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

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.

Crohns Disease Clinical Data

In moderate to severe adult Crohn's disease (CD) patients with active disease despite conventional therapies

HUMIRA induced clinical remission rapidly (at 4 weeks) for anti-TNF–naïve patients1,2

HUMIRA induced clinical remission rapidly (at 4 weeks) for anti-TNF–naïve adult CD patients

aClinical remission was defined as a Crohn's Disease Activity Index (CDAI) score <150 points

Rapid symptom relief with HUMIRA1,2

  • Response (CR-70) rates* in CLASSIC-I at Week 4 in anti-TNF–naïve patients: HUMIRA 58% (n=76) vs control 34% (n=74); (P<0.01 HUMIRA vs control)1,2

*Clinical response was defined as a reduction of ≥70 points from baseline CDAI score

Most Common Adverse Events (AEs)2

The most common AEs (≥5% in the HUMIRA 160 mg/80 mg arm) reported in the CLASSIC-I clinical trial were any type of injection site reactions, infections, headache, nausea, pharyngitis, abdominal tenderness, flatulence, and nasopharyngitis.

CLASSIC-I Study Design1,2

CLASSIC-I was a 4-week, randomized, double-blind, placebo-controlled, multicenter study of 3 doses of HUMIRA vs control (placebo), all ± concomitant therapy in 299 adult patients with moderately to severely active Crohn’s disease naïve to anti-TNF therapy. Patients were randomized to receive HUMIRA 160 mg at Week 0 and 80 mg at Week 2, HUMIRA 80 mg at Week 0 and 40 mg at Week 2, HUMIRA 40 mg at Week 0 and 20 mg at Week 2 or control and followed through Week 4. Primary endpoint was the percentage of patients achieving induction of clinical remission in the 2 higher doses compared with control at Week 4.

Study Design Details

CLASSIC-I Study Design1,2

DURATION: 4-week, randomized, double-blind, placebo-controlled, multicenter study
PATIENTS: 299 anti-TNF–naïve adult patients with moderately to severely active Crohn’s disease defined as a CDAI score of 220-450
DOSING: 3 regimens of HUMIRA were compared against control (placebo), all ± concomitant therapy:

  • HUMIRA 160 mg at Week 0 followed by 80 mg at Week 2
  • HUMIRA 80 mg at Week 0 followed by 40 mg at Week 2
  • HUMIRA 40 mg at Week 0 followed by 20 mg at Week 2

PRIMARY ENDPOINT: Percentage of patients achieving induction of clinical remission in the 2 higher doses compared with control at Week 4

SECONDARY ENDPOINT: Percentage of patients achieving clinical response (CR-70) at Week 4, defined as a reduction of ≥70 points from baseline CDAI score.

CONCOMITANT THERAPIES: Patients may have received concomitant stable doses of conventional therapies that included 5-aminosalicylates, immunomodulators, corticosteroids, and Crohn’s-related antibiotics.

HUMIRA maintained clinical remission in moderate to severe Crohn’s disease (CD)1,3

HUMIRA maintained clinical remission in moderate to severe adult Crohn’s disease (CD)

aClinical remission was defined as a Crohn's Disease Activity Index (CDAI) score <150 points.

Week 12:

In CHARM, patients who responded to HUMIRA typically did so within 12 weeks from the first dose; therapy that continued beyond 12 weeks did not result in significantly more responses.1

Response (CR-70) rates* at1,3:

  • Week 26: HUMIRA 54% (n=93/172) vs control 28% (n=48/170); (P<0.001)
  • Week 56: HUMIRA 43% (n=74/172) vs control 18% (n=30/170); (P<0.001)

*Clinical response was defined as a reduction of ≥70 points from baseline CDAI score

Most Common Adverse Events (AEs)3,4

The most common AEs (≥5% in the HUMIRA 40 mg EOW arm with an incidence ≥ control) during the double-blind period of the CHARM clinical trial were infections, injection site reaction related AEs, nasopharyngitis, arthralgia, headache, abdominal pain, nausea, pyrexia, and influenza.

CHARM Study Design1,3:

CHARM was a 56-week randomized, double-blind, placebo-controlled, multicenter study of 854 adult patients with moderately to severely active Crohn’s disease. All patients received open-label HUMIRA 80 mg at Week 0 and 40 mg at Week 2. At Week 4, patients who achieved clinical response (CR-70) were randomized to HUMIRA 40 mg EOW, HUMIRA 40 mg weekly, or control (placebo), all ± concomitant therapy. Co-primary endpoints were the percentage of patients achieving clinical remission at Weeks 26 and 56 for each HUMIRA group vs control in the 499 patients with CR-70 response at Week 4 after open-label induction therapy.

Study Design Details

CHARM Study Design1,3

DURATION: 56-week, randomized, double-blind, placebo-controlled, multicenter study
PATIENTS: 854 adult patients with moderately to severely active Crohn's disease defined as a CDAI score of 220-450
DOSING: All patients received open-label HUMIRA 80 mg at Week 0 and 40 mg at Week 2

  • Patients who achieved clinical response (CR-70) at Week 4 were randomized to control (placebo), HUMIRA 40 mg EOW, or HUMIRA 40 mg weekly, all ± concomitant therapy

CO-PRIMARY ENDPOINTS: Percentage of patients achieving clinical remission at Weeks 26 and 56 for each HUMIRA group vs control in the 499 patients with CR-70 response at Week 4 after open-label induction therapy
SECONDARY ENDPOINTS: Percentage of patients achieving clinical response (CR-70) at Weeks 26 and 56 for each HUMIRA group vs control in the 499 patients with CR-70 response at Week 4 after open-label induction therapy
CONCOMITANT THERAPIES: Patients may have received concomitant stable doses of conventional therapies that included 5-aminosalicylates, immunomodulators, corticosteroids, and Crohn’s-related antibiotics.

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.

CHARM open-label extension (OLE) study5

CHARM open-label extension (OLE) study for adult CD patients

a This subanalysis includes patients from the CHARM trial who were randomized responders, remained blinded on HUMIRA 40 mg EOW therapy for the duration of the trial, and entered the HUMIRA 40 mg EOW arm (n=75) of the OLE.
bClinical remission was defined as a Crohn’s Disease Activity Index (CDAI) score <150 points
EOW=every other week.

  • OLE populations generally consist of treatment responders, as patients who are unable to tolerate the drug or who do not respond to the drug drop out
  • The use of HUMIRA in CD beyond 1 year has not been evaluated in controlled clinical studies1

CHARM OLE study design5

This subanalysis evaluated clinical remission to 108 weeks in adult patients who received HUMIRA 40 mg EOW during the open-label extension (OLE) of the CHARM study. Patients who dropped out of the trial or who were missing CDAI scores were not included in the analysis at each time point.

CHARM OLE study design for adult CD patients

aThis subanalysis includes patients from the CHARM trial who were randomized responders, remained blinded on HUMIRA 40 mg EOW therapy for the duration of the trial, and entered the HUMIRA 40 mg EOW arm (n=75) of the OLE.
bA flare was defined as an increase in CDAI of ≥70 points and a CDAI above 220 when compared to Week 4 of the preceding randomized, controlled trial. Nonresponse was defined as a decrease of <70 points compared to the baseline visit in the preceding randomized, controlled trial.

HUMIRA induced clinical remission rapidly (at 4 weeks) for infliximab-failure patients1,6

HUMIRA induced clinical remission rapidly (at 4 weeks) for infliximab-experienced adult CD patients

aClinical remission was defined as a Crohn’s Disease Activity Index (CDAI) score <150 points

Rapid symptom relief with HUMIRA1,6

Response (CR-70) rates* in GAIN at Week4: HUMIRA 52% (n=82/159) vs control 34% (n=56/166); (P<0.01)1,6

*Clinical response was defined as a reduction of ≥70 points from baseline CDAI score

Most Common Adverse Events (AEs)6

The most common AEs (≥5% in the HUMIRA arm) in the GAIN clinical trial were infections, any type of injection site reactions, abdominal pain, arthralgia, and headache.

GAIN Study Design1,6

GAIN was a 4-week, randomized, double-blind, placebo-controlled, multicenter study of 325 adult patients with moderately to severely active Crohn’s disease who had lost response to, or were intolerant to, infliximab. Patients were randomized to receive 160 mg at Week 0 and 80 mg at Week 2 or control (placebo), both ± concomitant therapy and followed through Week 4. Primary endpoint was the percentage of patients achieving induction of clinical remission in HUMIRA-treated patients vs control at Week 4.

Study Design Details

GAIN Study Design1,6

DURATION: 4-week, randomized, double-blind, placebo-controlled, multicenter study
PATIENTS: 325 adults with moderately to severely active Crohn’s disease (defined as a CDAI score of 220-450) who lost response to, or were intolerant to, infliximab
DOSING: Patients were randomized to receive 160 mg at Week 0 and 80 mg at Week 2 or control (placebo), both ± concomitant therapy and followed through Week 4
PRIMARY ENDPOINT: Percentage of patients achieving induction of clinical remission in HUMIRA treated patients vs control at Week 4
SECONDARY ENDPOINT: Percentage of patients achieving clinical response (CR-70) at Week 4, defined as reduction of ≥70 points from baseline CDAI score.
CONCOMITANT THERAPIES: Patients may have received concomitant stable doses of conventional therapies that included 5-aminosalicylates, immunomodulators, corticosteroids, and Crohn’s-related antibiotics.

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. Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn's disease: the CLASSIC-I trial. Gastroenterology. 2006;130(2):323-333. 3. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial. Gastroenterology. 2007;132(1):52-65. 4. Data on File ABVRRTI61721. 5. Data on File ABVRRTI61726. 6. Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn's disease previously treated with infliximab: a randomized trial. Ann Intern Med. 2007;146(12):829-838.

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