Humira: Indications, Dosage, Precautions, Adverse Effects
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Humira - Product Information

Manufacture: AbbVie
Country: Canada
Condition: Ankylosing Spondylitis, Crohn's Disease, Maintenance, Crohn's Disease, Acute, Crohn's Disease, Hidradenitis Suppurativa, Plaque Psoriasis, Psoriatic Arthritis, Psoriasis, Rheumatoid Arthritis, Spondyloarthritis, Ulcerative Colitis
Class: Antirheumatics, TNF alfa inhibitors
Form: Liquid solution, Subcutaneous (SC)
Ingredients: adalimumab, citric acid monohydrate, dibasic sodium phosphate dihydrate, mannitol, monobasic sodium phosphate dihydrate, polysorbate 80, sodium citrate, sodium chloride

Summary product information

Route of
Administration
Dosage
Form/Strength
Clinically Relevant Non-medicinal Ingredients
subcutaneous injectionsterile solution (in either a vial*, pen or pre-filled syringe)/
40 mg in 0.8 mL
(50 mg/mL)
citric acid monohydrate, dibasic sodium phosphate dihydrate, mannitol, monobasic sodium phosphate dihydrate, polysorbate 80, sodium citrate, sodium chloride.

For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section.
* The vial is for pediatric use only.

Description

HUMIRA (adalimumab) is a recombinant human immunoglobulin (IgG1) monoclonal antibody. Adalimumab was created using phage display technology resulting in fully human heavy and light chain variable regions, which confer specificity to human tumor necrosis factor (TNF), and human IgG1 heavy chain and kappa light chain sequences. Adalimumab binds with high affinity and specificity to soluble tumor necrosis factor (TNF-alpha) but not lymphotoxin (TNF-beta). Adalimumab is produced by recombinant DNA technology in a mammalian cell expression system. It consists of 1,330 amino acids and has a molecular weight of approximately 148 kilodaltons.

Indications and clinical use

HUMIRA (adalimumab) treatment should be initiated and supervised by specialist physicians experienced in the diagnosis and treatment of rheumatoid arthritis (RA), polyarticular juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), adult and pediatric Crohn’s disease (CD), ulcerative colitis (UC), hidradenitis suppurativa (HS) or psoriasis (Ps), and familiar with the HUMIRA efficacy and safety profile.

HUMIRA is indicated for:

Rheumatoid Arthritis

  • reducing the signs and symptoms, inducing major clinical response and clinical remission, inhibiting the progression of structural damage and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate (MTX) or other disease-modifying anti-rheumatic drugs (DMARDs).

When used as first-line treatment in recently diagnosed patients who have not been previously treated with methotrexate, HUMIRA should be given in combination with methotrexate. HUMIRA can be given as monotherapy in case of intolerance to methotrexate or when treatment with methotrexate is contraindicated.

Polyarticular Juvenile Idiopathic Arthritis

  • in combination with methotrexate, reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 to 17 years of age who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs). HUMIRA can be used as monotherapy in case of intolerance to methotrexate or when continued treatment with methotrexate is not appropriate (see CLINICAL TRIALS, Pediatric, Polyarticular Juvenile Idiopathic Arthritis, Study Results). HUMIRA has not been studied in children with polyarticular juvenile idiopathic arthritis aged less than 2 years.

Psoriatic Arthritis

  • reducing the signs and symptoms of active arthritis and inhibiting the progression of structural damage and improving the physical function in adult psoriatic arthritis patients. HUMIRA can be used in combination with methotrexate (MTX) in patients who do not respond adequately to methotrexate alone.

Ankylosing Spondylitis

  • reducing signs and symptoms in patients with active ankylosing spondylitis who have had an inadequate response to conventional therapy.

Adult Crohn’s Disease

  • reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy, including corticosteroids and/or immunosuppressants. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Pediatric Crohn’s Disease

  • reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 13 to 17 years of age weighing ≥ 40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (a corticosteroid and/or aminosalicylate and/or an immunosuppressant) and/or a tumour necrosis factor alpha antagonist.

Ulcerative Colitis

  • treatment of adult patients with moderately to severely active ulcerative colitis (UC) who have had an inadequate response to conventional therapy including corticosteroids, azathioprine and/or 6-mercaptopurine (6-MP) or who are intolerant to such therapies. The efficacy of HUMIRA in patients who have lost response to or were intolerant to TNF blockers has not been established.

Hidradenitis Suppurativa

  • treatment of active moderate to severe hidradenitis suppurativa in adult patients, who have not responded to conventional therapy (including systemic antibiotics).

Plaque Psoriasis

  • treatment of adult patients with chronic moderate to severe plaque psoriasis who are candidates for systemic therapy. For patients with chronic moderate plaque psoriasis, HUMIRA should be used after phototherapy has been shown to be ineffective or inappropriate.

Geriatrics (> 65 years of age):

Evidence from clinical studies and experience suggests that use of HUMIRA in the geriatric population is not associated with differences in effectiveness. A brief discussion can be found under (WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Pediatrics (< 18 years of age):

Polyarticular JIA

HUMIRA has not been studied in patients with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

Pediatric Crohn’s Disease

The safety and efficacy of HUMIRA were authorised in pediatric patients 13 to 17 years of age weighing ≥ 40 kg with severely active Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy (see CLINICAL TRIALS).

Contraindications

  • Patients with known hypersensitivity to HUMIRA (adalimumab) or any of its components. For a complete listing, see the (DOSAGE FORMS, COMPOSITION AND PACKAGING) section.
  • Patients with severe infections such as sepsis, tuberculosis and opportunistic infections. See (WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions, Infections).
  • Patients with moderate to severe heart failure (NYHA class III/IV). See (WARNINGS AND PRECAUTIONS, Serious Warnings and Precautions, Cardiovascular).

Warnings and precautions

Serious Warnings and Precautions

Hepatosplenic T-Cell Lymphoma

Very rare post-marketing reports of hepatosplenic T-cell lymphoma (HSTCL), a rare aggressive lymphoma that is often fatal, have been identified in patients treated with HUMIRA (adalimumab). Most of the patients had prior infliximab therapy as well as concomitant azathioprine or 6-mercaptopurine use for Crohn’s disease. The potential risk with the combination of azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered. The causal association of HSTCL with HUMIRA is not clear.

Infections

Serious infections due to bacterial, mycobacterial, invasive fungal (disseminated or extrapulmonary histoplasmosis, aspergillosis, coccidiodomycosis), viral, parasitic, or other opportunistic infections have been reported in patients receiving tumor necrosis factor (TNF)-blocking agents. Sepsis, rare cases of tuberculosis, candidiasis, listeriosis, legionellosis and pneumocystis have also been reported with the use of TNF-blocking agents, including HUMIRA. Other serious infections seen in clinical trials include pneumonia, pyelonephritis, septic arthritis and septicemia. Hospitalization or fatal outcomes associated with infections have been reported. Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their underlying disease, could predispose them to infections.

Treatment with HUMIRA should not be initiated in patients with active infections, including chronic or localized infections, until infections are controlled. In patients who have been exposed to tuberculosis, and patients who have traveled in areas of high risk of tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis, the risk and benefits of treatment with HUMIRA should be considered prior to initiating therapy. See (WARNINGS AND PRECAUTIONS, Infections, Other Opportunistic Infections).

As with other TNF-blockers, patients should be monitored closely for infections (including tuberculosis) before, during and after treatment with HUMIRA.

Patients who develop a new infection while undergoing treatment with HUMIRA should be monitored closely and undergo a complete diagnostic evaluation. Administration of HUMIRA should be discontinued if a patient develops a serious infection or sepsis, and appropriate antimicrobial or antifungal therapy should be initiated.

Physicians should exercise caution when considering the use of HUMIRA in patients with a history of recurrent infection or with underlying conditions which may predispose them to infections, or patients who have resided in regions where tuberculosis and histoplasmosis are endemic. See (WARNINGS AND PRECAUTIONS, Infections, Tuberculosis) and (ADVERSE REACTIONS, Adverse Drug Reaction Overview, Infections). The benefits and risks of treatment with HUMIRA should be carefully considered before initiating therapy.

Pediatric Malignancy

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, including HUMIRA. See (WARNINGS AND PRECAUTIONS, Malignancies).

General

Concurrent Administration of Biologic DMARDs or TNF-Antagonists

Serious infections were seen in clinical studies with concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocking agent, etanercept, with no added benefit compared to etanercept alone. Because of the nature of the adverse events seen with the combination of etanercept and anakinra, similar toxicities may also result from the combination of anakinra and other TNF-blocking agents. Therefore, the combination of HUMIRA (adalimumab) and anakinra is not recommended. See (DRUG INTERACTIONS, Drug-Drug Interactions).

Concomitant administration of HUMIRA with other biologic DMARDs (e.g., anakinra and abatacept) or other TNF antagonists is not recommended based upon the increased risk for infections and other potential pharmacological interactions. See (DRUG INTERACTIONS, Drug-Drug Interactions).

Switching Between Biological DMARDs

When switching from one biologic to another, patients should continue to be monitored for signs of infection.

Surgery

There is limited safety experience of surgical procedures in patients treated with HUMIRA. The long half-life of adalimumab should be taken into consideration if a surgical procedure is planned. A patient who requires surgery while on HUMIRA should be closely monitored for infections, and appropriate actions should be taken. There is limited safety experience in patients undergoing arthroplasty while receiving HUMIRA.

Carcinogenesis and Mutagenesis

Long-term animal studies of adalimumab have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of adalimumab were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. See (TOXICOLOGY, Mutagenicity and Carcinogenicity, In vitro Genotoxicity).

Cardiovascular

Patients with Congestive Heart Failure

Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF-blockers. Cases of worsening CHF have also been observed with HUMIRA. HUMIRA has not been formally studied in patients with CHF; however, in clinical trials of another TNF-blocker, a higher rate of serious CHF-related adverse events was observed. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. HUMIRA is contraindicated in moderate to severe heart failure (see CONTRAINDICATIONS).

Gastrointestinal

Small Bowel Obstruction

Failure to respond to treatment for Crohn’s disease may indicate the presence of fixed fibrotic stricture that may require surgical treatment. Available data suggest that HUMIRA does not worsen or cause strictures.

Hematologic Events

Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF-blocking agents. Adverse events of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities.

Hypersensitivity Reactions

Allergic reactions (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients receiving HUMIRA in clinical trials. See (ADVERSE REACTIONS). Reports of serious allergic reactions, including anaphylaxis, have been received following HUMIRA administration. If an anaphylactic reaction or other serious allergic reactions occur, administration of HUMIRA should be discontinued immediately and appropriate therapy initiated.

The HUMIRA Pen and the pre-filled syringe are available with a 29 gauge ½ inch needle and a black needle cover that does not contain latex. See (DOSAGE FORMS, COMPOSITION AND PACKAGING).

Immune

Autoimmunity

Treatment with HUMIRA may result in the formation of autoantibodies and rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued. See (ADVERSE REACTIONS, Adverse Drug Reaction Overview, Autoantibodies).

Immunosuppression

The possibility exists for TNF-blocking agents, including HUMIRA, to affect host defences against infections and malignancies since TNF mediates inflammation and modulates cellular immune responses. In a study of 64 patients with rheumatoid arthritis who were treated with HUMIRA, there was no evidence of depression of delayed-type hypersensitivity, depression of immunoglobulin levels, or change in enumeration of effector T- and B-cells and NK-cells, monocyte/macrophages, and neutrophils. The impact of treatment with HUMIRA on the development and course of malignancies, as well as active and/or chronic infections, is not fully understood. See (WARNINGS AND PRECAUTIONS, Infections and Malignancies) and (ADVERSE REACTIONS, Adverse Drug Reaction Overview, Infections and Malignancies).

Immunizations

In a randomized, double-blind, placebo-controlled study in 226 adult rheumatoid arthritis patients treated with HUMIRA, antibody responses to concomitant pneumococcal and influenza vaccines were assessed. Protective antibody levels to the pneumococcal antigens were achieved by 86% of patients in the HUMIRA group compared to 82% in the placebo group. A total of 37% of HUMIRA-treated patients and 40% of placebo-treated patients achieved at least a 2-fold increase in antibody titer to at least three out of five pneumococcal antigens. In the same study, 98% of patients in the HUMIRA group and 95% in the placebo group achieved protective antibody levels to the influenza antigens. A total of 52% of HUMIRA-treated patients and 63% of placebo-treated patients achieved at least a 4-fold increase in antibody titer to at least two out of three influenza antigens.

It is recommended that pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy.

Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA.

Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for five months following the mother’s last HUMIRA injection during pregnancy. See (WARNINGS AND PRECAUTIONS, Special Populations, Pregnant Women).

Infections

Tuberculosis

Tuberculosis, including reactivation and new onset of tuberculosis, has been reported in patients receiving HUMIRA. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated). Before initiation, during and after treatment with HUMIRA, patients should be evaluated for active and inactive (“latent”) tuberculosis infection with a tuberculin skin test. Treatment of latent tuberculosis infections should be initiated prior to therapy with HUMIRA. When tuberculin skin testing is performed for latent tuberculosis infection, an induration size of 5 mm or greater should be considered positive, even if vaccinated previously with Bacille Calmette-Guérin (BCG).

If active tuberculosis is diagnosed, HUMIRA therapy must not be initiated.

The possibility of undetected latent tuberculosis should be considered, especially in patients who have immigrated from or traveled to countries with a high prevalence of tuberculosis or who had close contact with a person with active tuberculosis. If latent infection is diagnosed, appropriate treatment must be started with anti-tuberculosis prophylactic treatment, in accordance with the Canadian Tuberculosis Standards and Centers for Disease Control and Prevention guidelines, before the initiation of HUMIRA. Use of anti-tuberculosis prophylactic treatment should also be considered before the initiation of HUMIRA in patients with several or significant risk factors for tuberculosis despite a negative test for tuberculosis and in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed. The decision to initiate anti-tuberculosis therapy in these patients should only be made after taking into account both the risk for latent tuberculosis infection and the risks of anti-tuberculosis therapy. If necessary, consultation should occur with a physician with expertise in the treatment of tuberculosis.

Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients receiving HUMIRA. Also, active tuberculosis has developed in patients receiving HUMIRA whose screening for latent tuberculosis infection was negative, and some patients who have been successfully treated for active tuberculosis have redeveloped active tuberculosis while being treated with TNF-blocking agents.

Patients receiving HUMIRA should be monitored for signs and symptoms of active tuberculosis, particularly because tests for latent tuberculosis infection may be falsely negative. The risk of false negative tuberculin skin test results should be considered, especially in patients who are severely ill or immunocompromised. Patients should be instructed to seek medical advice if signs/symptoms suggestive of a tuberculosis infection (e.g., persistent cough, wasting/weight loss, low grade fever, listlessness) occur during or after therapy with HUMIRA, and physicians should monitor for signs and symptoms of active tuberculosis, including patients who are tuberculosis skin test negative.

Other Opportunistic Infections

Opportunistic infections, including invasive fungal infections, have been observed in patients receiving HUMIRA. These infections are not consistently recognized in patients taking TNF-blockers and this has resulted in delays in appropriate treatment, sometimes resulting in fatal outcomes.

Patients taking TNF-blockers are more susceptible to serious fungal infections such as histoplasmosis, coccidioidomycosis, blastomycosis, aspergillosis, candidiasis, and other opportunistic infections. Those who develop fever, malaise, weight loss, sweats, cough, dyspnea, and/or pulmonary infiltrates, or other serious systemic illness with or without concomitant shock should promptly seek medical attention for a diagnostic evaluation.

For patients who reside or travel in regions where mycoses are endemic, invasive fungal infections should be suspected if they develop the signs and symptoms of possible systemic fungal infection. Patients are at risk of histoplasmosis and other invasive fungal infections and hence clinicians should consider empiric antifungal treatment until the pathogen(s) are identified. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Patients who develop a severe fungal infection are also advised to stop the TNF-blocker until infections are controlled.

Hepatitis B Virus (HBV) Reactivation

Very rare cases of hepatitis B virus (HBV) reactivation have been associated with anti-TNF therapy. Clinically active HBV infection occurred following a latency period ranging from 3 to 20 months after initiation of therapy. In the majority of cases, patients were also taking other immunosuppressive drugs, including methotrexate, azathioprine, and/or corticosteroids. Hence, establishing a causal relationship to anti-TNF agents is confounded by the presence of these other medications. Where outcome information was provided, most patients were reported to have improved after antiviral treatment and/or discontinuation of the anti-TNF agent. However, fatal outcomes have also occurred in reported cases. Patients at risk of HBV infection should be evaluated for prior evidence of HBV infection before initiating anti-TNF therapy. Those identified as chronic carriers (i.e., surface antigen positive) should be monitored for signs and symptoms of active HBV infection throughout the course of therapy and for several months following discontinuation of therapy. Reactivation of HBV is not unique to anti-TNF-alpha agents and has been reported with other immunosuppressive drugs.

Malignancies

In the controlled portions of clinical trials of some TNF-blocking agents, including HUMIRA, more cases of malignancies have been observed among patients receiving those TNF-blockers compared to control patients.

In the controlled and uncontrolled open-label portions of clinical trials of HUMIRA, the more frequently observed malignancies, other than lymphoma and non-melanoma skin cancer, were breast, colon, prostate, lung, and melanoma.

Cases of acute and chronic leukemia have been reported in association with post-marketing TNF-blocker use in rheumatoid arthritis and other indications. Patients with rheumatoid arthritis may be at a higher risk (up to 2-fold) than the general population for the development of leukemia, even in the absence of TNF-blocking therapy.

Malignancies in Pediatric Patients and Young Adults

Malignancies, some fatal, have been reported among children, adolescents and young adults who received treatment with TNF-blocking agents (i.e., including HUMIRA). Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous post-marketing reports.

Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF-blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF-blocker cases have occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine (6-MP) concomitantly with a TNF-blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF-blocker or a TNF-blocker in combination with these other immunosuppressants. The potential risk with the combination of azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered.

No malignancies were observed in the indicated pediatric patient population with Crohn’s disease treated with HUMIRA (n=102) for 52 weeks in a clinical trial.

Treatment-emergent malignancies occurred in 2/480 HUMIRA-treated UC patients in the double-blind controlled portion of two clinical trials (range of treatment duration from Weeks 0 to 52). The malignancies were squamous cell carcinoma and gastric cancer. Gastric cancer was considered serious and the patient discontinued as a result.

With current data it is not known if adalimumab treatment influences the risk for developing dysplasia or colon cancer. All patients with ulcerative colitis who are at risk for dysplasia or colon carcinoma (for example, patients with long-standing ulcerative colitis or primary sclerosing cholangitis), or who had a prior history of dysplasia or colon carcinoma should be screened for dysplasia at regular intervals before therapy and throughout their disease course. This evaluation should include colonoscopy and biopsies per local recommendations.

Lymphoma

In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving TNF-blockers compared to control patients.

However, for HUMIRA, the occurrence of lymphoma was rare, and the follow-up period of placebo patients was shorter than for patients receiving TNF-antagonist therapy. The size of the control group and limited duration of the controlled portions of studies precludes the ability to draw firm conclusions. Furthermore, there is an increased background lymphoma risk in rheumatoid arthritis patients with long-standing, highly active, inflammatory disease, which complicates the risk estimation.

In combining the controlled and uncontrolled open-label portions of these clinical trials with a median duration of approximately 1.7 years, including 6,539 patients and over 16,000 patient-years of therapy, the observed rate of lymphomas is approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general population.

During the long-term open-label trials with HUMIRA, the overall standard incidence ratio (SIR) of malignancies was 0.99 [95% confidence interval (CI), 0.81 to 1.20]. With current knowledge in this area, a possible risk for development of lymphomas or other malignancies in patients treated with a TNF-antagonist cannot be excluded.

No studies have been conducted that include patients with a history of malignancy or that continue treatment in patients who develop malignancy while receiving HUMIRA. Additional caution should be exercised when considering HUMIRA treatment in these patients.

Non-Lymphoma Malignancy

During the controlled portions of HUMIRA trials in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa and psoriasis, malignancies, other than lymphoma and non-melanoma skin cancer, were observed at a rate (95% CI) of 6.2 (3.8, 9.9) per 1,000 patient-years among 4946 HUMIRA-treated patients versus a rate of 7.0 (3.7, 12.9) per 1,000 patient-years among 3097 control patients (median duration of treatment of 4.0 months for HUMIRA-treated patients and 3.9 months for control- treated patients).

During the controlled portions of HUMIRA rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa and psoriasis trials, the rate (95% CI) of non-melanoma skin cancers was 9.1 (6.1, 13.4) per 1,000 patient-years among HUMIRA-treated patients and 3.5 (1.4, 8.4) per 1,000 patient-years among control patients. Of these skin cancers, squamous cell carcinomas occurred at rates (95% CI) of 2.5 (1.2, 5.3) per 1,000 patient-years among HUMIRA-treated patients and 0.7 (0.1, 4.9) per 1,000 patient-years among control patients. The rate (95% CI) of lymphomas was 0.7 (0.2, 2.9) per 1,000 patient- years among HUMIRA-treated patients and 0.7 (0.1, 4.9) per 1,000 patient-years among control patients.

The observed rate of malignancies, other than lymphoma and non-melanoma skin cancers, is approximately 8.7 per 1,000 patient years in the controlled portion of clinical trials and in ongoing and completed open-label extension studies. The observed rate of non-melanoma skin cancers is approximately 9.9 per 1,000 patient years, and the observed rate of lymphomas is approximately 1.3 per 1,000 patient years. The median duration of these studies is approximately 3.4 years and included 5860 patients who were on HUMIRA for at least one year or who developed a malignancy within a year of starting therapy, representing over 25,000 patient years of therapy.

All patients, and in particular psoriasis patients with a medical history of extensive immunosuppressant therapy or psoriasis patients with a history of Psoralen Ultra-Violet A (PUVA) treatment should be examined for the presence of non-melanoma skin cancer prior to and during treatment with HUMIRA.

Neurologic Events

Use of TNF-blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of demyelinating disease, including multiple sclerosis, and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent onset central nervous system demyelinating disorders.

Special Populations

Pregnant Women

The extent of exposure in pregnancy during clinical trials is very limited, consisting only of individual cases.

An embryo-fetal perinatal developmental toxicity study has been performed in cynomolgus monkeys at dosages up to 100 mg/kg (266 times human area under the curve (AUC) when given 40 mg adalimumab subcutaneously with methotrexate every week, or 373 times when given 40 mg adalimumab subcutaneously without methotrexate) and has revealed no evidence of harm to the fetuses due to adalimumab. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed.

However, adalimumab may cross the placenta into the serum of infants born to women treated with HUMIRA during pregnancy. Consequently, these infants may be at increased risk for infection. Administration of live vaccines to infants exposed to adalimumab in utero is not recommended for five months following the mother’s last HUMIRA injection during pregnancy.

Labor and Delivery

There are no known effects of HUMIRA on labor or delivery.

Nursing Women

It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. However, because human immunoglobulins are excreted in milk, and because of the potential for serious adverse reactions, breast-feeding is not recommended for at least five months after the last HUMIRA treatment. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatrics (< 18 years of age)

Polyarticular JIA

The efficacy and safety of HUMIRA have been studied in patients aged 4 to 17 years (n=171) and 2 to 4 years (n=32). No overall differences were observed in the efficacy and safety between the two age groups. HUMIRA has not been studied in children with polyarticular JIA less than 2 years of age or in patients with a weight below 10 kg.

Pediatric Crohn’s Disease

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

Geriatrics (> 65 years of age)

A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years and older, received HUMIRA in clinical Studies DE009, DE011, DE019 and DE031. No overall differences in effectiveness were observed between these patients and younger patients. The frequency of serious infection and malignancy among HUMIRA-treated patients over age 65 was higher than for those under the age of 65. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly.

Monitoring and Laboratory Tests

There is no known interference between HUMIRA and laboratory tests.

Adverse reactions

Adverse Drug Reaction Overview

The most serious adverse reactions were [see (WARNINGS AND PRECAUTIONS)]:

  • serious infections
  • neurologic events
  • malignancies

The most common adverse reaction in rheumatoid arthritis patients treated with HUMIRA (adalimumab) was injection site reactions. In controlled trials for rheumatoid arthritis, polyarticular JIA, psoriatic arthritis, ankylosing spondylitis, adult and pediatric Crohn’s disease, ulcerative colitis, hidradenitis suppurativa and psoriasis, 13% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 7% of patients receiving control treatment. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation.

The proportion of rheumatoid arthritis patients who discontinued treatment due to adverse events during the double-blind, placebo-controlled portion of rheumatoid arthritis Studies DE009, DE011, DE019 and DE031 was 7.0% for patients taking HUMIRA, and 4.0% 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%).

Among patients with rheumatoid arthritis in placebo-controlled studies, deaths occurred in 8 of 1,380 (0.58%) HUMIRA-treated patients compared to 1 of 690 (0.14%) placebo-treated patients. The rate of deaths in both treatment arms is less than expected in the normal population with a standard mortality ratio (SMR) of 0.87 (95% CI, 0.38, 1.72) in the HUMIRA group and 0.25 (95% CI, 0.00, 1.37) in the placebo group.

In Study DE019, 553 patients were exposed to at least one dose of HUMIRA and 202 patients completed 10 years of study. A total of 24 patients died during the 10-year exposure period to HUMIRA (4 during the double-blind phase, 14 during the open-label extension phase and an additional 6 after study drug termination). Among the treatment-emergent deaths, the most common reasons were: 4 sepsis, 3 cancers and 3 respiratory system events. However, the total number of deaths was not higher than that calculated according to age-adjusted Standardized Mortality Rates.

Of the 553 patients, 23.0% discontinued due to an adverse event. The most common adverse events associated with discontinuation of study drug were pneumonia and breast cancer (n = 5 each). Fatigue, pneumonia, cellulitis, and histoplasmosis (n = 3 each) were the most common treatment-related adverse events leading to discontinuation of study drug.

In total, 49% of patients treated with HUMIRA experienced a serious adverse event; 15.7% were considered at least possibly related to study drug. The most common serious adverse events were rheumatoid arthritis disease flare (n = 35, 6.3%), pneumonia (n = 26, 4.7%) and myocardial infarction (n = 10, 1.8%); of these, only pneumonia was considered to be at least possibly related to study drug.

The most frequently reported treatment-emergent adverse events were infections (total n = 448, 81%; serious n = 85, 15.4%) and injection site reactions (n = 115, 20.8%).

Adverse events of special interest among the 553 patients included 35 patients with malignancies other than non-melanoma skin cancer (including 5 cases of lymphoma); and 3 patients with tuberculosis. Serious adverse events of special interest included 5 patients each with pulmonary embolism and diverticulitis; 2 patients with multiple sclerosis; and 1 patient with hypersensitivity reaction.

HUMIRA has also been studied in 542 patients with early rheumatoid arthritis (disease duration less than three years) who were methotrexate naïve (Study DE013). No new safety signals were seen in this patient population compared to the safety profile seen in HUMIRA Studies DE009, DE011, DE019 and DE031. In this study, deaths occurred in 5 of 542 (0.92%) HUMIRA- treated patients compared to 1 of 257 (0.39%) methotrexate-treated patients. The rate of deaths in both treatment arms is less than expected in the normal population with a standard mortality ratio (SMR) of 0.57 (95% CI, 0.18, 1.32) in the HUMIRA group and 0.22 (95% CI, 0.00, 1.23) in the methotrexate group.

HUMIRA has also been studied in 395 patients with psoriatic arthritis in two placebo- controlled studies and in an open-label extension study, in 393 patients with ankylosing spondylitis in two placebo-controlled studies and in over 1,500 patients with Crohn’s disease in five placebo-controlled and two open-label extension studies. The safety profile for patients with psoriatic arthritis treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with rheumatoid arthritis, HUMIRA Studies DE009, DE011, DE019, DE031 and DE013. During the controlled period of the psoriatic arthritis studies, no deaths occurred in the HUMIRA-treated or placebo-treated patients. During the psoriatic arthritis open-label study, two deaths occurred in 382 patients with 795.7 patient-years of exposure. The rate of deaths is less than expected in the normal population with a standard mortality ratio (SMR) of 0.39 (95% CI, 0.04, 1.43). Among patients enrolled in the psoriasis open-label study, 5 deaths occurred in 1,468 patients with 4,068.6 patient-years of exposure.

HUMIRA has also been studied in 1,010 patients with ulcerative colitis (UC) in two randomized, double-blind, placebo-controlled studies (M06-826, 8 weeks and M06-827, 52 weeks) and an open-label extension study. No new safety signals were seen in the ulcerative colitis patient population. During the controlled period of the ulcerative colitis studies, no deaths occurred in the HUMIRA-treated or placebo-treated patients. In the overall HUMIRA ulcerative colitis development program of 1,010 patients with 2007.4 patient years of exposure (622 patients were treated for >1 year), 2 treatment-emergent deaths occurred during the long- term open-label extension study (cardio-respiratory arrest and right ventricular failure). There were no new safety signals compared to the known safety profile of HUMIRA in the double- blind controlled portion of ulcerative colitis studies.

HUMIRA has also been studied in 727 patients with hidradenitis suppurativa (HS) in three randomized, double-blind, placebo-controlled studies and an open-label extension study. No deaths were reported during the placebo-control periods. In the overall HUMIRA hidradenitis suppurativa development program of 727 patients with 635.7 patient years of exposure (281patients were treated for >1 year), 2 treatment-emergent deaths occurred (cardio-respiratory arrest and autoimmune pancreatitis). No new safety signals were seen in the hidradenitis suppurativa patient population.

Autoantibodies

Patients had serum samples tested for autoantibodies at multiple time points in Studies DE009, DE011, DE019, DE031 and DE013. In those rheumatoid arthritis controlled trials, 11.9% of patients treated with HUMIRA and 8.1% of placebo- or active control-treated patients who had negative baseline antinuclear antibody (ANA) titers, developed positive titers at Week 24. Two patients out of 3441 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

Formation of anti-adalimumab antibodies is associated with increased clearance and reduced efficacy of HUMIRA. There is no apparent correlation between the presence of anti-adalimumab antibodies and adverse events.

Pediatric

In clinical trials with HUMIRA therapy for polyarticular JIA, the proportion of patients achieving PedACR response was lower in anti-adalimumab antibody (AAA)-positive patients compared with AAA-negative patients.

In patients with polyarticular JIA who were 4 to 17 years (Study DE038), anti-adalimumab antibodies were identified in 27/171 subjects (15.8%) treated with HUMIRA. In patients not given concomitant MTX, the incidence was 22/86 (25.6%), compared to 5/85 (5.9%) when HUMIRA was used as add-on to MTX. In patients with polyarticular JIA who were 2 to <4 years of age or 4 years of age and older weighing <15 kg (Study M10-444), anti-adalimumab antibodies were identified in 7% (1/15) of patients, and the one patient was receiving concomitant MTX.

In patients 13 to 17 years of age with severely active Crohn’s disease, anti-adalimumab antibodies were identified in 3.5% (4/114) of patients receiving HUMIRA.

Adult

Rheumatoid arthritis patients in Studies DE009, DE011, and DE019 were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58/1062) 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%). 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 American College of Rheumatology (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 psoriatic arthritis, anti-adalimumab antibodies were identified in 38/376 patients (10%) treated with HUMIRA. In patients not given concomitant methotrexate, the incidence was 13.5% (24/178 patients), compared to 7% (14/198 patients) when HUMIRA was used as add-on to methotrexate.

In patients with ankylosing spondylitis, anti-adalimumab antibodies were identified in 17/204 patients (8.3%) treated with HUMIRA. In patients not given concomitant methotrexate, the incidence was 16/185 (8.6%), compared to 1/19 (5.3%) when HUMIRA was used as add-on to methotrexate.

In patients with Crohn’s disease, anti-adalimumab antibodies were identified in 2.6% (7/269) of patients receiving HUMIRA.

In patients with ulcerative colitis, anti-adalimumab antibodies were identified in 5.0% (19/379) of patients receiving HUMIRA. The clinical significance of this is unknown.

In patients with moderate to severe HS, anti-adalimumab antibodies were identified in 10/99 patients (10.1%) treated with HUMIRA.

In patients with psoriasis, anti-adalimumab antibodies were identified in 77/920 patients (8.4%) treated with HUMIRA monotherapy.

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 mcg/mL. Among these patients whose serum adalimumab levels were < 2 mcg/mL (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In patients with plaque psoriasis on long-term HUMIRA monotherapy who participated in a withdrawal and retreatment study and whose serum adalimumab levels were < 2 mcg/mL (approximately 12% of total patients studied), the immunogenicity rate was 16%; the overall rate of antibody development prior to withdrawal was 1.9%, and 2.3% after retreatment.

The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab in an enzyme-linked immunosorbent assay (ELISA), 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.

Infections

Adults

In controlled trials for rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, ulcerative colitis, hidradenitis suppurativa and psoriasis, the rate of infection was 1.48 per patient-year in the HUMIRA-treated patients and 1.43 per patient-year in the control- treated patients. The infections consisted primarily of nasopharyngitis, upper respiratory tract infection, and sinusitis. Most patients continued on HUMIRA after the infection resolved.

The incidence of serious infections was 0.03 per patient-year in HUMIRA-treated patients and 0.03 per patient-year in placebo and active control-treated patients.

In controlled and open-label studies with HUMIRA, serious infections such as legionellosis (0.0002 per patient-year) have been reported. No cases of listeriosis have been reported and therefore, an estimated rate of 0.0001 per patient year was calculated. Both infections have been reported spontaneously during the post-marketing period.

In controlled and open-label studies with HUMIRA, serious infections (including fatal infections, which occurred rarely) have been reported, which include reports of tuberculosis (including miliary and extra-pulmonary locations) and invasive opportunistic infections (e.g., disseminated histoplasmosis, pneumocystis carinii pneumonia, and aspergillosis). Most of the cases of tuberculosis occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease.

In the double-blind controlled portion of two clinical trials with HUMIRA in patients with UC, serious infections occurred in 4/480 patients treated with adalimumab; they were appendicitis (n=1), anal abscess (n=1), catheter sepsis (n=1) and salmonellosis (n=1). Serious infections occurred in 8 placebo patients. Opportunistic infections occurred in 7/480 patients treated with adalimumab; they were candidiasis (n=3), oesophageal candidiasis (n=1) and oral candidiasis (n=3). Opportunistic infections occurred in 3 placebo patients.

In the double-blind controlled portion of three clinical trials with HUMIRA in patients with HS, serious infections occurred in 4/419 patients treated with adalimumab; they were Escherichia infection (n=1), genital infection bacterial (n=1), infection (n=1), pilonidal cyst (n=1) and pyelonephritis (n=1). Serious infections occurred in 2/366 placebo patients.

Pediatrics

In a controlled trial for polyarticular JIA (Study DE038), the rate of adverse events of infections was 2.38 per patient-year in the HUMIRA-treated JIA patients compared to 2.69 per patient- year in control (placebo) treated patients, and the rate of serious infections was 0.06 per patient- year in the HUMIRA-treated JIA patients compared to 0 events in control (placebo) treated patients.

In an open-label trial for polyarticular JIA (Study M10-444), the rate of adverse events of infections was 2.1 per patient-year while receiving HUMIRA and the rate of serious infections was 0.07 per patient-year while receiving HUMIRA.

In a randomized double-blind trial (M06-806) for the indicated pediatric patient population with Crohn’s disease, the rate of infections was 1.61 per patient-year for the High-Dose group and 2.26 per patient-year for the Low-Dose group. The rates of serious infections were 0.09 per patient-year for the High-Dose group and 0.04 per patient-year for the Low-Dose group. The rates of infections were 55.8% (29/52) and 52.0% (26/50) for High-Dose and Low-Dose groups, respectively. The rates of serious infections were 5.8% (3/52) and 2.0% (1/50) for High-Dose and Low-Dose groups, respectively and included anal abscess, gastroenteritis, and histoplasmosis disseminated in the High-Dose group and Bartholin’s abscess in the Low-Dose group.

Injection Site Reactions

In controlled trials in adults and children, 13% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 7% of patients receiving placebo or active control. Injection site reactions generally did not necessitate discontinuation of the medicinal product.

Malignancies

More cases of malignancy have been observed in HUMIRA-treated patients compared to control-treated patients in clinical trials. See (WARNINGS AND PRECAUTIONS, Malignancies).

Psoriasis: New Onset and Worsening

Cases of new onset psoriasis, including pustular psoriasis and palmoplantar psoriasis, and cases of worsening of pre-existing psoriasis have been reported with the use of TNF-blockers, including HUMIRA. Many of these patients were taking concomitant immunosuppressants (e.g., methotrexate, corticosteroids). Some of these patients required hospitalization. Most patients had improvement of their psoriasis following discontinuation of their TNF-blocker. Some patients have had recurrences of the psoriasis when they were re-challenged with a different TNF-blocker. Discontinuation of HUMIRA should be considered for severe cases and those that do not improve or that worsen despite topical treatments.

Liver Enzyme Elevations

In controlled Phase 3 trials of HUMIRA (40 mg s.c. every other week), in patients with RA and PsA with a control period duration ranging from 4 to 104 weeks, alanine aminotransferase (ALT) elevations ≥ 3 x ULN occurred in 3.7% of HUMIRA-treated patients and 1.6% of control- treated patients. Since many of the 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 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 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 a 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. The incidence of ALT elevations ≥5 x ULN was 0.5% in HUMIRA -treated patients and 0.2% in 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 a 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 Phase 3 trials of HUMIRA (40 mg every other week), in patients with ankylosing spondylitis with a control period of 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 0.7% 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 patients with hidradenitis suppurativa with a control period duration ranging from 12 to 16 weeks, ALT elevations ≥ 3 x ULN occurred in 0.3% of HUMIRA-treated patients and 0.6% of control-treated patients.

Across all adult indications in clinical trials, patients with raised ALT were asymptomatic and in most cases elevations were transient and resolved on continued treatment. However, there have been very rare postmarketing reports of severe hepatic reactions including liver failure as well as less severe liver disorders that may precede liver failure, such as hepatitis including autoimmune hepatitis, in patients receiving TNF blockers, including adalimumab. The causal relationship to adalimumab treatment remains unclear.

Concurrent treatment with azathioprine/6-mercaptopurine

In adult Crohn’s disease studies, higher incidences of malignant and serious infection-related adverse events were seen with the combination of HUMIRA and azathioprine/6-mercaptopurine compared with HUMIRA alone.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Pediatric

Polyarticular Juvenile Idiopathic Arthritis
Table 1. Number and Percentage of Subjects with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Double Blind Placebo-Controlled Phase in the Polyarticular JIA Trial(Study DE038)
System Organ Class
MedDRA 12.1 Preferred Term                                           
MTXNon-MTXOverall
Placebo
N = 37
n(%)  
Adalimumab
N = 38
n(%)
Placebo
N = 28
n(%)  
Adalimumab
N = 30
n(%)
Placebo
N = 65
n(%)
Adalimumab
N = 68
n(%)
Any at least possibly related adverse event17(45.9)22(57.9)9(32.1)16(53.3)26(40.0)38(55.9)
Blood and Lymphatic System Disorders
0

2(5.3)

0

1(3.3)

0

3(4.4)
Leukopenia
Neutropenia
0
0
1(2.6)
1(2.6)
0
0
0
1(3.3)
0
0
1(1.5)
2(2.9)
Ear and Labyrinth Disorders0001(3.3)01(1.5)
Ear pain0001(3.3)01(1.5)
Gastrointestinal Disorders1(2.7)1(2.6)001(1.5)1(1.5)
Gastroduodenitis
Vomiting
1(2.7)
0
0
1(2.6)
0
0
0
0
1(1.5)
0
0
1(1.5)
General Disorders and Administration Site Conditions10(27.0)15(39.5)6(21.4)11(36.7)16(24.6)26(38.2)
Application site reaction
Fatigue
Influenza like illness
Injection site erythema
Injection site haematoma
Injection site hypersensitivity
Injection site pain
Injection site pruritus
Injection site reaction
Pain
Pyrexia
1(2.7)
0
1(2.7)
1(2.7)
0
1(2.7)
7(18.9)
0
1(2.7)
0
0
1(2.6)
0
0
2(5.3)
1(2.6)
0
7(18.4)
1(2.6)
7(18.4)
1(2.6)
2(5.3)
0
0
0
0
0
0
3(10.7)
0
1(3.6)
2(7.1)
0
0
1(3.3)
0
1(3.3)
0
0
9(30.0)
1(3.3)
3(10.0)
2(6.7)
0
1(1.5)
0
1(1.5)
1(1.5)
0
1(1.5)
10(15.4)
0
2(3.1)
2(3.1)
0
1(1.5)
1(1.5)
0
3(4.4)
1(1.5)
0
16(23.5)
2(2.9)
10(14.7)
3(4.4)
2(2.9)
Immune System Disorder01(2.6)01(3.3)02(2.9)
Hypersensitivity01(2.6)01(3.3)02(2.9)
Infections and Infestations7(18.9)10(26.3)3(10.7)6(20.0)10(15.4)16(23.5)
Acute tonsillitis
Bronchitis
Ear infection
Folliculitis
Fungal infection
Herpes simplex
Herpes virus infection
Impetigo
Influenza
Molluscum contagiosum
Oral herpes
Paronychia
Pharyngotonsillitis
Rhinitis
Sinusitis
Staphylococcal skin infection
Upper respiratory tract infection
Urinary tract infection
Viral infection
Viral upper respiratory tract infection
1(2.7)
1(2.7)
0
1(2.7)
0
0
0
0
0
1(2.7)
1(2.7)
0
1(2.7)
0
0
0
2(5.4)
0
1(2.7)

0
1(2.6)
0
1(2.6)
0
0
0
0
1(2.6)
1(2.6)
0
1(2.6)
1(2.6)
0
2(5.3)
1(2.6)
0
3(7.9)
1(2.6)
3(7.9)

0
0
0
0
0
1(3.6)
0
0
0
1(3.6)
0
0
0
0
0
0
1(3.6)
0
0
0

0
0
1(3.3)
1(3.3)
0
0
1(3.3)
1(3.3)
1(3.3)
1(3.3)
0
0
0
1(3.3)
1(3.3)
0
0
2(6.7)
0
0

1(3.3)
1(1.5)
1(1.5)
0
1(1.5)
1(1.5)
0
0
0
1(1.5)
1(1.5)
1(1.5)
0
1(1.5)
0
0
1(1.5)
2(3.1)
0
1(1.5)

0
1(1.5)
1(1.5)
2(2.9)
0
0
1(1.5)
1(1.5)
2(2.9)
2(2.9)
0
1(1.5)
1(1.5)
1(1.5)
3(4.4)
1(1.5)
0
5(7.4)
1(1.5)
3(4.4)

1(1.5)
Injury, Poisoning and Procedural Complications1(2.7)*0*1(3.6) *0*2(3.1) *0*
Excoriation1(2.7)4(10.5)1(3.6)3(10.0)2(3.1)7(10.3)
Injury
Scratch
0
1(2.7)
0
0
1(3.6)
0
0
0
1(1.5)
1(1.5)
0
0
Investigations01(2.6)0001(1.5)
Lymphocyte count increased
Neutrophil count decreased
0
0
1(2.6)
1(2.6)
0
0
0
0
0
0
1(1.5)
1(1.5)
Metabolism and Nutrition Disorders1(2.7)0001(1.5)0
Enzyme abnormality1(2.7)0001(1.5)0
Musculoskeletal and Connective Tissue Disorders3(8.1)1(2.6)01(3.3)3(4.6)2(2.9)
Arthralgia
Groin pain
Juvenile arthritis
Rheumatoid arthritis
0
1(2.7)
1(2.7)
1(2.7)
0
0
1(2.6)
0
0
0
0
0
1(3.3)
0
0
0
0
1(1.5)
1(1.5)
1(1.5)
1(1.5)
0
1(1.5)
0
Nervous System Disorders1(2.7)001(3.3)1(1.5)1(1.5)
Headache1(2.7)001(3.3)1(1.5)1(1.5)
Renal and Urinary Disorders002(7.1)02(3.1)0
Dysuria
Proteinuria
0
0
0
0
1(3.6)
1(3.6)
0
0
1(1.5)
1(1.5)
0
0
Respiratory, Thoracic and Mediastinal Disorders02(5.3)01(3.3)03(4.4)
Asthma
Cough
Epistaxis
0
0
0
1(2.6)
0
1(2.6)
0
0
0
0
1(3.3)
0
0
0
0
1(1.5)
1(1.5)
1(1.5)
Skin and Subcutaneous Tissue Disorders1(2.7)*1(2.6)*01(3.3)*1(1.5)*2(2.9)*
Acne
Dermatitis
Rash
Rash papular
Skin lesion
0
1(2.7)
0
0
0
0
0
1(2.6)
0
1(2.6)
0
0
0
0
0
1(3.3)
0
2(6.7)
1(3.3)
0
0
1(1.5)
0
0
0
1(1.5)
0
3(4.4)
1(1.5)
1(1.5)
* Total only includes values for the terms that were considered possibly or probably related by the investigator.
Term was not considered possibly or probably related as assessed by the investigator; however, these terms were considered more common in patients treated with HUMIRA vs. placebo in the clinical trial.

In Study DE038, HUMIRA was studied in 171 patients aged 4 to 17 years with polyarticular JIA. Serious adverse events were observed in 28% of patients treated with HUMIRA and included neutropenia, streptococcal pharyngitis, increased aminotranferases, herpes zoster, myositis, metrorrhagia and appendicitis. Serious infections were observed in 6.4% of patients treated with HUMIRA and included cases of herpes zoster, appendicitis, pneumonia, urinary tract infection, streptococcal pharyngitis, viral infection and cervicitis. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment (see WARNINGS AND PRECAUTIONS, Infections). Granuloma annulare was reported in two patients (see WARNINGS AND PRECAUTIONS, Malignancies).

During the double-blind phase of Study DE038, the most common (≥ 5%) adverse reactions occurring in the JIA population treated with HUMIRA were viral infection (18%), injection site pain (18%), upper respiratory tract infection (16%), injection site reaction (15%), contusion (13%), excoriation (10%), rhinitis (7%), vomiting (6%) and drug hypersensitivity (6%).

Throughout Study DE038, 6% of children had mild to moderate allergic reaction adverse events primarily localized allergic hypersensitivity reactions and urticaria (see WARNINGS AND PRECAUTIONS, Hypersensitivity Reactions).

In the JIA trial, 10% of patients treated with HUMIRA who were negative at baseline for anti- double-stranded DNA antibodies developed positive titers after 48 weeks of treatment (see ADVERSE REACTIONS, Adverse Drug Reaction Overview, Immunogenicity, Pediatric).

In Study M10-444, 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 Study DE038.

In Study M10-444, 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 M10-444, non-serious allergic reactions were observed in 6% of patients and included intermittent urticaria and rash, which were all mild in severity.

Pediatric Crohn’s Disease

Table 2 summarizes adverse drug reactions reported in Study M06-806 at a rate of at least 1% in the indicated pediatric patient population with Crohn’s disease treated with HUMIRA.

Table 2. Number and Percentage of Patients with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug With Double-Blind Every Other Week Dosing in the Pediatric Crohn’s Disease Study (Study M06-806)
System Organ Class (SOC)High-Dose
40 mg eow
N = 52
n (%)
Low-Dose
20 mg eow
N = 50
n (%)
Blood and Lymphatic System Disorders3 (5.8)1 (2.0)
Leukopenia
Lymphadenitis
Neutropenia
Thrombocytosis
2 (3.8)
1 (1.9)
1 (1.9)
0
0
0
0
1 (2.0)
Eye Disorders1 (1.9)1 (2.0)
Conjunctivitis
Vision blurred
0
1 (1.9)
1 (2.0)
0
Gastrointestinal Disorders2 (3.8)3 (6.0)
Abdominal pain
Crohn's disease
Diarrhoea
Nausea
Pancreatitis acute
0
0
1 (1.9)
1 (1.9)
0
1 (2.0)
1 (2.0)
0
0
1 (2.0)
General Disorders and
Administration Site Conditions
10 (19.2)7 (14.0)
Injection site erythema
Injection site pain
Injection site pruritus
Injection site rash
Injection site reaction
Injection site swelling
Injection site warmth
Nodule
Pain
Pyrexia
Suprapubic pain
1 (1.9)
2 (3.8)
0
0
4 (7.7)
0
0
1 (1.9)
1 (1.9)
2 (3.8)
0
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
2 (4.0)
1 (2.0)
1 (2.0)
0
0
1 (2.0)
1 (2.0)
Infections and Infestations6 (11.5)11 (22.0)
Acute tonsillitis
Bartholin's abscess
Cellulitis pharyngeal
Folliculitis
Fungal infection
Histoplasmosis disseminated
Nasopharyngitis
Oral candidiasis
Otitis externa
Otitis media
Pertussis
Pharyngitis
Pharyngitis streptococcal
Staphylococcal infection
Upper respiratory tract infection
Urinary tract infection
Viral pharyngitis
Viral upper respiratory tract infection
Vulvovaginal mycotic infection
0
0
0
1 (1.9)
0
1 (1.9)
1 (1.9)
1 (1.9)
0
0
0
1 (1.9)
0
0
0
1 (1.9)
0
2 (3.8)
1 (1.9)
1 (2.0)
1 (2.0)
1 (2.0)
0
1 (2.0)
0
1 (2.0)
0
1 (2.0)
1 (2.0)
1 (2.0)
0
3 (6.0)
1 (2.0)
2 (4.0)
0
1 (2.0)
2 (4.0)
1 (2.0)
Injury, Poisoning and Procedural
Complications
1 (1.9)0
Contusion1 (1.9)0
Investigations4 (7.7)3 (6.0)
Alanine aminotransferase increased
Antinuclear antibody positive
Aspartate aminotransferase increased
Hepatic enzyme increased
White blood cell count decreased
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
0
2 (4.0)
0
0
0
1 (2.0)
Metabolism and Nutrition Disorders01 (2.0)
Hypertriglyceridaemia01 (2.0)
Musculoskeletal and Connective
Tissue Disorders
3 (5.8)1 (2.0)
Arthralgia
Arthritis
Muscle spasms
Scoliosis
1 (1.9)
1 (1.9)
0
1 (1.9)
0
0
1 (2.0)
0
Neoplasms Benign, Malignant and
Unspecified (including cysts and
polyps)
2 (3.8)1 (2.0)
Skin papilloma2 (3.8)1 (2.0)
Nervous System Disorders2 (3.8)4 (8.0)
Headache
Hypoaesthesia
Paraesthesia
Restless legs syndrome
2 (3.8)
0
1 (1.9)
0
1 (2.0)
1 (2.0)
1 (2.0)
1 (2.0)
Respiratory, Thoracic and
Mediastinal Disorders
5 (9.6)2 (4.0)
Asthma
Cough
Dyspnoea
Oropharyngeal pain
Rhinorrhoea
Sinus congestion
1 (1.9)
4 (7.7)
1 (1.9)
3 (5.8)
0
1 (1.9)
0
1 (2.0)
0
1 (2.0)
1 (2.0)
0
Skin and Subcutaneous Tissue
Disorders
8 (15.4)2 (4.0)
Acne
Alopecia
Dry skin
Erythema
Ingrowing nail
Leukoplakia
Photosensitivity allergic reaction
Post inflammatory pigmentation change
Psoriasis
Rash
Rash erythematous
Rash papular
Skin fissures
Skin reaction
Urticaria
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
2 (3.8)
1 (1.9)
1 (1.9)
0
1 (1.9)
0
0
0
0
0
0
0
0
0
1 (2.0)
0
0
0
1 (2.0)
0

All treatment-emergent serious adverse events were observed in 21% (11/52) of patients receiving High-Dose and 20% (10/50) of patients receiving Low-Dose. Serious infections were observed in 6% (3/52) of patients receiving High-Dose and 2% (1/50) of patients receiving Low-Dose. The serious adverse events in the High-Dose group included anaemia, Crohn’s disease, anal abscess, gastroenteritis, and histoplasmosis disseminated. The serious adverse events in the Low-Dose group included Crohn’s disease, pancreatitis acute, Bartholin’s abscess, and facial bones fracture.

A total of 56% (29/52) of patients receiving High-Dose and 52% (26/50) of patients receiving Low-Dose experienced an infection (see also WARNINGS AND PRECAUTIONS, Infections). Overall adverse events were observed in 96% (50/52) of patients receiving High-Dose and 86% (43/50) of patients receiving Low-Dose.

Adult

Rheumatoid Arthritis
Description of Data Sources

The data described below reflect exposure to HUMIRA in 3,046 patients, including more than 2,000 patients exposed for six months, and more than 1,500 exposed for more than one year (Studies DE009, DE011, DE019, DE031 and DE013). HUMIRA was studied in placebo- controlled trials and in long-term follow-up studies for up to 60 months duration in patients with moderately to severely active rheumatoid arthritis who had failed previous DMARD therapy; the mean age was 54 years, 77% were female and 91% Caucasian (Studies DE009, DE011, DE019, DE031). A further study (Study DE013) was in patients with recently diagnosed rheumatoid arthritis who had not previously been treated with methotrexate. Most patients received HUMIRA 40 mg every other week.

Relative Frequency of Adverse Drug Reactions

Table 3 summarizes adverse drug reactions reported at a rate of at least 1% in patients treated with HUMIRA 40 mg every other week, as well as all doses of HUMIRA tested, compared to placebo or methotrexate (Study DE013). Adverse reaction rates in patients treated with HUMIRA 40 mg weekly were similar to rates in patients treated with HUMIRA every other week. In Study DE019, the types and frequencies of adverse drug reactions in the 10-year open-label extension were similar to those observed in the one-year double-blind portion.

Table 3. Number and Percentage of Patients with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Control Period in Rheumatoid Arthritis Studies (Studies DE009, DE011, DE019, DE031, DE013)
System Organ Class (SOC)HUMIRA
40 mg s.c. eow
N = 1247
n (%)
HUMIRA
(all adalimumab)
N = 1922
n (%)
Placebo
(not Study DE013)
N = 690
n (%)
MTX
(Study DE013)
N = 257
n (%)
Gastrointestinal Disorders
Nausea
Diarrhea
Abdominal pain
Abdominal pain upper
Mouth ulceration
Dyspepsia
Vomiting
80(6.4)
47(3.8)
22(1.8)
20(1.6)
17(1.4)
14(1.1)
16(1.3)
112 (5.8)
60(3.1)
29(1.5)
25(1.3)
24 (1.2)
21(1.1)
20(1.0)
12(1.7)
17(2.5)
5(0.7)
0(0.0)
5 (0.7)
4(0.6)
5(0.7)
33 (12.8)
18(7.0)
3(1.2)
13(5.1)
12 (4.7)
7(2.7)
6(2.3)
General Disorders and Administration Site Conditions
Injection site irritation
Injection site reaction
Injection site pain
Injection site erythema
Fatigue
Injection site rash
Influenza-like illness
Pyrexia
74(5.9)
49(3.9)
36(2.9)
36(2.9)
37(3.0)
17(1.4)
15(1.2)
13(1.0)
122(6.3)
67(3.5)
63(3.3)
60(3.1)
58(3.0)
22(1.1)
21(1.1)
20(1.0)
61(8.8)
3(0.4)
24(3.5)
2(0.3)
7(1.0)
2(0.3)
2(0.3)
1(0.1)
3(1.2)
2(0.8)
6(2.3)
1(0.4)
9(3.5)
0(0.0)
8(3.1)
6(2.3)
Infections and Infestations
Nasopharyngitis
Upper respiratory infection
Sinusitis
Herpes simplex
Urinary tract infection
Bronchitis
Herpes zoster
Influenza
Pneumonia
61(4.9)
72(5.8)
46(3.7)
33(2.6)
31(2.5)
19(1.5)
17(1.4)
16(1.3)
17(1.4)
95(4.9)
93(4.8)
55(2.9)
48(2.5)
44(2.3)
29(1.5)
23(1.2)
21(1.1)
21(1.1)
10(1.5)
15(2.2)
17(2.5)
6(0.9)
6(0.9)
8(1.2)
8(1.2)
7(1.0)
3(0.4)
28(10.9)
17(6.6)
4(1.6)
5(1.9)
7(2.7)
9(3.5)
2(0.8)
5(1.9)
1(0.4)
Investigations
Lymphocyte count decreased
Alanine aminotransferase increased
Liver function test abnormal

11(0.9)

27(2.2)
19(1.5)

38(2.0)

33(1.7)
22(1.1)

11(1.6)

4(0.6)
4(0.6)

1(0.4)

9(3.5)
7(2.7)
Musculoskeletal and Connective Tissue Disorders
Rheumatoid arthritis11(0.9)28(1.5)7(1.0)2(0.8)
Nervous System Disorders
Headache
Dizziness
75(6.0)
23(1.8)
124(6.5)
32(1.7)
14(2.0)
6(0.9)
14(5.4)
3(1.2)
Respiratory, Thoracic and Mediastinal Disorders
Pharyngolaryngeal pain
Cough
33(2.6)
31(2.5)
44(2.3)
42(2.2)
9(1.3)
4(0.6)
7(2.7)
9(3.5)
Skin and Subcutaneous Tissue Disorders
Rash
Pruritus
Alopecia
Rash pruritic
44(3.5)
28(2.2)
22(1.8)
14(1.1)
66(3.4)
43(2.2)
28(1.5)
22(1.1)
9(1.3)
4(0.6)
2(0.3)
0(0.0)
8(3.1)
5(1.9)
6(2.3)
3(1.2)
Definition(s): s.c. = subcutaneous ; eow = every other week

Psoriatic Arthritis

Table 4 summarizes adverse drug reactions reported in placebo-controlled and open-label studies at a rate of at least 1% in psoriatic arthritis patients treated with HUMIRA 40 mg every other week.

Table 4. Number and Percentage of Patients with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Control and Open-Label Periods in Psoriatic Arthritis Studies (Studies M02-518, M02-570, and M02-537)
Double-Blind StudyOpen-Label Study
System Organ Class (SOC)Placebo
N = 211
n (%)
HUMIRA
40 mg s.c. eow
N = 202
n (%)
HUMIRA
40 mg s.c. eow
N = 382
n (%)
Gastrointestinal Disorders
Nausea2 (0.9)2 (1.0)3 (0.8)
General Disorders and Administration Site Conditions
Injection site reaction
Injection site pain
Injection site erythema
Injection site burning
Fatigue
5(2.4)
8(3.8)
0(0.0)
4(1.9)
5 (2.4)
11(5.4)
8(4.0)
4(2.0)
4(2.0)
0 (0.0)
21 (5.5)
2 (0.5)
2 (0.5)
4 (1.0)
4 (1.0)
Infections and Infestations
Upper respiratory infection
Herpes simplex
Skin fungal infection NOS
Pharyngitis
Sinusitis
Urinary tract infection
Bronchitis
Nasopharyngitis
Influenza
7(3.3)
3 (1.4)
0(0.0)
1 (0.5)
4 (1.9)
0 (0.0)
1 (0.5)
2 (0.9)
2 (0.9)
8(4.0)
6(3.0)
3(1.5)
2 (1.0)
2 (1.0)
2 (1.0)
1 (0.5)
1 (0.5)
0 (0.0)
17 (4.5)
7 (1.8)
-
4 (1.0)
12 (3.1)
6 (1.6)
5 (1.3)
8 (2.1)
5 (1.3)
Investigations
Liver function tests abnormal1 (0.5)2 (1.0)5 (1.3)
Nervous System Disorders
Headache
Paresthesia
5(2.4)
1(0.5)
5(2.5)
3(1.5)
5 (1.3)
2 (0.5)
Respiratory, Thoracic, and Mediastinal Disorders
Rhinitis NOS0 (0.0)3 (1.5)3 (0.8)
Skin and Subcutaneous Tissue Disorders
Erythema0(0.0)3(1.5)-
Definition(s): s.c. = subcutaneous; eow = every other week

Ankylosing Spondylitis

HUMIRA has been studied in 393 patients with ankylosing spondylitis in two placebo-controlled studies. The safety profile for patients with ankylosing spondylitis treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with rheumatoid arthritis, HUMIRA Studies DE009, DE011, DE019, and DE031. Table 5 summarizes adverse drug reactions reported at a rate of at least 1% in ankylosing spondylitis patients treated with HUMIRA 40 mg every other week compared to placebo.

Table 5. Number and Percentage of Patients with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Control Period in Ankylosing Spondylitis Studies (Studies M03-607 and M03-606)
System Organ Class (SOC)HUMIRA 40 mg s.c. eow
N = 246
n (%)
Placebo
N = 151
n (%)
General Disorders and Administration Site Conditions
Fatigue
Injection site erythema
Injection site irritation
Injection site pain
Injection site reaction
5(2.0)
5(2.0)
4(1.6)
6(2.4)
8(3.3)
3(2.0)
1(0.7)
2(1.3)
3(2.0)
1(0.7)
Infections and Infestations
Nasopharyngitis
Upper respiratory tract infection
8(3.3)
5(2.0)
0(0.0)
2(1.3)
Nervous System Disorders
Dizziness
Headache
3(1.2)
11(4.5)
3(2.0)
4(2.6)
Skin and Subcutaneous Tissue Disorders
Eczema
Pruritus
Pruritus generalized
Rash
Urticaria
3(1.2)
4(1.6)
3(1.2)
4(1.6)
3(1.2)
1(0.7)
1(0.7)
0(0.0)
1(0.7)
0(0.0)
Definition(s): s.c. = subcutaneous; eow = every other week

Crohn’s Disease
HUMIRA has been studied in over 1,500 patients with Crohn’s disease in five 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 including the safety profile for patients in placebo-controlled Study M05-769. No new safety signals occurred during the open-label long-term studies with HUMIRA exposure up to five years. The safety profile of HUMIRA in Crohn’s disease remains unaltered.

Table 6 and Table 7 summarize adverse drug reactions reported at a rate of at least 1% in Crohn’s disease patients treated with HUMIRA in induction and maintenance studies, respectively.

Table 6. Number and Percentage of Patients with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During Administration of Induction Study Medications in Crohn’s Disease Studies (Studies M02-403 and M04-691)
System Organ Class (SOC)HUMIRA 160/80 mg
N = 235
n (%)
HUMIRA 80/40 mg
N = 75
n (%)
Placebo
N = 240
n (%)
Eye Disorders
Corneal pigmentation
Visual disturbance
0 (0.0)
0 (0.0)
1(1.3)
1(1.3)
0 (0.0)
0 (0.0)
Gastrointestinal Disorders
Abdominal pain
Abdominal pain lower
Change of bowel habit
Cheilitis
Constipation
Crohn's disease
Flatulence
Nausea
Vomiting
5(2.1)
3(1.3)
0 (0.0)
0 (0.0)
2(0.9)
2(0.9)
3(1.3)
6(2.6)
1(0.4)
0 (0.0)
0 (0.0)
1(1.3)
1(1.3)
1(1.3)
1(1.3)
0 (0.0)
0 (0.0)
1(1.3)
2(0.8)
0 (0.0)
0 (0.0)
1(0.4)
3(1.3)
3(1.3)
0 (0.0)
4(1.7)
3(1.3)
General Disorders and Administration Site Conditions
Asthenia
Chills
Fatigue
Influenza like illness
Injection site bruising
Injection site erythema
Injection site irritation
Injection site pain
Injection site pruritus
Injection site reaction
Pain
Pyrexia
0 (0.0)
0 (0.0)
2(0.9)
0 (0.0)
5(2.1)
4(1.7)
19(8.1)
6(2.6)
3(1.3)
11(4.7)
2(0.9)
3(1.3)
1(1.3)
2(2.7)
1(1.3)
2(2.7)
1(1.3)
0 (0.0)
8(10.7)
4(5.3)
0 (0.0)
5(6.7)
1(1.3)
3(1.3)
1(0.4)
1(0.4)
10(4.2)
2(0.8)
1(0.4)
0 (0.0)
14(5.8)
9(3.8)
0 (0.0)
6(2.5)
3(1.3)
3(1.3)
Infections and Infestations
Staphylococcal infection0 (0.0)0 (0.0)0 (0.0)
Investigations
Double stranded DNA antibody
White blood cell count increased
0 (0.0)
0 (0.0)
1(1.3)
1(1.3)
0 (0.0)
0 (0.0)
Metabolism and Nutrition Disorders
Hypokalemia0 (0.0)1(1.3)0 (0.0)
Musculoskeletal and Connective Tissue Disorders
Arthralgia
Back pain
Muscle spasms
Pain in extremity
3(1.3)
0 (0.0)
0 (0.0)
0 (0.0)
1(1.3)
1(1.3)
1(1.3)
1(1.3)
2(0.8)
0 (0.0)
1(0.4)
0 (0.0)
Nervous System Disorders
Dizziness
Headache
Restless legs syndrome
3(1.3)
8(3.4)
0 (0.0)
0 (0.0)
2(2.7)
1(1.3)
2(0.8)
7(2.9)
0 (0.0)
Reproductive System and Breast Disorders
Genital pruritus female0 (0.0)1(1.3)0 (0.0)
Skin and Subcutaneous Tissue Disorders
Eczema
Erythema
Hyperhidrosis
Onychorrhexis
Pruritus
Rash
Rash maculo-papular
Rash pruritic
1(0.4)
1(0.4)
0 (0.0)
0 (0.0)
1(0.4)
2(0.9)
1(0.4)
0 (0.0)
1(1.3)
1(1.3)
1(1.3)
1(1.3)
0 (0.0)
2(2.7)
1(1.3)
1(1.3)
0 (0.0)
1(0.4)
0 (0.0)
0 (0.0)
4(1.7)
1(0.4)
0 (0.0)
1(0.4)

Table 7. Number and Percentage of Patients with ≥ 1% Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During Administration of Blinded Study Maintenance Medications in Crohn’s Disease Studies (Studies M02-404 and M02-433)
System Organ Class (SOC)HUMIRA
40 mg s.c. eow, 40 mg ew
N = 554
n (%)
Placebo
N = 279
n (%)
Gastrointestinal Disorders
Abdominal pain
Crohn's disease
Diarrhea
Nausea
7(1.3)
9(1.6)
7(1.3)
9(1.6)
4(1.4)
9(3.2)
1(0.4)
5(1.8)
General Disorders and Administration Site Conditions
Fatigue
Injection site bruising
Injection site erythema
Injection site irritation
Injection site pain
Injection site reaction
Pyrexia
10(1.8)
6(1.1)
10(1.8)
18(3.2)
8(1.4)
26(4.7)
7(1.3)
1(0.4)
1(0.4)
0(0.0)
2(0.7)
2(0.7)
1(0.4)
5(1.8)
Infections and Infestations
Herpes simplex
Nasopharyngitis
Rhinitis
6(1.1)
8(1.4)
7(1.3)
4(1.4)
2(0.7)
1(0.4)
Musculoskeletal and Connective Tissue Disorders
Arthralgia9(1.6)2(0.7)
NervousSystem Disorders
Headache19(3.4)6(2.2)
Skin and Subcutaneous Tissue Disorders
Rash11(2.0)5(1.8)
Definition(s): s.c. = subcutaneous; ew = every week; eow = every other week

Ulcerative Colitis

HUMIRA has been studied in 1,010 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 observed in patients with Crohn’s Disease.

Table 8 and Table 9 summarize adverse drug reactions reported at a rate of at least 1% in ulcerative colitis disease patients treated with HUMIRA during induction and maintenance periods, respectively.

Table 8. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During Administration of Induction Study Medications in Ulcerative Colitis Studies (Studies M06-826 and M06-827)
System Organ Class (SOC)HUMIRA 160/80 mg
N = 480
n (%)
HUMIRA 80/40 mg
N = 130
n (%)
Placebo
N = 483
n (%)
Gastrointestinal Disorders17 (3.5)7 (5.4)27 (5.6)
Abdominal pain
Colitis Ulcerative
Nausea
0 (0.0)
7 (1.5)
6 (1.3)
2 (1.5)
2 (1.5)
1 (0.8)
2 (0.4)
8 (1.7)
7 (1.4)
General Disorders and
Administration Site Conditions
44 (9.2)8 (6.2)34 (7.0)
Fatigue
Influenza like illness
Injection site erythema
Injection Site Haematoma
Injection site pain
Injection site pruritus
Injection site reaction
Pyrexia
9 (1.9)
1 (0.2)
8 (1.7)
2 (0.4)
11 (2.3)
6 (1.3)
5 (1.0)
3 (0.6)
1 (0.8)
1 (0.8)
1 (0.8)
2 (1.5)
2 (1.5)
1 (0.8)
1 (0.8)
1 (0.8)
7 (1.4)
5 (1.0)
2 (0.4)
0 (0.0)
11 (2.3)
1 (0.2)
2 (0.4)
7 (1.4)
Infections and Infestations19 (4.0)7 (5.4)24 (5.0)
Herpes simplex
Nasopharyngitis
Oral herpes
0 (0.0)
5 (1.0)
2 (0.4)
2 (1.5)
1 (0.8)
2 (1.5)
0 (0.0)
4 (0.8)
2 (0.4)
Nervous System Disorders14 (2.9)2 (1.5)25 (5.2)
Headache7 (1.5)2 (1.5)20 (4.1)
Pyschiatric Disorders1 (0.2)2 (1.5)4 (0.8)
Anxiety0 (0.0)2 (1.5)0 (0.0)
Skin and Subcutaneous Tissue
Disorders
19 (4.0)8 (6.2)17 (3.5)
Erythema
Rash
5 (1.0)
2(0.4)
2(1.5)
2(3.1)
1(0.2)
1(0.2)

Table 9. Number and Percentage of Subjects ≥ 1% Reporting Treatment-Emergent Adverse Events at Least Possibly Related to Study Drug During the Double-blind Induction and Maintenance Periods of Ulcerative Colitis Studies (Studies M06-826 and M06-827)
System Organ Class (SOC)HUMIRA 160/80 mg
N = 480
n (%)
Placebo
N = 483
n (%)
Gastrointestinal Disorders31 (6.5)36 (7.5)
Colitis ulcerative
Nausea
12 (2.5)
9 (1.9)
14 (2.9)
9 (1.9)
General Disorders And Administration
Site Conditions
64 (13.3)38 (7.9)
Fatigue
Influenza like illness
Injection site erythema
Injection site pain
Injection site pruritus
Injection site reaction
Injection site swelling
Malaise
Oedema peripheral
Pyrexia
10 (2.1)
3 (0.6)
15 (3.1)
11 (2.3)
9 (1.9)
11 (2.3)
5 (1.0)
5 (1.0)
5 (1.0)
3 (0.6)
8 (1.7)
5 (1.0)
3 (0.6)
12 (2.5)
2 (0.4)
2 (0.4)
0 (0.0)
2 (0.4)
1 (0.2)
9 (1.9)
Infections And Infestations40 (8.3)42 (8.7)
Influenza
Nasopharyngitis
Upper respiratory tract infection
0 (0.0)
9 (1.9)
5 (1.0)
5 (1.0)
7 (1.4)
7 (1.4)
Musculoskeletal And Connective Tissue
Disorders
12 (2.5)12 (2.5)
Arthralgia5 (1.0)4 (0.8)
Nervous System Disorders19 (4.0)28 (5.8)
Headache10 (2.1)22 (4.6)
Skin And Subcutaneous Tissue Disorders38 (7.9)29 (6.0)
Erythema
Pruritus
Rash
6 (1.3)
5 (1.0)
7 (1.5)
2 (0.4)
5 (1.0)
5 (1.0)

Serious adverse events resulting in hospitalizations were reported by 18% (67/379) in the HUMIRA-treated patients compared to 26% (56/214) in the placebo group adjusted for patient years at risk.

During the double-blind controlled clinical trials, the most common (≥5%) adverse drug reactions in subjects receiving HUMIRA 160/80 during induction were ulcerative colitis (n=35, 7.3%) and nasopharyngitis (n=26, 5.4%), and during maintenance were ulcerative colitis (n=38, 16.2 %), nasopharyngitis (n=26, 11.1%), abdominal pain (n=17, 7.3%), and arthralgia (n=17, 7.3%). There were 2/480 HUMIRA- treated patients who experienced severe leukopenia of which one case was serious. The patient with serious leukopenia, which was considered secondary to 6-MP, had an associated viral infection.

During the double-blind controlled clinical trials, the most common serious adverse event occurring in > 1 patient more often in the HUMIRA-treated patients compared to placebo when adjusted for exposure was deep vein thrombosis reported in 2 patients (4%, 1.12 events/100 patient-years).

During the double-blind controlled clinical trials, severe adverse events reported in > 1 patient occurring more often in the HUMIRA-treated patients compared to placebo when adjusted for exposure were deep vein thrombosis reported in 3 patients (0.6%, 1.68 events/100 patient-years), and constipation, leukopenia and fatigue, which were reported in 2 patients (0.4%, 1.12 events/100 patients-years).

The most common adverse event associated with discontinuation reported in > 1 subject during induction and maintenance was ulcerative colitis [n=18 (3.8%) and n=8 (3.4%), respectively].

Hidradenitis Suppurativa

HUMIRA has been studied in 727 patients with hidradenitis suppurativa in three placebo-controlled studies and one open-label extension study.

Table 10 summarizes adverse drug reactions reported at a rate of at least 1% in hidradenitis suppurativa patients treated with HUMIRA during the placebo-controlled portion of the studies.

Table 11. Number and Percentage of Patients > 1% Reporting Treatment-Emergent Adverse Events Possibly or Probably Related to Study Drug in Controlled Psoriasis Studies (Studies M03-656, M04-716 and M02-528)
System Organ Class (SOC)HUMIRA 40 mg
Every other week
N = 52
n (%)
HUMIRA 40 mg
weekly
N = 367
n (%)
Placebo
N = 366
n (%)
Eye Disorders
Cataract
Conjunctivitis
Vision blurred
1 (1.9)
1 (1.9)
1 (1.9)
0 (0.0)
0 (0.0)
1 (0.3)
0 (0.0)
0 (0.0)
0 (0.0)
Gastrointestinal Disorders
Abdominal pain
Abdominal pain upper
Diarrhoea
Nausea
Vomiting
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (0.3)
0 (0.0)
8 (2.2)
6 (1.6)
3 (0.8)
0 (0.0)
0 (0.0)
3 (0.8)
8 (2.2)
3 (0.8)
General Disorders and Administration Site Conditions
Asthenia
Chills
Fatigue
Injection site erythema
Injection site pain
Injection site pruritus
Injection site reaction
Oedema
Pain
Pyrexia
0 (0.0)
1 (1.9)
1 (1.9)
0 (0.0)
0 (0.0)
0 (0.0)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (0.3)
0 (0.0)
4 (1.1)
5 (1.4)
6 (1.6)
5 (1.4)
3 (0.8)
0 (0.0)
0 (0.0)
1 (0.3)
5 (1.4)
1 (0.3)
4 (1.1)
0 (0.0)
6 (1.6)
0 (0.0)
1 (0.3)
0 (0.0)
0 (0.0)
1 (0.3)
Infections and Infestations
Bronchitis
Cellulitis
Gastroeneritis
Herpes simplex
Localised infection
Nasopharyngitis
Pneumonia
Skin bacterial infection
Tooth abscess
Upper respiratory tract infection
Urinary tract infection
Vaginal infection
0 (0.0)
0 (0.0)
1 (1.9)
2 (3.8)
1 (1.9)
3 (5.8)
1 (1.9)
1 (1.9)
1 (1.9)
3 (5.8)
0 (0.0)
1 (1.9)
2 (0.5)
0 (0.0)
2 (0.5)
0 (0.0)
1 (0.3)
11 (3.0)
0 (0.0)
0 (0.0)
0 (0.0)
7 (1.9)
3 (0.8)
0 (0.0)
5 (1.4)
4 (1.1)
0 (0.0)
1 (0.3)
0 (0.0)
9 (2.5)
3 (0.8)
0 (0.0)
0 (0.0)
6 (1.6)
4 (1.1)
0 (0.0)
Musculoskeletal and Connective Tissue Disorders
Arthralgia
Pain in extremity
0 (0.0)
1 (1.9)
5 (1.4)
0 (0.0)
0 (0.0)
0 (0.0)
Nervous System Disorders
Dizziness
Dysgeusia
Headache
1 (1.9)
1 (1.9)
4 (7.7)
6 (1.6)
2 (0.5)
17 (4.6)
1 (0.3)
0 (0.0)
11 (3.0)
Respiratory, Thoracic and Mediastinal Disorders
Cough
Dyspnea
Interstitial lung disease
Nasal congestion
Oropharyngeal pain
Sneezing
0 (0.0)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
1 (1.9)
4 (1.1)
1 (0.3)
0 (0.0)
0 (0.0)
1 (0.3)
0 (0.0)
2 (0.5)
1 (0.3)
0 (0.0)
0 (0.0)
0 (0.0)
0 (0.0)
Skin and Subcutaneous Tissue Disorders
Hidradenitis
Pruritus
Pruritus generalised
2 (3.8)
2 (3.8)
1 (1.9)
11 (3.0)
2 (0.5)
0 (0.0)
16 (4.4)
1 (0.3)
0 (0.0)

Other Common Clinical Trial Adverse Drug Reactions

Other clinical trial adverse reactions occurring at an incidence of ≥ 1% that were observed among the various indications include:

Eye Disorders:conjunctivitis, visual impairment
Renal and Urinary Disorders:hematuria, renal impairment

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

Infrequent serious adverse drug reactions occurring at an incidence of less than 1% in patients treated with HUMIRA in RA Studies DE009, DE011, DE019, DE031 and DE013, JIA Study DE038, PsA Studies M02-518 and M02-570, AS Studies M03-607 and M03-606, CD Maintenance Studies M02-404 and M02-433, UC Studies M06-826 and M06-827, HS Studies M10-467, M11-313 and M11-810 and Ps Studies M03-656, M04-716, and M02-528:

Blood and Lymphatic System Disorders:agranulocytosis, anemia, eosinophilia, leukopenia, lymphadenopathy, lymphocytosis, neutropenia, pancytopenia
Cardiac Disorders:arrhythmia superventricular, cardiac arrest, chest pain, palpitations
Eye Disorders:blepharitis, diplopia, eye swelling
Gastrointestinal Disorders:abdominal pain, anal fistula, Crohn's disease, frequent bowel movements, hematochezia, hemorrhoidal hemorrhage, pancreatitis, rectal hemorrhage, small intestine obstruction
General Disorders and Administration Site Conditions:death, non-cardiac chest pain, pyrexia
Hepatobiliary Disorders:hepatic necrosis
Immune System Disorders:hypersensitivity
Infections and Infestations:abscess, abscess limb, arthritis bacterial, bronchitis, bronchopneumonia, cellulitis, cystitis, device-related infection, diverticulitis, erysipelas, escherichia sepsis, gastroenteritis, genital herpes, herpes virus infection, herpes zoster, histoplasmosis, infected skin ulcer, infection, lobar pneumonia, lower respiratory tract infection, meningitis viral, mycobacterium avium complex infection, necrotizing fasciitis, perianal abscess, pharyngitis, pneumonia, pneumonia pneumococcal, pyelonephritis, respiratory tract infection, sepsis, septic shock, sinusitis, tuberculosis, urinary tract infection, urosepsis, viral infection, wound infection
Injury, Poisoning and Procedural Complications:postoperative wound complication
Investigations:double-stranded DNA antibody, hepatic enzyme increased
Metabolism and Nutrition Disorders:hyperglycemia*
Musculoskeletal and Connective Tissue Disorders:arthritis, arthropathy, back pain, muscular weakness, musculoskeletal chest pain, osteitis, rheumatoid arthritis, systemic lupus erythematosus
Neoplasms Benign, Malignant and Unspecified (Including Cysts and Polyps):basal cell carcinoma, B-cell lymphoma, breast cancer, malignant melanoma in situ, metastases to liver, ovarian cancer, squamous cell carcinoma, testicular seminoma (pure)
Nervous System Disorders:clonus, hyperreflexia, hydrocephalus, hypertensive encephalopathy, intention tremor, multiple sclerosis, paresthesia, tremor, neuropathy
Pregnancy, Puerperium and Perinatal Conditions:abortion spontaneous
Psychiatric Disorders:confusional state
Renal and Urinary Disorders:nocturia
Reproductive System and Breast Disorders:cervical dysplasia, endometrial hyperplasia
Respiratory, Thoracic and Mediastinal Disorders:psoriasis, pustular psoriasis, rash bronchospasm, lung infiltration, pleural effusion, pleurisy, pneumonitis, respiratory failure
Skin and Subcutaneous Tissue Disorders:psoriasis, pustular psoriasis, rash
Surgical and Medical Procedures:arthrodesis
Vascular Disorders:circulatory collapse, rheumatoid vasculitis

*Hyperglycemia ADR in trials were nonserious

Abnormal Hematologic and Clinical Chemistry Findings

There are no known laboratory tests that may be helpful in following the patient’s response or in identifying possible adverse reactions.

Pediatric

In the polyarticular juvenile idiopathic arthritis trial (Study DE038), 10/171 (5.8%) and 5/171 (2.9%) of children treated with HUMIRA developed severe elevations of ALT and aspartate aminotransferase (AST) (exceeding > 3 times the upper limit of normal [ULN] of ALT and AST, respectively). Forty two (42)/171 (25%) developed elevations of creatine phosphokinase (CPK); with 10/171 (5.8%) children with severe elevations.

Liver enzyme elevations were more frequent among those treated with the combination of HUMIRA and MTX than treated with HUMIRA alone (ALT: 9.5% vs. 2.3%; AST: 5.9% vs.0%).

No ALT or AST elevations ≥ 3 x ULN occurred in the open-label study of HUMIRA in patients with polyarticular JIA who were 2 to < 4 years of age (Study M10-444).

In the Phase 3 trial of HUMIRA in patients with pediatric Crohn’s disease which evaluated efficacy and safety of two body weight adjusted maintenance dose regimens following body weight adjusted induction therapy up to 52 weeks of treatment, ALT elevations ≥ 3 X ULN occurred in 2.9% of patients all of whom were exposed to concomitant immunosuppressants at baseline.

The rates of hepatic adverse events were 7.7% (4/52) in the High-Dose group and 8.0% (4/50) in the Low-Dose group for pediatric patients 13 to 17 years of age weighing ≥ 40 kg with Crohn’s disease.

Adult

In controlled rheumatoid arthritis clinical trials (Studies DE009, DE011, DE019, and DE031), elevations of alanine aminotransferase (ALT) were similar in patients receiving HUMIRA or placebo. In patients with early rheumatoid arthritis (disease duration of less than three years) (Study DE013), elevations of ALT were more common in the combination arm (HUMIRA + methotrexate) compared to the methotrexate monotherapy arm or the HUMIRA monotherapy arm.

In psoriatic arthritis clinical trials, elevations in ALT were more common in psoriatic arthritis patients compared with patients in rheumatoid arthritis clinical studies.

In controlled Crohn’s disease clinical trials and ulcerative colitis, elevations of ALT were similar in patients receiving HUMIRA or placebo.

In all indications, patients with raised ALT were asymptomatic and in most cases, elevations were transient and resolved on continued treatment.

Post-Market Adverse Drug Reactions

The following post-market adverse drug reactions have been reported:

Cardiac Disorders:myocardial infarction
Gastrointestinal Disorders:diverticulitis, intestinal perforation, pancreatitis
General disorders and administration site conditions:pyrexia
Hematologic Events:thrombocytopenia
Hepatobiliary Disorders:liver failure, hepatitis, autoimmune hepatitis
Hypersensitivity Reactions:anaphylaxis, angioedema, angioneurotic edema
Immune System Disorders:sarcoidosis
Infections:infections in infants exposed in utero, legionellosis, listeriosis, reactivation of hepatitis B virus (HBV)
Musculoskeletal and Connective Tissue Disorders:lupus-like syndrome*
Neoplasia:hepatosplenic T-cell lymphoma (HSTCL) , leukemia, Merkel cell carcinoma (neuroendocrine carcinoma of the skin)
Nervous System Disorders:cerebrovascular accident, demyelinating disorders (e.g., Guillain-Barr├й syndrome, optic neuritis)
Skin Reactions:alopecia, cutaneous vasculitis, erythema multiforme, new onset or worsening of psoriasis (including palmoplantar pustular psoriasis)*, Stevens-Johnson syndrome
Respiratory, Thoracic and Mediastinal Disorders:interstitial lung disease (including pulmonary fibrosis), pulmonary embolism
Vascular Disorders:deep vein thrombosis, systemic vasculitis

See (WARNINGS AND PRECAUTIONS)

* See (ADVERSE REACTIONS, Adverse Drug Reaction Overview)

Drug interactions

Serious Drug Interactions

  • Serious infections and sepsis, including fatalities, have been reported with the use of TNF-blocking agents, including HUMIRA (adalimumab). Many of the serious infections have occurred in patients on concomitant immunosuppressive therapy that, in addition to their rheumatoid arthritis, could predispose them to infections. Tuberculosis and invasive opportunistic fungal infections have been observed in patients treated with TNF-blocking agents, including HUMIRA.

Overview

Population pharmacokinetic analyses with data from over 1,200 rheumatoid arthritis patients revealed that co-administration of methotrexate had an intrinsic effect on the apparent clearance of adalimumab (CL/F). See (DRUG INTERACTIONS, Drug-Drug Interactions). As expected, there was a trend toward higher apparent clearance of adalimumab with increasing body weight and in the presence of anti-adalimumab antibodies.

Other more minor factors were also identified: higher apparent clearance was predicted in rheumatoid arthritis patients receiving doses lower than the recommended dose, and in rheumatoid arthritis patients with high rheumatoid factor or C-reactive protein (CRP) concentrations. These factors are not likely to be clinically important.

HUMIRA (adalimumab) has been studied in rheumatoid arthritis patients taking concomitant methotrexate. See (CLINICAL TRIALS). The data do not suggest the need for dose adjustment of either HUMIRA or methotrexate.

Drug-Drug Interactions

Table 12. Established or Potential Drug-Drug Interactions
Concomitant Drug NameClinical Comment
AbataceptConcurrent administration of TNF-blockers and abatacept has been associated with an increased risk of infections including serious infections compared to TNF-blockers alone. This combination has not demonstrated increased clinical benefit. Thus the combined use of TNF-blockers and abatacept is not recommended.
AnakinraConcurrent 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, General, Concurrent Administration of Biologic DMARDS or TNF-antagonists).
Cytochrome P450 (CYP450) SubstratesThe formation of CYP450 enzymes may be suppressed by increased levels of cytokines (e.g., TNFОα, 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.
Methotrexate (MTX)When HUMIRA was administered to 21 rheumatoid arthritis patients on stable MTX therapy, there were no statistically significant changes in the serum MTX concentration profiles. In contrast, after single and multiple dosing, MTX reduced adalimumab apparent clearances by 29 and 44% respectively, in patients with rheumatoid arthritis. See (CLINICAL TRIALS).
OtherInteractions between HUMIRA and drugs other than MTX have not been evaluated in formal pharmacokinetic studies. In rheumatoid arthritis clinical trials where HUMIRA was co-administered with commonly-used DMARDs (sulfasalazine, hydrochloroquine, leflunomide and parenteral gold), glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs or analgesics, no safety signals were seen.
There is no data on other DMARDs, and patients with prior treatment with alkylating agents (e.g., cyclophosphamide) were excluded.
Definition(s): DMARDs = disease-modifying anti-rheumatic drugs; MTX = methotrexate; TNF = tumor necrosis factor

Drug-Food Interactions

HUMIRA is administered as a subcutaneous injection. Interactions with food are therefore not applicable.

Drug-Herb Interactions

Interactions with herbal products have not been established.

Drug-Laboratory Interactions

There are no known laboratory tests that may be helpful in following the patient’s response or in identifying possible adverse reactions.

Drug-Lifestyle Interactions

HUMIRA may have a minor influence on the ability to drive and use machines. Dizziness (including vertigo, vision disorder and fatigue) may occur following administration of HUMIRA.

Dosage and administration

Dosing Considerations

Pediatrics

Polyarticular JIA

See DOSAGE AND ADMINISTRATION, Recommended Dosage and Dosage Adjustment,Pediatrics, Polyarticular Juvenile Idiopathic Arthritis.

Safety and effectiveness in pediatric patients with Polyarticular JIA less than 2 years have not been established. Limited data are available for HUMIRA treatment in pediatric patients with Polyarticular JIA with a weight below 10 kg.

Pediatric Crohn’s Disease.

See DOSAGE AND ADMINISTRATION, Recommended Dosage and Dosage Adjustment,Pediatrics, Pediatric Crohn’s Disease.

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

Geriatrics

Evidence from clinical studies and experience suggests that use of HUMIRA in the geriatric population is not associated with differences in effectiveness. No dose adjustment is needed for this population. A brief discussion can be found under (WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Gender

No gender-related pharmacokinetic differences were observed after correction for a patient’s body weight. Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics.

Race

No differences in immunoglobulin clearance would be expected among races. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab. Dosage adjustment is not required.

Hepatic Insufficiency

No pharmacokinetic data are available in patients with hepatic impairment. No dose recommendation can be made.

Renal Insufficiency

No pharmacokinetic data are available in patients with renal impairment. No dose recommendation can be made.

Disease States

Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics. See (ACTION AND CLINICAL PHARMACOLOGY, Special Populations and Conditions, Disease States).

Concomitant Medications

Methotrexate, glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs (NSAIDs), analgesics or other DMARDs may be continued during treatment with HUMIRA. When treated with HUMIRA as monotherapy, some rheumatoid arthritis patients who experience a decrease in their response to HUMIRA 40 mg every other week may benefit from an increase in dose intensity to HUMIRA 40 mg every week.

Recommended Dose and Dosage Adjustment

Pediatrics

Polyarticular Juvenile Idiopathic Arthritis

The recommended dose of HUMIRA for patients with polyarticular JIA, 2 to 17 years of age, is 24 mg/m2 body surface area up to a maximum single dose of 20 mg HUMIRA (for patients 2 to <4 years of age) and up to a maximum single dose of 40 mg HUMIRA (for patients 4 to 17 years of age) administered every other week via subcutaneous injection. The volume for injection is selected based on the patient’s height and weight (Table 13). A 40 mg vial (for pediatric use) is available for patients who need to administer less than the full 40 mg dose.

Table 13. HUMIRA Dose in Milliliters (mL) by Height and Weight of Children for Polyarticular JIA
Height
(cm)
Total Body Weight (kg)
10152025303540455055606570
800.20.30.30.3
900.20.30.30.40.40.4
1000.30.30.30.40.40.40.50.5
1100.30.30.40.40.40.50.50.50.50.60.6
1200.30.40.40.40.50.50.50.60.60.60.60.70.7
1300.40.40.50.50.50.60.60.60.60.70.70.7
1400.40.40.50.50.60.60.60.70.70.70.70.8*
1500.50.50.60.60.60.70.70.70.70.8*0.8*
1600.50.50.60.60.70.70.70.8*0.8*0.8*0.8*
1700.60.60.60.70.70.8*0.8*0.8*0.8*0.8*
1800.60.70.70.8*0.8*0.8*0.8*0.8*0.8*

* Maximum single dose is 40 mg (0.8 mL)


Available data suggest that clinical response is usually achieved within 12 weeks of treatment. Efficacy and safety in patients who do not respond by Week 16 have not been established.

Pediatric Crohn’s Disease

The recommended HUMIRA induction dose regimen for pediatric patients with severely active Crohn’s disease and moderately active Crohn’s disease with no response to conventional therapy is 160 mg at Week 0 (dose can be administered as four injections in one day or as two injections per day for two consecutive days), followed by 80 mg at Week 2 (given as two 40 mg injections in one day).

The recommended HUMIRA maintenance dose regimen is 20 mg every other week beginning at Week 4.

For pediatric patients who experience a disease flare or non-response, dose escalation to 40 mg every other week may be considered. See (CLINICAL TRIALS).

The use of HUMIRA in pediatric patients with Crohn’s disease ages 13 to 17 has been evaluated up to one year in clinical studies.

If a patient has not responded by Week 12, continued therapy should be carefully reconsidered.

A 40 mg pen and a 40 mg pre-filled syringe are also available for patients to administer a full 40 mg dose.

Adults

Rheumatoid Arthritis

The recommended dose of HUMIRA for adult patients with rheumatoid arthritis is 40 mg administered every other week as a subcutaneous injection.

Psoriatic Arthritis

The recommended dose of HUMIRA for adult patients with psoriatic arthritis is 40 mg administered every other week as a subcutaneous injection.

For the rheumatoid arthritis and psoriatic arthritis indications, available data suggest that the clinical response is usually achieved within 12 weeks of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

Ankylosing Spondylitis

The recommended dose of HUMIRA for patients with ankylosing spondylitis is HUMIRA 40 mg administered every other week as a single-dose via subcutaneous injection. Glucocorticoids, salicylates, nonsteroidal anti-inflammatory drugs, analgesics or disease modifying anti-rheumatic drugs can be continued during treatment with HUMIRA.

Crohn’s Disease

The recommended HUMIRA induction dose regimen for adult patients with Crohn’s disease is 160 mg at Week 0 (dose can be administered as four subcutaneous injections in one day or as two subcutaneous injections per day for two consecutive days), followed by 80 mg at Week 2.

The recommended HUMIRA maintenance dose regimen for adult patients with Crohn’s disease is 40 mg every other week beginning at Week 4.

During treatment with HUMIRA, other concomitant therapies (e.g., corticosteroids and/or immunomodulatory agents) should be optimized.

For patients who experience a disease flare, dose escalation may be considered. See (CLINICAL TRIALS).

Some patients who have not responded by Week 4 (induction period) may benefit from continued maintenance therapy through Week 12. Available data suggest that the clinical response is usually achieved at Week 4 of treatment. Continued therapy should be carefully reconsidered in a patient not responding within this time period.

The use of HUMIRA in Crohn’s disease has been evaluated up to one year in controlled clinical studies. In open-label studies, 510/1,594 patients were evaluated for three years, and 118/1,594 patients for at least five years.

Ulcerative Colitis

The recommended HUMIRA induction dose regimen for adult patients with ulcerative colitis is 160 mg at Week 0 (administered as four subcutaneous injections in one day or as two subcutaneous injections per day for two consecutive days), followed by 80 mg at Week 2. Beginning at Week 4, continue with a dose of 40 mg every other week. Adalimumab should only be continued in patients who have responded during the first 8 weeks of therapy.

Aminosalicylates and/or corticosteroids may be continued during treatment with HUMIRA. Azathioprine and 6-mercaptopurine (6-MP) may be continued during treatment with HUMIRA if necessary (see Serious Warnings and Precautions).

During maintenance treatment, corticosteroids may be tapered in accordance with clinical practice guidelines.

Hidradenitis Suppurativa

The recommended HUMIRA initial dose for adult patients with hidradenitis suppurativa is 160 mg, followed by 80 mg two weeks later. The first dose of 160 mg can be administered as four injections in one day or as two injections per day for two consecutive days. The second dose of 80 mg is given as two 40 mg injections in one day.

The recommended HUMIRA maintenance dose regimen for adult patients with hidradenitis suppurativa is 40 mg every week beginning four weeks after the initial dose.

Antibiotics may be continued during treatment with HUMIRA if necessary.

In patients without any benefit after 12 weeks of treatment, continued therapy should be reconsidered.

Psoriasis

The recommended dose of HUMIRA for adult patients with psoriasis is an initial dose of 80 mg administered subcutaneously, followed by 40 mg subcutaneously given every other week starting one week after the initial dose.

Continued therapy beyond 16 weeks should be carefully reconsidered in a patient not responding within this time period.

Missed Dose

Patients who miss a dose of HUMIRA should be advised to inject this missed dose as soon as they become aware of it, and then follow with their next scheduled dose.

Administration

HUMIRA is intended for use under the guidance and supervision of a physician. Patients may self-inject HUMIRA if their physician determines that it is appropriate and with medical follow-up, as necessary, after proper training in subcutaneous injection technique.

Vial

The solution in the vial should be carefully inspected visually for particulate matter and discolouration prior to subcutaneous administration. If particulates and discolourations are noted, the product should not be used. HUMIRA does not contain preservatives; therefore, unused portions of drug remaining in the vial should be discarded.

Pediatric patients using the vial should be instructed to withdraw only the prescribed amount of solution from the vial according to the directions provided in the CONSUMER INFORMATION. Each 0.8 mL of adalimumab provides 40 mg of HUMIRA. The required amount should be injected according to the directions provided in the CONSUMER INFORMATION. Any unused product in the vial should be discarded.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard (see CONSUMER INFORMATION).

Pre-filled Syringe or Pre-filled Pen

The solution in the Pen or pre-filled syringe should be carefully inspected visually for particulate matter and discolouration prior to subcutaneous administration. If particulates and discolourations are noted, the product should not be used. HUMIRA does not contain preservatives; therefore, unused portions of drug remaining in the syringe should be discarded.

The HUMIRA Pen and the pre-filled syringe are available with a 29 gauge ½ inch needle and a black needle cover that does not contain latex.

Patients using the pre-filled syringes should be instructed to inject the full amount in the syringe (0.8 mL), which provides 40 mg of HUMIRA, according to the directions provided in the CONSUMER INFORMATION.

Injection sites should be rotated and injections should never be given into areas where the skin is tender, bruised, red or hard. See (CONSUMER INFORMATION).

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

The maximum tolerated dose of HUMIRA (adalimumab) has not been established in humans. Multiple doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately.

Action and clinical pharmacology

Mechanism of Action

Adalimumab binds specifically to TNF-alpha and blocks its interaction with the p55 and p75 cell surface TNF receptors. Adalimumab also lyses surface TNF-expressing cells in vitro in the presence of complement. Adalimumab does not bind or inactivate lymphotoxin (TNF-beta). TNF is a naturally-occurring cytokine that is involved in normal inflammatory and immune responses. Elevated levels of TNF are found in the synovial fluid of rheumatoid arthritis, including polyarticular JIA, psoriatic arthritis and ankylosing spondylitis patients and play an important role in both pathologic inflammation and joint destruction that are hallmarks of these diseases. Increased levels of TNF are also found in psoriasis plaques, which contribute to the inflammatory response, to the proliferation and decreased maturation of keratinocytes and to the associated vascular damages that are characteristic of the disease. Increased levels of TNF are also found in hidradenitis suppurativa lesions.

Adalimumab also modulates biological responses that are induced or regulated by TNF, including changes in the levels of adhesion molecules responsible for leukocyte migration [ELAM-1, VCAM-1, and ICAM-1 with a half maximal inhibitory concentration (IC50) of 1 to 2 x 10-10M].

Pharmacodynamics

After treatment with HUMIRA (adalimumab), a rapid decrease in levels of acute phase reactants of inflammation [C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)] and serum cytokines (IL-6) was observed compared to baseline in patients with rheumatoid arthritis. A rapid decrease in CRP levels was also observed in patients with Crohn’s disease ulcerative colitis and hidradenitis suppurativa. Serum levels of matrix metalloproteinases (MMP- 1 and MMP-3) that produce tissue remodeling responsible for cartilage destruction were also decreased after HUMIRA administration.

The serum adalimumab concentration-efficacy relationship as measured by the American College of Rheumatology response criteria (ACR 20) appears to follow the Hill Emax equation as shown in Figure 1.


Figure 1. Serum Adalimumab Concentration-Efficacy Relationship as Measured by the American College of Rheumatology Response Criteria (ACR 20)

The half maximal effective concentration (EC50) estimates ranging from 0.8 to 1.4 mcg/mL were obtained through pharmacokinetic / pharmacodynamic modelling of swollen joint count, tender joint count and ACR 20 response from patients participating in Phase 2 and 3 trials.

Pharmacokinetics

Pediatric

Following the administration of 24 mg/m2 (up to a maximum of 40 mg) subcutaneously every other week to patients with polyarticular JIA who were 4 to 17 years, the mean trough steady-state (values measured from Week 20 to 48) serum adalimumab concentration was 5.5 ± 5.6 mcg/mL (102% CV) HUMIRA monotherapy and 10.9 ± 5.2 mcg/mL (47.7% CV) with concomitant MTX. In patients with polyarticular JIA who were 2 to <4 years old or aged 4 and above weighing <15 kg dosed with HUMIRA 24 mg/m2, the mean trough steady-state serum adalimumab concentrations was 6.0 ± 6.1 μg/mL (101% CV) HUMIRA monotherapy and 7.9 ± 5.6 μg/mL (71.2% CV) with concomitant MTX.

In pediatric patients 13 to 17 years of age weighing ≥ 40 kg with severelyactive Crohn’s disease and/or who have had an inadequate response or were intolerant to conventional therapy, the mean ± SD serum adalimumab trough concentration achieved at Week 4 was 15.7 ± 6.64 mcg/mL following administration of 160 mg HUMIRA at Week 0 and 80 mg HUMIRA at Week 2. The mean ± SD adalimumab trough concentrations at Week 4 were 17.2 ± 6.67 mcg/mL (n=45) for patients who were naïve to infliximab. The mean ± SD adalimumab trough concentrations at Week 4 were 14.4 ± 6.40 mcg/mL (n=51) for patients who were infliximab-experienced.

For patients who stayed on their randomized double-blind therapy, the mean ± SD adalimumab trough concentration at Week 52 was 9.43 ± 4.98 mcg/mL following administration of 40 mg HUMIRA every other week and 3.59 ± 2.91 mcg/mL following administration of 20 mg HUMIRA every other week. For patients who stayed on their randomized double-blind therapy and were naïve to infliximab, the mean ± SD adalimumab trough concentrations at Week 52 were 12.0 ± 3.89 mcg/mL (n=11) and 3.06 ± 2.02 mcg/mL (n=10) for the High-Dose and Low-Dose groups, respectively. For patients who stayed on their randomized double-blind therapy and were infliximab-experienced, the mean ± SD adalimumab trough concentrations at Week 52 were 6.85 ± 4.72 mcg/mL (n=11) and 4.27 ± 2.82 mcg/mL (n=8) for the High-Dose and Low-Dose groups, respectively.

Adult

The single-dose pharmacokinetics of adalimumab in rheumatoid arthritis patients were determined in several studies with intravenous doses ranging from 0.25 to 10.0 mg/kg. The distribution volume (Vss) ranged from 4.7 to 6.0 L. The systemic clearance of adalimumab is approximately 12 mL/h. The mean terminal half-life was approximately two weeks, ranging from 10 to 20 days across studies. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.

Adalimumab mean steady-state trough concentrations of approximately 5 mcg/mL and 8 to 9 mcg/mL, were observed in rheumatoid arthritis patients with and without methotrexate, respectively. The serum adalimumab trough levels at steady-state increased approximately proportionally with dose following 20, 40 and 80 mg every other week and every week subcutaneous dosing. In long-term studies with dosing more than two years, there was no evidence of changes in clearance over time.

Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that there was a trend toward higher apparent clearance of adalimumab in the presence of anti-adalimumab antibodies.

In patients with psoriatic arthritis, adalimumab mean steady-state trough concentrations of 8.5 to 12 mcg/mL and 6 to 10 mcg/mL were observed in patients with and without methotrexate, respectively.

In patients with Crohn’s disease, the loading dose of 160 mg HUMIRA on Week 0 followed by 80 mg HUMIRA on Week 2 achieves mean serum adalimumab trough concentrations of approximately 12 mcg/mL at Week 2 and Week 4. Mean steady-state trough levels of approximately 7 mcg/mL were observed at Week 24 and Week 56 in Crohn’s disease patients who received a maintenance dose of HUMIRA 40 mg every other week.

Population pharmacokinetic analysis in patients with Crohn’s disease revealed a lower apparent clearance of adalimumab as compared to patients with rheumatoid arthritis.

In patients with ulcerative colitis, a loading dose of 160 mg HUMIRA on Week 0 followed by 80 mg HUMIRA on Week 2 achieved serum adalimumab trough concentrations of 11.8 ± 4.0 mcg/mL at Week 2 (n=167) and 12.3 ± 5.4 mcg/mL at Week 4 (n=160). At Week 52, trough levels of 8.0 ± 6.1 mcg/mL were observed in UC patients who received a maintenance dose of 40 mg HUMIRA every other week (n=101). Trough levels at Week 52 were 10.8 ± 7.5 mcg/mL in UC patients achieving remission (n=39) and 6.2± 4.2 mcg/mL in UC patients not achieving remission (n=62).

In patients with HS, a dose of 160 mg HUMIRA on Week 0 followed by 80 mg HUMIRA on Week 2 achieved serum adalimumab trough concentrations of approximately 7 to 8 mcg/mL at Week 2 and Week 4. The mean steady-state trough concentration at Week 12 through Week 36 were approximately 8 to 10 mcg/mL during HUMIRA 40 mg every week treatment.

In patients with psoriasis, the mean steady-state trough concentration was 5 mcg/mL during HUMIRA 40 mg every other week monotherapy treatment.

Absorption

The maximum serum concentration (Cmax) and the time to reach the maximum concentration (Tmax) were 4.7 ± 1.6 mcg/mL and 131 ± 56 hours respectively, following a single 40 mg subcutaneous administration of HUMIRA to healthy adult subjects. The average absolute bioavailability of adalimumab estimated from three studies following a single 40 mg subcutaneous dose was 64%. The pharmacokinetics of adalimumab were linear over the dose range of 0.5 to 10.0 mg/kg following a single intravenous dose.

Distribution

Adalimumab concentrations in the synovial fluid from five rheumatoid arthritis patients ranged from 31 to 96% of those in serum.

Metabolism

No formal studies have been conducted to evaluate the metabolism of adalimumab. However, as adalimumab is an IgG1 antibody of entirely human sequences, it is expected that its metabolism would follow the course of other IgG molecules.

Excretion

No formal studies have been conducted to evaluate the excretion of adalimumab. However, as adalimumab is an IgG1 antibody of entirely human sequences, it is expected that its excretion would follow the course of other IgG molecules.

Special Populations and Conditions

Pediatrics

HUMIRA has not been studied in children with polyarticular JIA less than 2 years of age or in patients with a weight <10 kg.

The majority (102/192) of pediatric patients with Crohn’s disease studied were 13 to 17 years of age weighing ≥ 40 kg.

Geriatrics

Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that there was a trend toward lower clearance with increasing age in patients aged 40 to > 75 years of age.

Gender

Population pharmacokinetic analyses in patients with rheumatoid arthritis revealed that no gender-related pharmacokinetic differences were observed after correction for a patient’s body weight.

Race

No differences in immunoglobulin clearance would be expected among races. From limited data in non-Caucasians, no important kinetic differences were observed for adalimumab.

Hepatic Insufficiency

No pharmacokinetic data are available in patients with hepatic impairment.

Renal Insufficiency

No pharmacokinetic data are available in patients with renal impairment.

Disease States

Healthy volunteers and patients with rheumatoid arthritis displayed similar adalimumab pharmacokinetics. Population pharmacokinetic analyses predicted minor increases in apparent clearance in patients receiving doses lower than the recommended dose and in patients with high rheumatoid factor or C-reactive protein (CRP) concentrations. These increases are not likely to be clinically important. See (DOSAGE AND ADMINISTRATION, Dosing Considerations, Disease States).

Storage and stability

HUMIRA (adalimumab) must be refrigerated between 2 and 8°C. Store in original carton until time of administration. DO NOT FREEZE. Protect from light. Do not use beyond the expiration date.

The patient has the option to store the HUMIRA Pen or pre-filled syringe at temperatures up to a maximum of 25°C (77°F) for a single period of up to 14 days. The HUMIRA Pen or pre-filled syringe stored at temperatures up to a maximum of 25°C (77°F) must be discarded if not used within the 14-day period.

Special handling instructions

HUMIRA vial (for pediatric use) does not contain preservatives. Any unused product or waste material should be disposed of in accordance with local requirements.

A puncture-resistant container for disposal of needles, vials and syringes (including the Pen) should be used. Patients or caregivers should be instructed in the handling technique as well as proper syringe and needle disposal, and be cautioned against reuse of these items.

A healthcare professional (e.g., doctor, nurse or pharmacist) should be consulted for instructions on how to properly dispose of used needles, vials and syringes (including the Pen). Special provincial or local laws regarding the proper disposal of needles, vials and syringes should be followed. Needles, vials or syringes (including the Pen) should NEVER be thrown in the household trash or recycling bin.

  • Used needles, vials and syringes (including the Pen) should be placed in a container made especially for this purpose (sharps container), or a hard plastic container with a screw-on cap or metal container with a plastic lid labelled “Used Syringes”. Glass or clear plastic containers should not be used.
  • The container should always be kept out of the reach of children.
  • When the container is about two-thirds full, the cap or lid should be taped down so that it does not come off. The container should be disposed of as instructed by a healthcare professional. CONTAINERS SHOULD NEVER BE THROWN IN THE HOUSEHOLD TRASH OR RECYCLING BIN.
  • Unless otherwise instructed by a healthcare professional, used alcohol pads (not included in HUMIRA kit) may be placed in the trash. Dose trays and covers may be recycled.

Dosage forms, composition and packaging

HUMIRA (adalimumab) is supplied as a sterile solution for subcutaneous administration in the following packaging configurations:

Vial

HUMIRA vial (for pediatric use) is available in a carton containing two boxes. Each box contains one empty sterile injection syringe, one sterile 30 gauge ½ inch needle, one sterile vial adapter and one single-use vial providing 40 mg of adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL). All contents of the vial carton (including vial, accessories and packaging) are latex-free.

Pen

HUMIRA Pen is available as a Pen in a carton containing two dose trays. Each dose tray contains a single-use Pen containing a 1 mL pre-filled glass syringe with a fixed 29 gauge ½ inch needle with a black needle cover providing 40 mg of adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL). All contents of the Pen carton (including Pen, accessories and packaging) are latex-free.

Pre-Filled Syringe

HUMIRA is also available as a pre-filled syringe in a carton containing two dose trays. Each dose tray contains a single-use, 1 mL pre-filled glass syringe with a fixed 29 gauge ½ inch needle with a black needle cover providing 40 mg of adalimumab dissolved in 0.8 mL sterile solution (50 mg/mL). All contents of the pre-filled syringe carton (including syringe, accessories and packaging) are latex-free.

Listing of Non-Medicinal Ingredients

In addition to the active ingredient adalimumab, each HUMIRA 50 mg/mL vial, Pen or pre- filled syringe contains the following non-medicinal ingredients: citric acid monohydrate, dibasic sodium phosphate dihydrate, mannitol, monobasic sodium phosphate dihydrate, polysorbate 80, sodium citrate, sodium chloride, sodium hydroxide (added as necessary to adjust pH), and water for injection.