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.

HUMIRA + MTX helps patients with rheumatoid arthritis (RA) get the most out of HUMIRA treatment

HUMIRA demonstrated results in clinical trials of patients with both early and established moderate to severe RA1

HUMIRA data in early moderate to severe RA

PREMIER: A pivotal trial (N=799) in patients with early moderate to severe RA and who were methotrexate (MTX)-naïve2,3

PREMIER was a 2-year, multicenter, double-blind, active comparator-controlled study. 799 patients were randomized to receive HUMIRA 40 mg every other week (EOW) + MTX weekly (n=268), HUMIRA 40 mg EOW (n=274), or MTX weekly (n=257). All patients had moderate to severe early RA (less than 3 years’ duration) and were MTX-naïve at baseline.

Primary efficacy endpoints were ACR50 response and change from baseline in modified total Sharp score (mTSS) at Week 52. Select secondary endpoints were ACR50 and ACR70 responses at Year 2, mean change from baseline in HAQ-DI, mean change from baseline in mTSS at Year 2, major clinical response at Year 2,* and clinical remission as defined by DAS28 <2.6. At Year 2, 497 patients entered the open-label extension (OLE). All patients received 40 mg EOW; physician could add MTX at any time.

*Major clinical response defined as achieving an ACR70 response and maintaining it for ≥6 months.

Study Design Details

PREMIER: A pivotal study in moderate to severe early RA patients2,3

The clinical design of the PREMIER study of patients with early moderate to severe RA.

EOW=every other week; MTX=methotrexate.
aIntent-to-treat (ITT) population.
bObserved data.
cStable doses of concomitant nonsteroidal anti-inflammatory drugs (NSAID) and corticosteroids were permitted. Patients taking MTX escalated to
20 mg/week by Week 8, as needed/as tolerated.

PREMIER RCT baseline patient characteristics and disease duration were comparable between groups

>

aP<0.05 among all treatment groups.
bHUMIRA + MTX (n=267), HUMIRA (n=271), MTX (n=251).
Baseline demographics and disease characteristics were generally similar between the OLE and RCT patient populations.

PREMIER: HUMIRA + MTX improved signs and symptoms in early moderate to severe RA

HUMIRA + MTX delivered significantly higher ACR20, 50, and 70 response rates at Weeks 52 and 104 vs MTX alone2

HUMIRA clinical data in improving signs and symptoms of early rheumatoid arthritis.

EOW=every other week.
aThe above analysis is of the intent-to-treat (ITT) population using nonresponder imputation (NRI) methodology. Patients who withdrew or had missing values were considered nonresponders.

RCT Major clinical response and OLE ACR response rate results2-4

PREMIER RCT

  • ~2x More patients achieved major clinical response* with HUMIRA + MTX at Year 2 vs MTX alone (49% vs 27%, respectively; P>0.001)2

*Major clinical response defined as achieving an ACR70 response and maintaining it for ≥6 months.

PREMIER Open-label extension (OLE)

  • 76% and 64% of HUMIRA-treated patients in the OLE at 264 weeks achieved ACR50 and ACR70 responses, respectively3,4
  • The OLE completer cohort was defined as patients with available Year 5 ACR response scores and mTSS; results are based on 124 patients randomized to HUMIRA + MTX. MTX could have been added at any time after the start of the open-label period based on clinical judgment

OLE limitations: As with any long-term open-label extension, there are several limitations with the OLE portion of this study. For example, there is the potential for enrichment of long-term data in the remaining patient population, as those who remain in the study generally fare better than those who discontinue.

~2x More patients achieved clinical remission measure (DAS28 <2.6) with HUMIRA + MTX vs MTX alone at Years 1 and 22

See clinical remission (DAS<2.6) data for HUMIRA in early moderate to severe RA.

aClinical remission was defined as DAS28 <2.6. Disease Activity Score (DAS) is a composite index that includes variables such as the number of tender and swollen joints and either erythrocyte sedimentation rate or C-reactive protein (CRP), and may include the patient’s assessment of disease activity.

HUMIRA data in established moderate to severe rheumatoid arthritis (RA)

DE019: A pivotal trial (N=619) in patients with established moderate to severe RA who had an inadequate response to methotrexate (MTX)1,5,6

The DE019 trial was a 1-year, multicenter, double-blind, parallel-group, placebo-controlled study of 619 patients with established moderate to severe RA who had an inadequate response to MTX. Patients were randomized to receive HUMIRA 40 mg every other week (EOW) + methotrexate (MTX) (n=207), HUMIRA 20 mg EOW + MTX (n=212), or placebo + MTX (n=200).

There were 3 co-primary endpoints: ACR20 response at Week 24,1,5 mean change from baseline in modified total Sharp score (mTSS) at Week 52,5 and mean change from baseline in HAQ-DI physical function score at Week 52.5 At Year 1, 457 patients enrolled in the open-label extension (OLE), with all patients receiving HUMIRA 40 mg EOW + MTX.6

Study Design Details

DE019: Clinical study in established moderate to severe RA1,5,6

The clinical design of the DE019 study of patients with early moderate to severe RA.

EOW=every other week; MTX=methotrexate.
aIntent-to-treat population (ITT).
bObserved data.
cStable doses of concomitant nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids were permitted.

DE019 baseline patient characteristics and disease duration were comparable between groups5

  • Baseline demographics and disease characteristics in the open-label extension (OLE) were similar to that of the original study population6

DE019: HUMIRA + MTX demonstrated significantly higher ACR responses vs placebo + MTX at 24 weeks5

HUMIRA + MTX delivered significantly higher ACR20, 50, and 70 response rates at Week 24 that were maintained through Week 52

See HUMIRA ACR responses for established moderate to severe RA.

EOW=every other week.
aNonresponder imputation (NRI) analysis of intent-to-treat (ITT) population. Patients who withdrew or received additional traditional DMARDs on or after Week 16 were considered nonresponders.

DE019: Significantly greater change from baseline to Week 24 in pain with HUMIRA + MTX vs placebo + MTX (P<0.001)1

See HUMIRA pain scores in patients with established moderate to severe rheumatoid arthritis.

RCT and OLE ACR response rate results

DE019 RCT

  • ~2x More HUMIRA + MTX patients demonstrated ACR20 response at first visit (Week 2) (26% vs 13%, respectively; P≤0.001)5

DE019 OLE

  • 75% of HUMIRA + MTX (n=237) patients achieved ACR20 response at Year 8 of the OLE4
  • All data were observed. No imputation was employed. Clinical efficacy was evaluated in patients who entered the DE019 OLE by duration of exposure to HUMIRA. Patients randomized to placebo + MTX during the first year could have up to 7 years of HUMIRA exposure and are not included in the 8-year results4

OLE limitations: As with any long-term open-label extension, there are several limitations with the OLE portion of this study. For example, there is the potential for enrichment of long-term data in the remaining patient population, as those who remain in the study generally fare better than those who discontinue.

HUMIRA + MTX can have a significant impact on the course of radiographic progression and help prevent further joint damage2,5

PREMIER: Greater inhibition of radiographic progression with HUMIRA + MTX vs MTX alone in patients with moderate to severe early RA

See HUMIRA radiographic progression data damage in early moderate to severe RA patients.

EOW=every other week.
aThis analysis is of the intent-to-treat study population. Values for missing data were imputed by a predefined linear progression method.

All patients had early moderate to severe RA (less than 3 years’ duration) and were MTX-naïve at baseline2

Learn how HUMIRA works in helping patients with moderate to severe rheumatoid arthritis.

JE=joint erosion; JSN=joint space narrowing.

PREMIER Study Results

PREMIER RCT

  • 5x Greater inhibition of radiographic progression with HUMIRA + MTX vs MTX alone at Year 2 (P<0.001)2

PREMIER OLE

  • 8 years of radiographic progression data (mean change from baseline at Year 8: 3.8)7
  • Observed analysis. The OLE completer cohort was defined as patients with available mTSS data at baseline and Year 8; results are based on patients originally randomized to HUMIRA + MTX (n=103). MTX could have been added at any time after the start of the open-label period on clinical judgment7

OLE limitations: As with any long-term open-label extension, there are several limitations with the OLE portion of this study. For example, there is the potential for enrichment of long-term data in the remaining patient population, as those who remain in the study generally fare better than those who discontinue.

DE019: Significantly less joint damage progression with HUMIRA + MTX vs placebo + MTX in patients with established moderate to severe RA

See less joint damage progression in patients with established moderate to severe rheumatoid arthritis.

EOW=every other week.
aExtrapolated analysis of the intent-to-treat (ITT) population. Missing Sharp score values were imputed by linear extrapolation from baseline and Week 24 to 52.

Study results

DE019 RCT

  • Significantly greater inhibition of radiographic disease progression with HUMIRA + MTX vs placebo + MTX at Year 1 (P≤0.001)5

DE019 OLE

  • 10 Years of radiographic progression data (mean change from baseline at Year 10: 0.72)6
  • Observed analysis: Only patients with available X-rays at baseline and Year 10 who received HUMIRA 40 mg EOW + MTX during the original RCT and through 10 years of treatment were included in this analysis (n=79)6

OLE limitations: As with any long-term open-label extension, there are several limitations with the OLE portion of this study. For example, there is the potential for enrichment of long-term data in the remaining patient population, as those who remain in the study generally fare better than those who discontinue.

HUMIRA + MTX can help improve physical function so patients can get back to their daily activities2,5

PREMIER: Significantly greater improvement in HAQ-DI at Year 1 with HUMIRA + MTX vs MTX alone (P<0.001)2

HAQ-DI scores at baseline and year 1 for patients with early moderate to severe rheumatoid arthritis.

bAll data were observed; no imputation was employed.

All patients had early moderate to severe RA (less than 3 years’ duration) and were MTX-naïve at baseline2

Study results

PREMIER RCT

  • Significantly greater improvement from baseline in physical function with HUMIRA + MTX vs MTX alone at Years 1 and 2: –1.1 vs –0.8 (P<0.001) and –1.0 vs –0.9 (P<0.05), respectively2

PREMIER OLE

  • For the completer cohort (n=97), the mean HAQ-DI through Year 8 in HUMIRA-treated patients in the OLE was ~0.74,7

The OLE completer cohort was defined as patients with available mTSS data at baseline and Year 8; results are based on 103 patients originally randomized to HUMIRA + MTX. MTX could have been added at any time after the start of the open-label period based on clinical judgment.

OLE limitations: As with any long-term open-label extension, there are several limitations with the OLE portion of this study. For example, there is the potential for enrichment of long-term data in the remaining patient population, as those who remain in the study generally fare better than those who discontinue.

DE019: Significantly greater improvement in physical function at Year 1 with HUMIRA + MTX vs placebo + MTX (P≤0.001)5,a

Physical function in patients with established moderate to severe rheumatoid arthritis.

bLast observation carried forward (LOCF) analysis of the intent-to-treat (ITT) study population.

DE019: Study Results

DE019 RCT

  • Improvement in HAQ-DI was greater in HUMIRA + MTX-treated patients vs placebo + MTX patients at Year 1: –0.59 vs –0.25 (P≤0.001)5

DE019 OLE

  • The mean change from baseline in HAQ-DI at Year 10 was –0.62 (n=149)6
  • All data were observed. No imputation was employed. Physical function was evaluated in patients who entered the DE019 OLE by duration of exposure to HUMIRA. Patients randomized to placebo + MTX during the first year could have up to 9 years of HUMIRA exposure and are not included in Year 10 results6


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 adult patients with moderate to severe hidradenitis suppurativa.
  • Uveitis: HUMIRA is indicated for the treatment of non-infectious intermediate, posterior and panuveitis in adult patients.

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. Breedveld FC, Weisman MH, Kavanaugh AF, et al; for the PREMIER Investigators. The PREMIER study: a multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive, rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006;54(1):26-37. 3. van der Heijde D, Breedveld FC, Kavanaugh A, et al. Disease activity, physical function, and radiographic progression after longterm therapy with adalimumab plus methotrexate: 5-year results of PREMIER. J Rheumatol. 2010;37(11):2237-2246. 4. Data on file, AbbVie Inc. 5. Keystone EC, Kavanaugh AF, Sharp JT, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400-1411. 6. Keystone EC, van der Heijde D, Kavanaugh A, et al. Clinical, functional, and radiographic benefits of long-term adalimumab plus methotrexate: final 10-year data in longstanding rheumatoid arthritis. J Rheumatol. 2013;40(9):1487-1497. 7. Breedveld FC, Keystone EC, van der Heijde D, et al. Initial combination therapy with adalimumab plus methotrexate leads to better long-term outcomes than with either monotherapy in patients with early rheumatoid arthritis: 8-year results of an open-label extension of a phase 3 trial. Poster presented at: 2011 ACR/ARHP Annual Scientific Meeting: November 5-9, 2011; Chicago, IL.

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