Clinical Studies Experience

The most serious adverse reactions were [see WARNINGS and PRECAUTIONS]:

• Serious Infections
• Neurologic Reactions
• 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 reactions during the double-blind, placebo-controlled portion of 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 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 rheumatoid arthritis 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 and PRECAUTIONS].

Tuberculosis and Opportunistic Infections

In completed and ongoing global clinical studies that include over 13,000 patients, the overall rate of tuberculosis is approximately 0.26 per 100 patient-years. In over 4500 patients in the US and Canada, the rate is approximately 0.07 per 100 patient-years. These studies include reports of miliary, lymphatic, peritoneal, as well as pulmonary. Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. Cases of opportunistic infections have also been reported in these clinical trials at an overall rate of approximately 0.075/100 patient- years. Some cases of opportunistic infections and tuberculosis have been fatal [see WARNINGS and PRECAUTIONS].

Malignancies

More cases of malignancy have been observed in HUMIRA-treated patients compared to control-treated patients in clinical trials [seeWARNINGS and PRECAUTIONS].

Autoantibodies

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.

Immunogenicity

Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate 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 juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy.

In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRA-treated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn's disease, the rate of antibody development was 2.6%. The immunogenicity rate was 8% for plaque psoriasis patients who were treated with HUMIRA monotherapy.

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

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. Adverse reaction rates in patients treated with HUMIRA 40 mg weekly were similar to rates in patients treated with HUMIRA 40 mg every other week. 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 Rheumatoid Arthritis Studies

Other Adverse Reactions

Other infrequent serious adverse reactions occurring at an incidence of less than 5% in rheumatoid arthritis 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

Hemic And Lymphatic System: Agranulocytosis, granulocytopenia, leukopenia, lymphoma like reaction, pancytopenia, polycythemia [see WARNINGS and PRECAUTIONS]

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

Juvenile Idiopathic Arthritis Clinical Studies

In general, the adverse reactions in pediatric patients were similar in frequency and type to those seen in adult patients [see WARNINGS and PRECAUTIONS and other sections under ADVERSE REACTIONS.]. Important findings and differences from adults are discussed in the following paragraphs.

HUMIRA has been studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular juvenile idiopathic arthritis. 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 juvenile idiopathic arthritis patients were generally similar to those commonly seen in outpatient JIA populations. 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 juvenile idiopathic arthritis exposed to HUMIRA alone; liver function tests (LFT) elevations were more frequent among those treated with the combination of HUMIRA and MTX. In general, these elevations did not lead to discontinuation of HUMIRA treatment.

In the juvenile idiopathic arthritis 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 in two placebo- controlled trials and in an open label study and in 393 patients with ankylosing spondylitis in two placebo-controlled studies. The safety profile for patients with psoriatic arthritis and ankylosing spondylitis treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with rheumatoid arthritis, HUMIRA Studies RA-I through IV. In the clinical trials of patients with psoriatic arthritis and ankylosing spondylitis, elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving HUMIRA than in controls, both when HUMIRA was given as monotherapy and when it was used in combination with other immunosuppressive agents. Most elevations of ALT and AST observed were in the range of 1.5 to 3 times the upper limit of normal. In general, patients who developed ALT and AST elevations were asymptomatic, and the abnormalities decreased or resolved with either continuation or discontinuation of HUMIRA, or modification of concomitant medications.

Crohn's Disease Clinical Studies

HUMIRA has been studied in 1478 patients with Crohn's disease in four placebo- controlled and two open-label extension studies. The safety profile for patients with Crohn's disease treated with HUMIRA was similar to the safety profile seen in patients with rheumatoid arthritis.

Plaque Psoriasis Clinical Studies

HUMIRA has been studied in 1696 patients with plaque psoriasis in placebo- controlled and open-label extension studies. The safety profile for patients with plaque psoriasis treated with HUMIRA was similar to the safety profile seen in patients with rheumatoid arthritis with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%).

Elevations of aminotransferases were observed (ALT more common than AST) in a greater proportion of patients receiving HUMIRA than in controls. Most elevations of ALT and AST observed were in the range of 1.5 to 3 times the upper limit of normal. In general, patients who developed ALT and AST elevations were asymptomatic, and most of the abnormalities decreased or resolved with either continuation or discontinuation of HUMIRA.

Postmarketing Experience

Adverse reactions have been reported 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.

Hematologic reactions: Thrombocytopenia [see WARNINGS and PRECAUTIONS]

Hypersensitivity reactions: Anaphylaxis, angioneurotic edema [see WARNINGS and PRECAUTIONS]

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis

Skin reactions: Cutaneous vasculitis, erythema multiforme

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. Therefore, the combination of anakinra with other TNF-blocking agents, including HUMIRA, may also result in similar toxicities [see WARNINGS and PRECAUTIONS].

Live Vaccines

Live vaccines should not be given concurrently with HUMIRA [see WARNINGS and PRECAUTIONS].

Methotrexate

HUMIRA has been studied in rheumatoid arthritis patients taking concomitant methotrexate. Although methotrexate reduced the apparent adalimumab clearance [see CLINICAL PHARMACOLOGY], the data do not suggest the need for dose adjustment of either HUMIRA or methotrexate.

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