Humira (Adalimumab) - Side Effects and Adverse Reactions

ADVERSE REACTIONS

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, II, 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 miliary, 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 treated in clinical trials with HUMIRA for a median of 24 months, 48 malignancies of various types were observed, including 10 patients with lymphoma. The Standardized Incidence Ratio (SIR) (ratio of observed rate to age-adjusted expected frequency in the general population) for malignancies was 1.0 (95% CI, 0.7, 1.3) and for lymphomas was 5.4 (95% CI, 2.6, 10.0). An increase of up to several fold in the rate of lymphomas has been reported in the rheumatoid arthritis patient population⁴, and may be further increased in patients with more severe disease activity⁵(see WARNINGS - Malignancies). The other malignancies observed during use of HUMIRA were breast, colon-rectum, uterine-cervical, prostate, melanoma, gallbladder-bile ducts, and other carcinomas.

AUTOANTIBODIES

In the 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. One patient out of 2334 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patient 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 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-titer antibodies to adalimumab at least once during treatment, 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, II, III, 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.

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

Hemic And Lymphatic System: Agranulocytosis, granulocytopenia, leukopenia, lymphoma like reaction, pancytopenia, polycythemia

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