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

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.

In moderate to severe ulcerative colitis (UC) patients with active disease despite immunosuppressants such as corticosteroids, azathioprine, or 6-mercaptopurine

HUMIRA induced rapid remission1

At 8 weeks, HUMIRA controlled persistently active disease1

ULTRA 1: Clinical remission rates at Week 8 in anti-TNF-naive patients with moderate to severe UC.

aClinical remission was defined as a total Mayo score of ≤2 with no subscore >1.
bTreatment difference (95% CI): 9.3% (0.9%, 17.6%), P<0.05

ULTRA 1 was an 8-week, multicenter, randomized, double-blind, placebo-controlled study of 390 anti-TNF–naïve adult patients with moderate to severe UC despite concurrent or prior treatment with oral corticosteroids and/or azathioprine/6-mercaptopurone (AZA/6-MP). Patients were randomized to receive HUMIRA 160 mg at Week 0, 80 mg at Week 2, and 40 mg at Weeks 4 and 6 (± concomitant therapies) or control (placebo ± concomitant therapies). The original protocol was amended to include a second HUMIRA induction group (HUMIRA 80 mg at Week 0, 40 mg at Weeks 2, 4, and 6, ± concomitant therapies). Primary endpoint was the percentage of patients achieving clinical remission (Mayo score ≤2 with no individual subscore >1) at Week 8 for each HUMIRA arm.2

Entry Criteria and Study Design Details

HUMIRA: The first and only anti-TNF to prespecify clinical remission as the primary endpoint in UC pivotal trials1

Clinical remission is a key goal according to ACG3

HUMIRA: The first and only anti-TNF to prespecify clinical remission as the primary endpoint in UC pivotal trials.

Anti-TNF=anti-tumor necrosis factor.
ACG=American College of Gastroenterology.
aPatient-reported.
bEach patient serves as his or her own control to establish normal stool frequency and the degree of abnormal stool frequency.
cThe daily bleeding score represents the most severe bleeding of the day.
dThe PGA acknowledges the 3 other subscores, the subject’s daily record of abdominal discomfort and functional assessment, and other observations such as physical findings, and the subject’s performance status.

ULTRA 1 study design: induction of clinical remission2

ULTRA 1 study design: induction of clinical remission in patients with moderate to severe UC.

DURATION: 8-week, multicenter, randomized, double-blind, placebo-controlled study2

PATIENTS: 390 anti-TNF–naïve adult patients with moderate to severe UC defined as a Mayo score of ≥6 points and an endoscopy subscore of 2 or 3 despite concurrent or prior treatment with oral corticosteroids and/or azathioprine/6-mercaptopurine (AZA/6-MP)

CONCOMITANT THERAPIES: Patients in all study arms may have received stable doses of concomitant therapies that included AZA/6-MP, aminosalicylates, and oral corticosteroids

DOSING:

  • HUMIRA 160 mg at Week 0, 80 mg at Week 2, and 40 mg at Weeks 4 and 6 (± concomitant therapies)
  • Control (placebo ± concomitant therapies)
  • Amendment 3 (A3): The original protocol was amended to include a second HUMIRA induction group (HUMIRA 80 mg at Week 0, 40 mg at Weeks 2, 4, and 6 ± concomitant therapies)

PRIMARY ENDPOINTS: Percentage of patients achieving clinical remission (Mayo score ≤2 with no individual subscore >1) at Week 8 for each HUMIRA arm

ANALYSIS: Intent-to-treat (ITT-A3) study population using nonresponder imputation. ITT-A3 includes all randomized patients with confirmed UC enrolled under A3 or later who received ≥1 dose of study drug or control

  • Patients with missing or incomplete data were classified as not in clinical remission
ULTRA 1: Most common adverse events (8 weeks) in patients with UC.

AE=adverse events.

ULTRA 2 study: Clinical remission rates at Week 8 in patients with moderate to severe UC.

aClinical remission was defined as a total Mayo score of ≤2 with no subscore >1
bTreatment difference (95% CI): 7.2% (1.2%, 12.9%), P<0.05

Only continue HUMIRA in patients who have shown evidence of clinical remission by 8 weeks of therapy.1

Clinical remission at Week 52 with HUMIRA1

ULTRA 2 study: Clinical remission rates at Week 52 in patients with moderate to severe UC.

aClinical remission was defined as a total Mayo score of ≤2 with no subscore >1
bTreatment difference (95% CI): 8.8% (2.8%, 14.5%), P<0.05

Sustained remission with HUMIRA1

ULTRA 2 study: Sustained clinical remission: clinical remission at both weeks 8 and 52 in patients with moderate to severe UC.

aTo achieve sustained clinical remission, the same patient had to achieve clinical remission at both Weeks 8 and 52
bTreatment difference (95% CI): 4.4% (0.1%, 8.6%), P<0.05

Patients who lost response to or were intolerant to anti-TNF agents were allowed entry into the trial.5

ULTRA 2 was a 52-week, multicenter, randomized, double-blind, placebo-controlled study of 518* adult patients with moderate to severe UC despite concurrent or prior treatment with oral corticosteroids and/or azathioprine/6-mercaptopurone (AZA/6-MP). Patients who lost response to or were intolerant to anti-TNF agents were allowed entry into the trial. Patients were stratified by prior exposure to anti-TNF agents and randomized to receive HUMIRA 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (EOW) starting at Week 4 (± concomitant therapies) or control (placebo ± concomitant therapies). Co-primary endpoints were the percentage of patients achieving clinical remission (Mayo score ≤2 with no individual subscore >1) at Week 8 and at Week 52. Another endpoint included the percentage of patients who sustained clinical remission (clinical remission at both Week 8 and at Week 52).5

*24 patients were not included in the efficacy analysis due to site noncompliance.
Patients with prior exposure to HUMIRA were excluded from the study.

Entry Criteria and Study Design Details

HUMIRA: The first and only anti-TNF to prespecify clinical remission as the primary endpoint in UC pivotal trials1

Clinical remission is a key goal according to ACG3

Entry criteria and clinical remission endpoint for ULTRA 1 and ULTRA 2.

Anti-TNF=anti-tumor necrosis factor.
ACG=American College of Gastroenterology.
aPatient-reported.
bEach patient serves as his or her own control to establish normal stool frequency and the degree of abnormal stool frequency.
cThe daily bleeding score represents the most severe bleeding of the day.
dThe PGA acknowledges the 3 other subscores, the subject’s daily record of abdominal discomfort and functional assessment, and other observations such as physical findings, and the subject’s performance status.

ULTRA 2 study design (52-week study): induction of and sustained clinical remission5

ULTRA 2 study design (52-week study): induction of and sustained clinical remission

DURATION: 52-week, multicenter, randomized, double-blind, placebo-controlled study5

PATIENTS: 518* adult patients with moderate to severe UC for at least 3 months defined as a Mayo score of 6-12 points and an endoscopy subscore of at least 2 despite concurrent or prior therapy with oral corticosteroids and/or AZA/6-MP. Patients who lost response to or were intolerant to anti-TNF agents were allowed entry into trial.

CONCOMITANT THERAPIES: Patients in both study arms may have received stable doses of concomitant therapies that included AZA/6-MP, aminosalicylates, and oral corticosteroids. Corticosteroid dose could be tapered after Week 8.

DOSING:

  • Patients were stratified by prior exposure to anti-TNF agents and assigned to 1 of 2 treatment groups:
    • HUMIRA 160 mg at Week 0, 80 mg at Week 2, and 40 mg every other week (EOW) starting at Week 4 (± concomitant therapies)
    • Control (placebo ± concomitant therapies)

CO-PRIMARY ENDPOINTS: Percentage of patients achieving clinical remission (Mayo score ≤2 with no individual subscore >1) at Week 8 and at Week 52

OTHER ENDPOINT: Percentage of patients achieving sustained clinical remission (clinical remission at both Week 8 and Week 52)

ANALYSIS: Intent-to-treat (ITT) study population using nonresponder imputation. ITT includes all patients with confirmed UC who received ≥1 dose of study drug or control.

  • Patients with missing or incomplete data, or discontinued double-blind treatment, were classified as not in clinical remission

*24 patients were not included in the efficacy analysis due to site noncompliance.
Patients with prior exposure to HUMIRA were excluded from the study.

ULTRA 2 study: Most common adverse events (52 weeks) for patients with moderate to severe UC.

AE=adverse events.

Risk of HSTCL1

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

Additional endpoints in HUMIRA UC pivotal trials

Statistical Considerations

  • The statistical analyses for the endpoints in both ULTRA 1 and ULTRA 2 were carried out in hierarchical order from the first to the second ranked co-primary endpoints, and then to the ranked secondary endpoints. If a higher ranked endpoint did not meet the criteria for statistical significance (P value <0.05), then the analyses of the remaining ranked endpoints would be considered exploratory
  • For ULTRA 1, the co-primary endpoint of clinical remission at Week 8 for the 80/40/40 mg dosing arm did not achieve statistical significance. As a result, the analyses of the ranked secondary endpoints are considered exploratory
  • For ULTRA 2, results of ranked secondary endpoints that were considered exploratory are not presented in the chart
HUMIRA UC pivotal trials: Results of select prespecified endpoints in UC pivotal studies.

NS=not statistically significant.
aGray areas of chart indicate that endpoints were non-prespecified.
bClinical response is defined as a decrease in Mayo score of ≥3 points from baseline and decrease in Mayo score of ≥30% from baseline and decrease in the rectal bleeding score ≥1 or an absolute rectal bleeding score of 0 or 1.
cMucosal healing is defined as an endoscopy subscore of 0 or 1.
dRestricted to patients using corticosteroids at baseline (control, n=140; HUMIRA, n=150).



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

1641190-1880520

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References: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc. 2. Reinisch W, Sandborn WJ, Hommes DW, et al. Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis: results of a randomised controlled trial. Gut. 2011;60(6):780-787. 3. Kornbluth A, Sachar DB and The Practice Parameters Committee of the American College of Gastroenterology. Ulcerative colitis practice guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol. 2010;105(3):501-523. 4. Ha C. Clinical measure of disease activity. In: Bayless TM, Hanauer SB, eds. Advanced Therapy in Inflammatory Bowel Disease. 3rd ed. Shelton, CT: People's Medical Publishing House - USA; 2011:125-130. 5. Sandborn WJ, van Assche G, Reinisch W, et al. Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology. 2012;142(2):257-265.

1641190-1832109


Important Safety Information New HUMIRA (adalimumab) data for treating moderate to severe fingernail psoriasis.

THIS IS WORTH POINTING OUT.

There's a treatment for moderate to severe chronic plaque psoriasis with new data for moderate to severe fingernail psoriasis.




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Indication1

Plaque Psoriasis: HUMIRA (adalimumab) 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.

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.