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

Uveitis: HUMIRA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older.

Clinical Trial Overview

SYCAMORE study design: A multicenter, double-masked, randomized, placebo-controlled trial evaluating HUMIRA + methotrexate (MTX) in pediatric patients 2 years of age or older with active JIA-associated non-infectious uveitis1,2

The safety and efficacy of HUMIRA + MTX vs placebo + MTX were evaluated in 90 patients with regard to controlling disease activity in pediatric patients with JIA-associated NI uveitis.1

  • Patients with active JIA-associated NI uveitis received 20 mg HUMIRA + MTX every other week (EOW) if < 30 kg or 40 mg HUMIRA + MTX if ≥ 30 kg, or placebo + MTX weekly.

The primary endpoint in SYCAMORE was time to treatment failure.

Treatment failure was a composite measure defined by worsening or sustained non-improvement in ocular inflammation, and/or worsening of ocular co-morbidities (reduction in vision, raised IOP, hypotony, disc swelling, or CME).

Primary endpoint in SYCAMORE2

Ocular co-morbidities are defined as: i) disc swelling and/or cystoid macular edema (CME) as gauged clinically and where possible by OCT evidence; and/or ii) raised intraocular pressure (IOP) (>25 mmHg) sustained over 2 consecutive visits not responding to single ocular hypotensive agent, and/or iii) hypotony (<6 mmHg) sustained over 2 consecutive visits, and/or iv) development of unexplained reduction in vision (logarithm of the minimum angle of resolution [LogMAR]) over two consecutive visits of 0.3 LogMAR units (in the event of cataract, participants will remain in trial, also if cataract surgery is required. Failure will still remain as described in endpoints above).

EOW=every other week; JIA=juvenile idiopathic arthritis; SC=subcutaneous; AC=anterior cell; OCT=optical coherence tomography; SUN=Standardization of Uveitis Nomenclature.

The SYCAMORE trial was stopped early after 90 patients been randomized because efficacy analysis met the pre-specified statistical stopping guidelines2

Study Design and Patient Characteristics

Multicenter, double-blind, randomized, placebo-controlled trial.1,2

  • Patients failed 12 weeks of methotrexate (MTX) as well as topical or systemic corticosteroids
  • All patients received a stable weekly dose (10-20 mg/m2 of body-surface area; maximum dose of 25 mg) of MTX during the study
  • Corticosteroids were permitted at study entry followed by a mandatory reduction in topical corticosteroids within 3 months
HUMIRA’s VISUAL 1 study design details: Active disease while being treated with oral prednisone, 1–60mg/d for ≥2 weeks

Key patient characteristics:

  • Age ranged from 2-18 years. Mean age was 9 years.1,2
  • N=90 (HUMIRA group=60 patients; placebo group=30 patients).1
  • Patients had active anterior uveitis: Sustained grade of cellular infiltrate in anterior chamber of the SUN criteria grade 1+ or more of more during the preceding 12 weeks. HUMIRA is not indicated for anterior uveitis.2
  • Patients had not used disease modifying immunosuppressive drugs other than MTX in the 4 weeks prior to screening.2

Baseline characteristics2

aPlus–minus values are means ±SD.

bScores for the log of the minimum angle of resolution (LogMAR) are on a scale from 0.00 to 2.00, with higher values indicating poorer vision.

cThe anterior chamber cell count and flare score were assessed according to the Standardization of Uveitis Nomenclature criteria. Scores range from 0 to 4+,with higher scores indicating poorer vision.

dVitreous haze grade was assessed on a scale from 0 to 4+, with higher grades indicating poorer vision.

eThe type of juvenile idiopathic arthritis (JIA) was classified according to the International League of Associations for Rheumatology criteria.

fThe physician’s global assessment of disease activity was assessed on a 10-cm visual-analogue scale, with higher grades indicating more disease activity.

gData on rheumatoid factor and antinuclear antibody were not available in some patients because repeat blood testing for the purpose of data-set completion was not warranted on the basis of clinical needs.

Pediatric patients with active disease (Sycamore)

HUMIRA + MTX was proven to provide early and sustained disease control1,2

  • HUMIRA + MTX prolonged time to treatment failure vs MTX alone.1
    • Median time to treatment failure not estimable for HUMIRA + MTX vs 24.1 weeks for MTX alone (95% CI, 12.4-81)2
    • Less than half of at-risk patients treated with HUMIRA + MTX experienced a treatment failure2

HUMIRA is not indicated for anterior uveitis.

HUMIRA + MTX was proven to provide early and sustained disease control1,2 HUMIRA + MTX was proven to provide early and sustained disease control1,2

Topical Steriod-sparing Efficacy: HUMIRA + MTX Helped Reduce the Use of Topical Corticosteroids

  • Corticosteroids were permitted at study entry followed by a mandatory reduction in topical corticosteroids within 3 months.

The SYCAMORE trial was stopped early after 90 patients been randomized because efficacy analysis met the pre-specified statistical stopping guidelines 2

VISUAL I/II Trials: Non-infectious (NI) Intermediate, Posterior and Panuveitis Clinical Data in Adult Patients

The safety and efficacy of HUMIRA were evaluated in 2 randomized, multicenter, double-masked, placebo-controlled trials (VISUAL l and VISUAL ll) of adult patients with NI uveitis.1,3,4*

Adult patients received placebo or HUMIRA at an initial dose of 80 mg followed by 40 mg every other week starting one week after the initial dose.1,3,4

The primary efficacy endpoint in both VISUAL I and VISUAL II was time to treatment failure.1

Treatment failure (TF) was defined by a multi-component outcome based on development of new inflammatory chorioretinal and/or inflammatory retinal vascular lesions, an increase in anterior chamber (AC) cell grade or vitreous haze (VH) grade or a decrease in best corrected visual acuity (BCVA).1,3,4

*Non-infectious intermediate, posterior and panuveitis.

VISUAL I/II Trials: Non-infectious (NI) Intermediate, Posterior and Panuveitis Clinical Data in Adult Patients. VISUAL I/II Trials: Non-infectious (NI) Intermediate, Posterior and Panuveitis Clinical Data in Adult Patients.

To be considered a treatment failure, ≥1 of these 4 criteria need to be present in at least 1 eye.

A 2-step increase is represented by a change of Grade 0 to Grade 2+; or Grade 0.5+ to Grade 3+.

NEI=National Eye Institute; SUN=Standardization of Uveitis Nomenclature.

VISUAL I: A study of adult patients with active Non-infectious (NI) Intermediate, Posterior, and Panuveitis1

VISUAL I evaluated 217 adult patients with active disease in at least 1 eye while being treated with oral prednisone at a dose of 10 to 60 mg/day for 2 weeks or longer.1,3

HUMIRA is proven to significantly prolong disease control vs placebo

VISUAL 1: Adult patients with active non-infectious uveitis: Median time to treatment failure vs placebo VISUAL 1: Adult patients with active non-infectious uveitis: Median time to treatment failure vs placebo
  • There was a 50% decrease in the risk for treatment failure in the HUMIRA group compared with the placebo group.1

    • The Kaplan-Meler curves summarizing treatment failure over time showed separation at the first measurable time point (Week 6) and remained separated throughout the duration of the study1,3
    • Treatment failure at or after Week 6 was counted as an event. Subjects who discontinued the study were censored at the time of dropping out1

Median time to treatment failure: 5.6 months for HUMIRA vs 3.0 months for placebo1

87% longer time to treatment failure when using HUMIRA 87% longer time to treatment failure when using HUMIRA

VISUAL II: A study of adult patients with inactive Non-infectious (NI) Intermediate, Posterior, and Panuveitis1

VISUAL II evaluated 226 adult patients with inactive NI uveitis* while being treated with oral prednisone 10 to 35 mg/day for ≥28 days at baseline.1,4

*Non-infectious intermediate, posterior and panuveitis.

HUMIRA demonstrated statistically significant reduction of the risk of treatment failure in adult patients with NI uveitis1,4*

VISUAL II: A study of adult patients with inactive Non-infectious (NI) Intermediate, Posterior, and Panuveitis

*Non-infectious intermediate, posterior, and panuveitis.

  • During the study, less than half of at-risk patients treated with HUMIRA experienced a treatment failure.1

    • Median time to treatment failure: Not estimatable for HUMIRA vs 8.3 months for placebo (95% CI, 4.8-12.0)1
  • HUMIRA patients had 43% reduced risk of treatment failure vs placebo (HR, 0.57 [95% CI, 0.39-0.84])1
IMPORTANT SAFETY INFORMATION for HUMIRA (adalimumab)1

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: 1. with chronic or recurrent infection, 2. who have been exposed to TB, 3. with a history of opportunistic infection, 4. who resided in or traveled in regions where mycoses are endemic, 5. with underlying conditions that may predispose them to 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 during 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.
  • If an infection develops, monitor carefully and initiate appropriate therapy.
  • Drug interactions with biologic products: A higher rate of serious infections has been observed in RA patients treated with rituximab who received subsequent treatment with a TNF blocker. An increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no demonstrated added benefit in patients with RA. Concomitant administration of HUMIRA with other biologic DMARDs (e.g., anakinra or abatacept) or other TNF blockers is not recommended based on the possible increased risk for infections and other potential pharmacological interactions.
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 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 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.
  • In clinical trials, more cases of malignancies were observed among HUMIRA-treated patients compared to control patients.
  • Non-melanoma skin cancer (NMSC) was reported during clinical trials for HUMIRA-treated patients. Examine all patients, particularly those with a 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 those 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 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 HUMIRA treatment.
  • Discontinue HUMIRA and begin antiviral therapy in patients who develop HBV reactivation. Exercise caution when resuming HUMIRA after HBV treatment.
NEUROLOGIC REACTIONS
  • TNF blockers, including HUMIRA, have been associated with rare cases of 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; discontinuation of HUMIRA should be considered if any of these disorders develop.
  • There is a known association between intermediate uveitis and central demyelinating disorders.
HEMATOLOGIC REACTIONS
  • Rare reports of pancytopenia, including aplastic anemia, have been reported with TNF blockers. Medically significant cytopenia has been infrequently reported with HUMIRA.
  • Consider stopping HUMIRA if significant hematologic abnormalities occur.
CONGESTIVE HEART FAILURE
  • Worsening and new onset congestive heart failure (CHF) has been reported with TNF blockers. Cases of worsening CHF have been observed with HUMIRA; exercise caution and monitor 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.
  • Pediatric patients, if possible, should be brought up to date with all immunizations before initiating HUMIRA therapy.
  • Adalimumab is actively transferred across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant. The safety of administering live or live-attenuated vaccines in infants exposed to HUMIRA in utero is unknown. Risks and benefits should be considered prior to vaccinating (live or live-attenuated) exposed infants.
ADVERSE REACTIONS
  • The most common adverse reactions in HUMIRA clinical trials (>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 patients 2 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.
  • Adult 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.
  • Pediatric Crohn’s Disease: HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active Crohn’s disease who have had an inadequate response to corticosteroids or immunomodulators such as azathioprine, 6-mercaptopurine, or methotrexate.
  • 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.
  • Hidradenitis Suppurativa: HUMIRA is indicated for the treatment of moderate to severe hidradenitis suppurativa in patients 12 years of age and older.
  • Uveitis: HUMIRA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adults and pediatric patients 2 years of age and older.

For full Prescribing Information, visit rxabbvie.com/pdf/humira.pdf

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References: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc. 2. Ramanan AV, Dick AD, Jones AP, et al. Adalimumab plus methotrexate for uveitis in juvenile idiopathic arthritis. N Engl J Med. 2017;376(17):1637-1646. 3. Jaffe GJ, Dick AD, Brezin AP, et al. Adalimumab in patients with active noninfectious uveitis. N Engl J Med. 2016;375(10):932-943. 4. Nguyen QD, Merrill PT, Jaffe GJ, et al. Adalimumab for prevention of uveitic flare in patients with inactive non-infectious uveitis controlled by corticosteroids (VISUAL II): a multicentre, double-masked, randomised, placebo-controlled phase 3 trial. Lancet. 2016;388(10050):1183-1192.

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