studies (Studies I, n, HI,
and IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term
follow up studies for up to 36 months duration. The population had a mean age
of 54 years, 77% were female, 91% were Caucasian and had moderately to severely
active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other
week.
Table 4 summarizes events reported at a rate of at least 5%
in patients treated with HUMIRA 40 mg every other week compared to placebo and
with an incidence higher than placebo. Adverse event rates in patients treated
with HUMIRA 40 mg weekly were similar to rates in patients treated with HUMIRA
40 mg every other week.
|
Table 4: Adverse Events Reported by >5% of Patients
Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis
Studies
|
|
|
HUMIRA 40 mg subcutaneous Every Other Week (N=705)
|
Placebo (N=690)
|
|
Adverse Event (Preferred Term)
|
Percentage
|
Percentage
|
|
Respiratory
|
|
Upper respiratory infection
|
17
|
13
|
|
Sinusitis
|
11
|
9
|
|
Flu syndrome
|
7
|
6
|
|
Gastrointestinal
|
|
Nausea
|
9
|
8
|
|
Abdominal pain
|
7
|
4
|
|
Laboratory Tests*
|
|
Laboratory test abnormal
|
8
|
7
|
|
Hypercholesterolemia
|
6
|
4
|
|
Hyperlipidemia
|
7
|
5
|
|
Hematuria
|
5
|
4
|
|
Alkaline phosphatase increased
|
5
|
3
|
|
Other
|
|
Injection Site pain
|
12
|
12
|
|
Headache
|
12
|
8
|
|
Rash
|
12
|
6
|
|
Accidental injury
|
10
|
8
|
|
Injection site reaction**
|
8
|
1
|
|
Back pain
|
6
|
4
|
|
Urinary tract infection
|
8
|
5
|
|
Hypertension
|
5
|
3
|
|
* Laboratory test abnormalities were reported as adverse
events in European trials
|
|
** Does not include erythema and/or itching, hemorrhage,
pain or swelling
|
Other Adverse Events
Other infrequent serious adverse events occurring at an incidence
of less than 5% in patients treated with HUMIRA were:
Body As A Whole: Fever, infection, pain in extremity,
pelvic pain, sepsis, surgery, thorax pain, tuberculosis reactivated
Cardiovascular System: Arrhythmia, atrial fibrillation,
cardiovascular disorder, chest pain, congestive heart failure, coronary artery
disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation,
pericardial effusion, pericarditis, syncope, tachycardia, vascular disorder
Collagen Disorder: Lupus erythematosus syndrome
Digestive System: Cholecystitis, cholelithiasis, esophagitis,
gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, hepatic
necrosis, vomiting
Endocrine System: Parathyroid disorder
Heroic And Lymphatic System: Agranulocytosis, granulocytopenia,
leukopenia, lymphoma like reaction, pancytopenia, polycythemia (see WARNINGS,
Hematologic Events)
Metabolic And Nutritional Disorders: Dehydration, healing
abnormal, ketosis, paraproteinemia, peripheral edema
Musculo — Skeletal System: Arthritis, bone disorder,
bone fracture (not spontaneous), bone necrosis, joint disorder, muscle cramps,
myasthenia, pyogenic arthritis, synovitis, tendon disorder
Neoplasia: Adenoma, carcinomas such as breast, gastrointestinal,
skin, urogenital, and others; lymphoma and melanoma.
Nervous System: Confusion, multiple sclerosis, paresthesia,
subdural hematoma, tremor
Respiratory System: Asthma, bronchospasm, dyspnea, lung
disorder, lung function decreased, pleural effusion, pneumonia
Skin And Appendages: Cellulitis, erysipelas, herpes
zoster
Special Senses; Cataract
Thrombosis: Thrombosis leg
Urogenital System: Cystitis, kidney calculus, menstrual
disorder, pyelonephritis
Adverse Reaction Information from Spontaneous Reports:
Adverse Events have been reported during post-approval use
of HUMIRA. 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 HUMIRA exposure
Hematologic Events: Thrombocytopenia (see WARNINGS,
Hematologic Events).
Hypersensitivity reactions: Anaphylaxis (see WARNINGS,
Hypersensitivity Reactions).
DRUG INTERACTIONS
Methotrexate
HUMIRA has been studied in rheumatoid arthritis patients taking
concomitant MTX (see CLINICAL PHARMACOLOGY;
Drug Interactions). The data do not suggest the need for dose adjustment of
either HUMIRA or MTX.
Anakinra
Concurrent administration of anakinra (an interleukin-1 antagonist)
and another TNF-blocking agent has been associated with an increased risk of
serious infections, an increased risk of neutropenia and no additional benefit
compared to these medicinal products alone. The safety and efficacy of anakinra
used in combination with HUMIRA has not been studied. Therefore the, combination
of anakinra with other TNF-blocking agents, including HUMIRA, may also result
i n similar toxicities (see WARNINGS, SERIOUS
INFECTIONS).
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