Humira Side Effects

Generic Name: adalimumab

Please note - some side effects for Humira may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Side Effects of Humira - for the Consumer

Humira

All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome when using Humira:

Back pain; headache; mild pain, redness, or swelling at the injection site; mild stomach pain; nausea; runny or stuff nose.

Seek medical attention right away if any of these SEVERE side effects occur when using Humira:

Severe allergic reactions (rash; hives; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue; unusual hoarseness); black, tarry, or bloody stools; blood in the urine; burning, numbness, or tingling; butterfly-shaped rash on the nose and cheeks; change in the appearance of a mole; chest pain; confusion; fainting; fast or irregular heartbeat; mental or mood changes; muscle pain or weakness; new or worsening joint pain; open sore that does not heal; persistent pain, swelling, or redness at the injection site; red, swollen, blistered, or peeling skin; severe or persistent headache or dizziness; severe or persistent stomach pain; shortness of breath; signs of infection (eg, fever, chills, or persistent sore throat; persistent cough; flu-like symptoms; warm, red, or painful skin; increased or painful urination); swelling of the ankles, hands, or feet; tremor; unexplained weight loss or weight gain; unusual bruising or bleeding; unusual lumps; unusual skin growth or other skin changes; unusual tiredness or weakness; unusually pale skin; vision changes; vomit that looks like coffee grounds.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. To report side effects to the appropriate agency, please read the Guide to Reporting Problems to FDA.

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Humira Side Effects - for the Professional

Humira

Clinical Studies Experience

The most serious adverse reactions were:

• Serious Infections [see Warnings and Precautions (5.1)]
• Malignancies [see Warnings and Precautions (5.2)]

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 the controlled portions of the 32 global Humira clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 Humira-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions (5.1)].

Tuberculosis and Opportunistic Infections

In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 Humira-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 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 0.06 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 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal [see Warnings and Precautions (5.1)].

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.

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 Crohn’s disease 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 dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis 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.

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 3%. In patients with plaque psoriasis, 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 plaque psoriasis 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

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 Rheumatoid Arthritis Studies

	Humira 40 mg subcutaneous Every Other Week	Placebo
	(N=705)	(N=690)
Adverse Reaction (Preferred Term)
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
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 reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Other Adverse Reactions

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

Digestive System: Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal hemorrhage, hepatic necrosis, vomiting

Endocrine System: Parathyroid disorder

Hemic And Lymphatic System: Agranulocytosis, 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

Nervous System: Confusion, paresthesia, subdural hematoma, tremor

Respiratory System: Asthma, bronchospasm, dyspnea, lung function decreased, pleural effusion

Special Senses: Cataract

Thrombosis: Thrombosis leg

Urogenital System: Cystitis, kidney calculus, menstrual disorder

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 (5), Adverse Reactions (6)]. 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 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 RA.

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 RA 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%).

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.

Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis

Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar)

Vascular disorders: Systemic vasculitis

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Side Effects by Body System - for Healthcare Professionals

General

The most serious adverse reactions associated with adalimumab have been serious infections, neurologic events, and malignancies. The most common adverse reactions have been injection site reactions. In clinical trials, 7% of patients discontinued treatment due to adverse events (vs 4% with placebo).

Other

The incidence of infection was 1 per patient year (vs. 0.9 with placebo). The most common infections were upper respiratory tract infections (17%), bronchitis, and urinary tract infections (8%). The incidence of serious infections was 0.04 per patient year (vs. 0.02 with placebo). Serious infections included pneumonia, septic arthritis, prosthetic and postsurgical infections, erysipelas, cellulitis, diverticulitis, pyelonephritis, tuberculosis (13 cases), and invasive opportunistic infections (6 cases). One fatality due to herpes zoster with secondary streptococcal necrotizing fasciitis was reported during a clinical trial (n=636). A leprosy reaction has been reported following discontinuation of adalimumab.

Most of the tuberculosis cases occurred within the first 8 months of therapy and included miliary, lymphatic, peritoneal, and pulmonary types. Opportunistic infections were due to histoplasma, aspergillus, and nocardia.

Nervous system

Nervous system side effects have included headache (12%). Confusion, multiple sclerosis, paresthesia, subdural hematoma, and tremor have been reported in less than 5% of patients. A case of hypertrophic pachymeningitis has also been reported. Adalimumab and other TNF blockers have been associated with symptoms or evidence suggestive of demyelinating disease.

Oncologic

Oncologic side effects have included adenoma, carcinomas (breast, gastrointestinal, skin, urogenital), lymphoma, and melanoma in less than 5% of patients. A case of acute myelogenic leukemia has also been reported. A rare cancer of the white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), mostly in adolescents and young adults being treated with tumor necrosis factors (TNF) blockers, continues to be reported to FDA.

During the controlled portions of adalimumab trials in patients with moderately to severely active rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, malignancies (other than lymphoma and non-melanoma skin cancer) were observed at a rate of 0.7 per 100 patient-years among adalimumab-treated patients versus a rate of 0.3 per 100 patient-years among control patients. The median duration of treatment was 5.7 months for adalimumab-treated patients and 5.5 months for control-treated patients.

During the controlled portions of adalimumab rheumatoid arthritis trials, the rate of non-melanoma skin cancers was 0.9 per 100 patient-years among adalimumab-treated patients and 0.2 per 100 patient-years among control patients.

More cases of malignancies have been observed among patients receiving TNF blockers, including adalimumab, compared to controls. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk for the development of lymphoma.

A meta-analysis has reported that there is dose-dependent increased risk of malignancies in patients with rheumatoid arthritis treated with anti-TNF antibody therapy.

Immunologic

Immunologic side effects have included development of autoantibodies. Positive ANA titers were observed at week 24 in 12% of patients (vs 7% with placebo). One patient (0.04%) developed symptoms of new-onset lupus-like syndrome and recovered after discontinuation of adalimumab.

Low-titer antibodies to adalimumab have been observed at least once during treatment in 5% of patients (n=1062). Antibodies developed in 12% of patients on adalimumab monotherapy and in 1% of patients on concurrent methotrexate. During monotherapy, the ACR20 (American College of Rheumatology criteria) response was lower in antibody-positive patients.

A meta-analysis has reported that there is evidence of an increased risk of serious infections in patients with rheumatoid arthritis treated with anti-TNF antibody therapy.

Musculoskeletal

Musculoskeletal side effects have included back pain in 6% of patients; and arthritis, bone disorder, nonspontaneous bone fracture, bone necrosis, joint disorder, muscle cramps, myasthenia, pyogenic arthritis, synovitis, and tendon disorder in less than 5% of patients. A case of severe myalgia has also been reported.

Respiratory

Respiratory side effects have included upper respiratory infection (17%), sinusitis (11%), and flu syndrome (7%). Asthma, bronchospasm, dyspnea, lung disorder, decrease lung function, pleural effusion, pneumonia, and interstitial lung disease including pulmonary fibrosis have been reported in less than 5% of patients.

Gastrointestinal

Gastrointestinal side effects have included nausea (9%) and abdominal pain (7%). Cholecystitis, cholelithiasis, esophagitis, gastroenteritis, gastrointestinal disorder, gastrointestinal hemorrhage, hepatic necrosis, and vomiting have been reported in less than 5% of patients.

Metabolic

Metabolic side effects have included hypercholesterolemia (6%), hyperlipidemia (7%), increased alkaline phosphatase (5%), and unspecified abnormal laboratory tests (8%). Dehydration, abnormal healing, ketosis, paraproteinemia, and peripheral edema have been reported in less than 5% of patients.

Genitourinary

Genitourinary side effects have included urinary tract infection (8%) and hematuria (5%). Cystitis, kidney calculus, menstrual disorder and pyelonephritis have been reported in less than 5% of patients.

Local

Local side effects have included injection site pain (12%) and injection site reaction (8%).

Dermatologic

Dermatologic side effects have included rash (12%). Cellulitis, erysipelas, cutaneous vasculitis, and herpes zoster have been reported in less than 5% of patients. There have been postmarketing reports of erythema multiforme and new or worsening psoriasis (all subtypes including pustular and palmoplantar). A case of alopecia areata universalis has also been reported.

Cardiovascular

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers, including adalimumab. In clinical studies of another TNF blocker, a higher rate of serious CHF-related adverse events was observed.

Cardiovascular side effects have included hypertension (5%). 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, and vascular disorder have been reported in less than 5% of patients. A case of vasculitis has also been reported.

Endocrine

Endocrine side effects have included parathyroid disorder in less than 5% of patients.

Hematologic

Hematologic side effects have included agranulocytosis, granulocytopenia, leukopenia, thrombocytopenia, lymphoma-like reaction, pancytopenia, polycythemia, and leg thrombosis in less than 5% of patients. A case of hypertriglyceridemia has also been reported.

Other

Side effects affecting the body as a whole have included fever, infection, extremity pain, pelvic pain, sepsis, surgery, thorax pain, and reactivated tuberculosis in less than 5% of patients.

Other

Accidental injury has been reported in 10% of patients.

Ocular

Ocular side effects have included cataract (<5%).

Hypersensitivity

Hypersensitivity side effects including anaphylaxis and angioneurotic edema have been reported.

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