HUMIRA SIDE EFFECTS

SIDE EFFECTS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Serious Infections.
• Malignancies.
• Hypersensitivity Reactions.
• Hepatitis B Virus Reactivation.
• Neurologic Reactions.
• Hematological Reactions.
• Heart Failure.
• Autoimmunity.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The most common adverse reaction with HUMIRA was injection site reactions. In placebocontrolled 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, RAII, 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%).

Infections

In the controlled portions of the 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate of serious infections was 4.3 per 100 patient-years in 7973 HUMIRA-treated patients versus a rate of 2.9 per 100 patient-years in 4848 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and postsurgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis.

Tuberculosis And Opportunistic Infections

In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV that included 24,605 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup of 10,113 U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 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 0.05 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal.

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 newonset 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 controltreated 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 a controlled Phase 3 trial of HUMIRA in patients with polyarticular JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% of HUMIRA-treated patients and 1.5% of control-treated patients (ALT more common than AST); 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. No ALT elevations ≥ 3 x ULN occurred in the open-label study of HUMIRA in patients with polyarticular JIA who were 2 to <4 years.

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 adult patients with Crohn’s Disease with a 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 the Phase 3 trial of HUMIRA in pediatric patients with Crohn’s disease which evaluated efficacy and safety of two body weight based maintenance dose regimens following body weight based induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 were receiving concomitant immunosuppressants at baseline; none of these patients discontinued due to abnormalities in ALT tests. 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 adult 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 the controlled Phase 3 trial of HUMIRA in patients with pediatric ulcerative colitis (N=93), which evaluated efficacy and safety of a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every other week (N=31) and a maintenance dose of 0.6 mg/kg (maximum of 40 mg) every week (N=32), following body weight based induction doses of 2.4 mg/kg (maximum of 160 mg) at Week 0 and Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=63), or an induction dose of 2.4 mg/kg (maximum of 160 mg) at Week 0, placebo at Week 1, and 1.2 mg/kg (maximum of 80 mg) at Week 2 (N=30), ALT elevations ≥ 3 X ULN occurred in 1.1% (1/93) of 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. In controlled trials of HUMIRA (initial doses of 160 mg at Week 0 and 80 mg at Week 2, followed by 40 mg every week starting at Week 4), in subjects with HS with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of HUMIRA-treated subjects and 0.6% of control-treated subjects. In controlled trials of HUMIRA (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in adult patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients.

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 placebocontrolled 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 (N=705)	Placebo (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

 

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

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 patients in the polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) were similar in frequency and type to those seen in adult patients. Important findings and differences from adults are discussed in the following paragraphs.

In Study JIA-I, HUMIRA was studied in 171 patients who were 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, and 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.

In Study JIA-I, 45% of patients 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 polyarticular JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in this patient population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in patients receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment.

In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity reactions were seen in approximately 6% of patients and included primarily localized allergic hypersensitivity reactions and allergic rash.

In Study JIA-I, 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 patients treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK concentrations decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption.

In Study JIA-II, HUMIRA was studied in 32 patients who were 2 to <4 years of age or 4 years of age and older weighing <15 kg with polyarticular JIA. The safety profile for this patient population was similar to the safety profile seen in patients 4 to 17 years of age with polyarticular JIA.

In Study JIA-II, 78% of patients experienced an infection while receiving HUMIRA. These included nasopharyngitis, bronchitis, upper respiratory tract infection, otitis media, and were mostly mild to moderate in severity. Serious infections were observed in 9% of patients receiving HUMIRA in the study and included dental caries, rotavirus gastroenteritis, and varicella.

In Study JIA-II, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

Psoriatic Arthritis And Ankylosing Spondylitis Clinical Studies

HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebocontrolled 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

Adults

The safety profile of HUMIRA in 1478 adult patients with Crohn’s disease from four placebo-controlled and two open-label extension studies was similar to the safety profile seen in patients with RA.

Pediatric Patients 6 Years To 17 Years

The safety profile of HUMIRA in 192 pediatric patients from one double-blind study (Study PCD-I) and one open-label extension study was similar to the safety profile seen in adult patients with Crohn’s disease. During the 4-week open label induction phase of Study PCD-I, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (6% and 5%, respectively).

A total of 67% of children experienced an infection while receiving HUMIRA in Study PCD-I. These included upper respiratory tract infection and nasopharyngitis.

A total of 5% of children experienced a serious infection while receiving HUMIRA in Study PCD-I. These included viral infection, device related sepsis (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis.

In Study PCD-I, allergic reactions were observed in 5% of children which were all non-serious and were primarily localized reactions.

Ulcerative Colitis Clinical Studies

Adults

The safety profile of HUMIRA in 1010 adult patients with ulcerative colitis (UC) from two placebo-controlled studies and one open-label extension study was similar to the safety profile seen in patients with RA.

Pediatric Patients 5 Years To 17 Years

The safety profile of HUMIRA in 93 pediatric patients with ulcerative colitis from one double-blind study and one open-label extension study was similar to the safety profile seen in adult patients with ulcerative colitis.

Plaque Psoriasis Clinical Studies

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

Hidradenitis Suppurativa Clinical Studies

HUMIRA has been studied in 727 subjects with hidradenitis suppurativa (HS) in three placebocontrolled studies and one open-label extension study. The safety profile for subjects with HS treated with HUMIRA weekly was consistent with the known safety profile of HUMIRA.

Flare of HS, defined as ≥25% increase from baseline in abscesses and inflammatory nodule counts and with a minimum of 2 additional lesions, was documented in 22 (22%) of the 100 subjects who were withdrawn from HUMIRA treatment following the primary efficacy timepoint in two studies.

Uveitis Clinical Studies

HUMIRA has been studied in 464 adult patients with uveitis (UV) in placebo-controlled and open-label extension studies and in 90 pediatric patients with uveitis (Study PUV-I) . The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA.

Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other adalimumab products may be misleading.

There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples. The incidence of antiadalimumab antibody (AAA) development in patients treated with HUMIRA are presented in Table 2.

Table 2: Anti-Adalimumab Antibody Development Determined by ELISA and ECL Assay in Patients Treated with HUMIRA

Indications		Study Duration	Anti-Adalimumab Antibody Incidence by ELISA (n/N)		Anti-Adalimumab Antibody Incidence by ECL Assay (n/N)
			In all patients who received adalimumab	In patients with serum adalimumab concentrations < 2 mcg/mL
Rheumatoid Arthritisa		6 to 12 months	5% (58/1062)	NR	NA
Juvenile Idiopathic Arthritis (JIA)	4 to 17 years of ageb	48 weeks	16% (27/171)	NR	NA
	2 to 4 years of age or ≥ 4 years of age and weighing < 15 kg	24 weeks	7% (1/15)c	NR	NA
Psoriatic Arthritisd		48 weekse	13% (24/178)	NR	NA
Ankylosing Spondylitis		24 weeks	9% (16/185)	NR	NA
Adult Crohn’s Disease		56 weeks	3% (7/269)	8% (7/86)	NA
Pediatric Crohn’s Disease		52 weeks	3% (6/182)	10% (6/58)	NA
Adult Ulcerative Colitis		52 weeks	5% (19/360)	21% (19/92)	NA
Pediatric Ulcerative Colitis		52 weeks	3% (3/100)	13% (3/23)	33% (33/100)i
Plaque Psoriasisf		Up to 52 weeksg	8% (77/920)	21% (77/372)	NA
Hidradenitis Suppurativa		36 weeks	7% (30/461)	28% (58/207)h	61% (272/445)j
Non-infectious Uveitis		52 weeks	5% (12/249)	21% (12/57)	40% (99/249)k
n: number of patients with anti-adalimumab antibody; NR: not reported; NA: Not applicable (not performed) a In patients receiving concomitant methotrexate (MTX), the incidence of anti-adalimumab antibody was 1% compared to 12% with HUMIRA monotherapy b In patients receiving concomitant MTX, the incidence of anti-adalimumab antibody was 6% compared to 26% with HUMIRA monotherapy c This patient received concomitant MTX d In patients receiving concomitant MTX, the incidence of antibody development was 7% compared to 1% in RA e Subjects enrolled after completing 2 previous studies of 24 weeks or 12 weeks of treatments. f 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 g One 12-week Phase 2 study and one 52-week Phase 3 study h Among subjects in the 2 Phase 3 studies who stopped HUMIRA treatment for up to 24 weeks and in whom adalimumab serum levels subsequently declined to <2 mcg/mL (approximately 22% of total subjects studied) i No apparent association between antibody development and safety was observed. The association of antibody development and efficacy outcome was not assessed due to limited number of subjects in each treatment group stratified by anti-adalimumab antibody titer. j No apparent association between antibody development and safety was observed k No correlation of antibody development to safety or efficacy outcomes was observed

 

Rheumatoid Arthritis And Psoriatic Arthritis

Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12month period. 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.

Postmarketing Experience

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.

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

General disorders and administration site conditions: Pyrexia

Hepato-biliary disorders: Liver failure, hepatitis

Immune system disorders: Sarcoidosis

Neoplasms benign, malignant and unspecified (including cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)

Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident

Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, pulmonary embolism

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

Vascular disorders: Systemic vasculitis, deep vein thrombosis