"Nov. 6, 2012 -- The FDA has approved Pfizer's Xeljanz (tofacitinib), a first-of-its-kind treatment for rheumatoid arthritis.
Xeljanz is approved for use by patients not helped by methotrexate, the usual first treatment for RA. It's a "...
The most serious adverse reactions described elsewhere in the labeling include the following:
Clinical Trials Experience
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. 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 reactions during the double-blind, placebo-controlled portion of studies in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA in these RA studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%).
In the controlled portions of the 34 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC and Ps, the rate of serious infections was 4.6 per 100 patient-years in 7304 HUMIRA-treated patients versus a rate of 3.1 per 100 patient-years in 4232 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see WARNINGS AND PRECAUTIONS].
Tuberculosis and Opportunistic Infections
In 47 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC and Ps that included 23,036 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. In a subgroup of 9396 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD conversion was 0.08 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.08 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see WARNINGS AND PRECAUTIONS].
In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation 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.
Liver Enzyme Elevations
There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with CD with control period duration ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 respectively, followed by 40 mg every other week) in patients with UC with control period duration ranging from 1 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with Ps with control period duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients.
Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6-to 12month period. Approximately 5% (58 of 1062) of adult RA patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate (MTX) had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions 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.
In patients with JIA, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant MTX, the incidence was 6% compared to 26% with HUMIRA monotherapy.
In patients with AS, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with RA.
In patients with PsA, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with RA; however, in patients receiving concomitant MTX the rate was 7% compared to 1% in RA.
In patients with CD, the rate of antibody development was 3%.
In patients with moderately to severely active UC, the rate of antibody development in patients receiving HUMIRA was 5%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 25% of total patients studied), the immunogenicity rate was 20.7%.
In patients with Ps, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In Ps patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal.
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. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, 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
Rheumatoid Arthritis Clinical Studies
The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-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 1 summarizes reactions 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. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion.
Table 1: Adverse Reactions Reported by ≥ 5% of
Patients Treated with HUMIRA During Placebo-Controlled Period of Pooled RA
Studies (Studies RA-I, RA-II, RA-III, and RA-IV)
|HUMIRA 40 mg subcutaneous Every Other Week
|Adverse Reaction (Preferred Term)|
|Upper respiratory infection||17%||13%|
|Laboratory test abnormal||8%||7%|
|Alkaline phosphatase increased||5%||3%|
|Injection site reaction **||8%||1%|
|Urinary tract infection||8%||5%|
|* Laboratory test abnormalities were reported as adverse
reactions in European trials
** Does not include injection site erythema, itching, hemorrhage, pain or swelling
Less Common Adverse Reactions in Rheumatoid Arthritis Clinical Studies
Other infrequent serious adverse reactions that do not appear in the WARNINGS AND PRECAUTIONS or Adverse Reaction sections that occurred at an incidence of less than 5% in HUMIRA-treated patients in RA studies were:
Body As A Whole: Pain in extremity, pelvic pain, surgery, thorax pain
Cardiovascular System: Arrhythmia, atrial fibrillation, chest pain, coronary artery disorder, heart arrest, hypertensive encephalopathy, myocardial infarct, palpitation, pericardial effusion, pericarditis, syncope, tachycardia
Endocrine System: Parathyroid disorder
Metabolic And Nutritional Disorders: Dehydration, healing abnormal, ketosis, paraproteinemia, peripheral edema
Special Senses: Cataract
Thrombosis: Thrombosis leg
Juvenile Idiopathic Arthritis Clinical Studies
In general, the adverse reactions in the HUMIRA-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS Important findings and differences from adults are discussed in the following paragraphs.
HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster.
A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment.
In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash.
Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial.
Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.
Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies
HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV.
Crohn's Disease Clinical Studies
HUMIRA has been studied in 1478 patients with Crohn's disease (CD) in four placebo-controlled and two open-label extension studies. The safety profile for patients with CD treated with HUMIRA was similar to the safety profile seen in patients with RA.
Ulcerative Colitis Clinical Studies
HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two placebo-controlled studies and one open-label extension study. The safety profile for patients with UC treated with HUMIRA was similar to the safety profile seen in patients with RA.
Plaque Psoriasis Clinical Studies
HUMIRA has been studied in 1696 patients with plaque psoriasis (Ps) in placebo-controlled and open-label extension studies. The safety profile for patients with Ps treated with HUMIRA was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in Ps patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).
The following adverse reactions have been identified during post-approval use of HUMIRA. 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 HUMIRA exposure.
Hepato-biliary disorders: Liver failure
Immune system disorders: Sarcoidosis
Vascular disorders: Systemic vasculitis, deep vein thrombosis
Read the Humira (adalimumab) Side Effects Center for a complete guide to possible side effects »
HUMIRA has been studied in rheumatoid arthritis (RA) patients taking concomitant methotrexate (MTX). Although MTX reduced the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX [see CLINICAL PHARMACOLOGY].
In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see WARNINGS AND PRECAUTIONS]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information to provide recommendations regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, and Ps.
Cytochrome P450 Substrates
The formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible for a molecule that antagonizes cytokine activity, such as adalimumab, to influence the formation of CYP450 enzymes. Upon initiation or discontinuation of HUMIRA in patients being treated with CYP450 substrates with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or drug concentration (e.g., cyclosporine or theophylline) is recommended and the individual dose of the drug product may be adjusted as needed.
Last reviewed on RxList: 5/13/2013
This monograph has been modified to include the generic and brand name in many instances.
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