SAFETY CONSIDERATIONS1

Serious Infections

Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Malignancies

Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA.

Other Serious Adverse Reactions

Patients treated with HUMIRA also may be at risk for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome.


INDICATIONS1


Rheumatoid Arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.

Juvenile Idiopathic Arthritis: HUMIRA is indicated, alone or in combination with methotrexate, for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older.

Psoriatic Arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.

Ankylosing Spondylitis: HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

Crohn's Disease: HUMIRA is indicated for 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, and reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.

Ulcerative Colitis: HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine. The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to anti-TNF agents.

Plaque Psoriasis: HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.


Serious adverse events of interest
in HUMIRA clinical trials2

Methodology

  • Evaluated nearly 12 years of long term safety data in 23,458 patients from 71 HUMIRA global clinical trials including randomized controlled, open label and long term extension studies.
  • Assessed serious adverse events (AEs) of interest.
  • Clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not predict the rates observed in a broader patient population in clinical practice.1
Click to enlarge

a Data were derived from global clinical trials of HUMIRA, including randomized controlled and open-label trials and long-term extension
studies—36 in RA, 4 in PsA, 4 in AS, 13 in Ps, 3 in JIA, and 11 in CD.

b Malignancies excluding lymphoma and non-melanoma skin cancer and malignancies not considered serious by investigators.

The safety of HUMIRA in pediatric patients for uses other than JIA has not been established.1

RISK OF SERIOUS INFECTIONS1

  • Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.
  • HUMIRA should be discontinued if a patient develops a serious infection or sepsis.
  • Perform test for latent TB; if positive, start treatment for TB prior to starting HUMIRA.
  • Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

POSTMARKETING REPORTS OF PEDIATRIC MALIGNANCY1

  • Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF-blockers, of which HUMIRA is a member.

POSTMARKETING REPORTS OF HEPATOSPLENIC T-CELL LYMPHOMA (HSTCL)1

  • Postmarketing cases of HSTCL, a rare type of fatal lymphoma, have been reported in patients treated with TNF blockers, including HUMIRA. The majority of these cases were in adolescent and young adult males with inflammatory bowel disease who had received concomitant or prior treatment with azathioprine or 6-mercaptopurine.

THE RISKS AND BENEFITS OF HUMIRA SHOULD BE CAREFULLY CONSIDERED PRIOR TO INITIATING THERAPY

Patients treated with HUMIRA may be at risk for other serious adverse reactions including:

  • Malignancies - More cases were observed among HUMIRA-treated adult patients than in controls. Lymphoma, non-melanoma skin cancer (NMSC), acute and chronic leukemia, and others have been reported. All patients should be examined for the presence of NMSC prior to and during treatment.
  • Hypersensitivity - Anaphylaxis or serious allergic reactions may occur. Stop HUMIRA and begin appropriate therapy.
  • Hepatitis B virus (HBV) reactivation - Increased risk of reactivation in patients who are chronic carriers. Monitor HBV carriers during and several months after therapy. If reactivation occurs, stop HUMIRA and begin appropriate therapy.
  • Demyelinating disease - Exacerbation or new onset central nervous system or peripheral demyelinating disease may occur. Exercise caution when considering HUMIRA for patients with these disorders.
  • Cytopenias, pancytopenia - Consider stopping HUMIRA in patients with significant hematologic abnormalities.
  • Heart failure - Worsening or new onset congestive heart failure (CHF) may occur. Exercise caution in patients with CHF and monitor them carefully.
  • Lupus-like syndrome - Development of autoantibodies and lupus-like syndrome. Stop HUMIRA if syndrome develops.

Juvenile Idiopathic Arthritis (JIA) Clinical Trial - In general, the adverse reactions in JIA patients were similar in frequency and type to those seen in adult patients. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. Reported severe adverse reactions, some that differ from adults, include neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. The safety of HUMIRA in pediatric patients other than JIA has not been established.1

IMPORTANT SAFETY INFORMATION1

SERIOUS INFECTIONS

Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

Discontinue HUMIRA if a patient develops a serious infection or sepsis.

Reported infections include:

  • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for latent TB before HUMIRA use and during therapy. Initiate treatment for latent TB prior to HUMIRA use.
  • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Consider empiric anti-fungal therapy in patients at risk for invasive fungal infections who develop severe systemic illness.
  • Bacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria.

Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients with chronic or recurrent infection. Monitor patients closely for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

  • Do not start HUMIRA in patients with an active infection, including localized infections.
  • Patients older than 65 years, patients with co-morbid conditions, and/or patients taking concomitant immunosuppressants may be at greater risk of infection.
  • Consider the risks and benefits of treatment in patients with chronic or recurrent infection or with underlying conditions which may predispose them to infection, patients who have been exposed to TB, patients with a history of opportunistic infection, or patients who have resided or traveled in regions where TB or mycoses are endemic.
  • Patients who develop a new infection should undergo a prompt and complete diagnostic workup, and appropriate antimicrobial therapy should be initiated.
  • Drug interactions with biologic products: Concurrent use of anakinra or abatacept with HUMIRA is not recommended, as the combination of anakinra or abatacept with TNF blockers has been associated with an increased risk of serious infections. This risk has also been observed with rheumatoid arthritis patients treated with rituximab who received subsequent treatment with a TNF blocker.

MALIGNANCY

Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, including HUMIRA. Postmarketing 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 has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine 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.

  • Consider the risks and benefits of HUMIRA treatment prior to initiating or continuing therapy in a patient with known malignancy.
  • More cases of malignancies were observed among HUMIRA-treated patients compared to control patients in clinical trials.
  • Non-melanoma skin cancer (NMSC) has been reported during clinical trials for HUMIRA-treated patients. Examine all patients, particularly those with history of prolonged immunosuppressant or PUVA therapy, for the presence of NMSC prior to and during treatment with HUMIRA.
  • In HUMIRA clinical trials, there was an approximate 3-fold higher rate of lymphoma than expected in the general U.S. population. Patients with chronic inflammatory diseases, particularly with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at higher risk of lymphoma than the general population, even in the absence of TNF blockers.
  • Postmarketing cases of acute and chronic leukemia were reported with TNF blocker use.
  • Approximately half of the postmarketing cases of malignancies in children, adolescents, and young adults receiving TNF blockers were lymphomas; other cases included rare malignancies associated with immunosuppression and malignancies not usually observed in children and adolescents.

HYPERSENSITIVITY

  • Anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration.
  • If a serious allergic reaction occurs, stop HUMIRA and institute appropriate therapy.

HEPATITIS B VIRUS REACTIVATION

  • Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers. Some cases have been fatal.
  • Evaluate patients at risk for HBV infection for prior evidence of HBV infection before initiating TNF blocker therapy.
  • Exercise caution in patients who are carriers of HBV and monitor them during and after treatment with HUMIRA.
  • Discontinue HUMIRA and begin antiviral therapy in patients who develop HBV reactivation.
  • Exercise caution when considering resumption of HUMIRA therapy after appropriate treatment for HBV.

NEUROLOGIC REACTIONS

  • TNF blockers, including HUMIRA, have been associated in rare cases with new onset or exacerbation of central nervous system and peripheral demyelinating diseases, including multiple sclerosis, optic neuritis, and Guillain-Barré syndrome.
  • Exercise caution when considering HUMIRA for patients with these disorders.

HEMATOLOGIC REACTIONS

  • Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia (e.g. thrombocytopenia, leukopenia) has been infrequently reported with HUMIRA.
  • Consider stopping HUMIRA in patients with significant hematologic abnormalities.

CONGESTIVE HEART FAILURE

  • Worsening or new onset congestive heart failure (CHF) may occur.
  • Exercise caution in patients with CHF and monitor them carefully.

AUTOIMMUNITY

  • Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in development of a lupus-like syndrome.
  • Discontinue treatment if symptoms of a lupus-like syndrome develop.

IMMUNIZATIONS

  • Patients on HUMIRA should not receive live vaccines.
  • It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy.

ADVERSE REACTIONS

  • The most common adverse reactions in HUMIRA clinical trials (incidence >10%) were: infections (e.g., upper respiratory, sinusitis), injection site reactions, headache, and rash.

INDICATIONS1

  • Rheumatoid Arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis.
  • Juvenile Idiopathic Arthritis: HUMIRA is indicated, alone or in combination with methotrexate, for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older.
  • Psoriatic Arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis.
  • Ankylosing Spondylitis: HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.
  • Crohn's Disease: HUMIRA is indicated for 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, and reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab.
  • Ulcerative Colitis: HUMIRA is indicated for inducing and sustaining clinical remission in adult patients with moderately to severely active ulcerative colitis who have had an inadequate response to immunosuppressants such as corticosteroids, azathioprine or 6-mercaptopurine. The effectiveness of HUMIRA has not been established in patients who have lost response to or were intolerant to anti-TNF agents.
  • Plaque Psoriasis: HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician.

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References:
1. HUMIRA Injection [package insert]. 2. Burmester GR, Panaccione R, Gordon KB, McIlraith MJ, Lacerda APM. Adalimumab: long-term safety in 23,458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Ann Rheum Dis Published Online First: 5 May 2012 doi:10.1136/annrheumdis-2011-201244

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