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

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

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.

The general management of ulcerative colitis (UC) in clinical practice includes a focus on immune-mediated inflammation as the cause of symptoms2,3

UC and Crohn's disease (CD) have similar pathophysiologies2

The underlying inflammatory process that drives disease in UC is similar to that in CD2

Illustration of the underlying inflammatory process in Crohn’s disease and ulcerative colitis.

Inflammation can lead to symptoms of UC4:

  • Diarrhea
  • Looser, more urgent bowel movements
  • Rectal bleeding/bloody stools
  • Crampy abdominal pain
  • Loss of appetite
  • Weight loss
  • Fever

UC can progress beyond initial disease presentation5-7

In some patients, the disease can be progressive. Therefore, it is important to regularly re-assess patients after UC diagnosis for worsening of disease by monitoring for3, 5-7:

  • Disease extension throughout the colon
    • Left-sided disease can progress to pancolitis
  • Worsening signs and symptoms
    • Milder symptoms may increase in frequency and severity
  • Response to conventional therapy
    • Patients’ response to initial therapy should be evaluated within several weeks5
  • Other systemic presentations
  • Risk factors8,9:
    • Younger age at diagnosis (<40 years)
    • Treatment history of corticosteroids
    • Pancolitis
    • Deep mucosal ulceration

Currently, there are no formal recommendations regarding these risk factors, but some evidence suggests these could be associated with a more complicated disease course.

Recognizing the patient who is beyond mild disease and has moderate to severe disease

UC disease severity is defined by both symptoms and signs of inflammation3

Pictures of mild to severe ulcerative colitis, taken from an endoscopy.

No single therapeutic approach can be applied to all patients11; therefore, quickly evaluating treatment response is essential.5,6

Proactive monitoring and prompt adjustment of therapy may be needed to effectively manage persistently active disease.

Decision points: Assessing the right time to step up treatment

Timely treatment of moderate to severe UC based on clinical evidence3

Assessing the right time to step up treatment for patients with UC.

HUMIRA (adalimumab) clinical trials included adults with active moderate to severe UC* despite previous/current treatment with immunosuppressants12,13

HUMIRA trials included adults with moderate to severe UC despite previous/current treatment with immunosuppressants.

*Defined as Mayo score of 6-12 with an endoscopy subscore of 2-3.
Within previous 5 years of study.
Or equivalent.

Entry criteria and clinical remission endpoint in ULTRA 1 and ULTRA 2 studies for patients with moderate to severe ulcerative colitis.

Anti-TNF=anti-tumor necrosis factor.
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.

Use anti-TNF therapy to reduce signs and symptoms and achieve remission in adults with active moderate to severe CD when adequate response is not achieved on conventional therapy15

Inflammation—the underlying process of active CD2

Illustration of the underlying inflammatory process in Crohn’s disease and ulcerative colitis.

Inflammation can lead to symptoms of CD4:

  • Diarrhea
  • Abdominal pain
  • Fever
  • Rectal bleeding
  • Weight loss
  • Malaise
  • Nausea and vomiting
  • Anorexia

In CD, the majority of patients present with uncomplicated disease16; however 60% of patients will eventually develop complications due to inflammation-driven tissue damage, some of which may be irreversible and more difficult to treat.16,17

In many patients, CD behaves in a progressive manner17

It is important to regularly re-assess patients after CD diagnosis for worsening disease by monitoring for:

  • Signs of worsening severity
    • Increasing stool frequency, fever, significant weight loss, abdominal pain or tenderness, intermittent nausea or vomiting (without obstructive findings), or significant anemia4
  • Inflammatory symptoms beyond the GI tract (joints, skin, or eyes)4
  • Disease behavioral changes
  • Steroid dependency/resistance5
  • Response to conventional therapy
    • Patients' response to initial therapy should be evaluated within several weeks5
  • Risk factors17:
    • Perianal disease, smoker, younger age at diagnosis, need for steroids
    • Currently, there are no formal recommendations regarding these risk factors, but some evidence suggests these could be associated with a more complicated disease course

Identifying when a CD patient is beyond mild disease and has moderate to severe disease

CD activity levels defined by the American College of Gastroenterology (ACG)15

Pictures of mild to severe ulcerative colitis, taken from an endoscopy.

*Asymptomatic or without inflammatory sequelae following medical or surgical intervention, no residual active disease, not steroid dependent.

Ambulatory, able to tolerate oral alimentation without manifestations of dehydration, toxicity, abdominal tenderness, painful mass, obstruction, or >10% weight loss.

Failed response to treatment for mild to moderate disease or with more prominent symptoms (fever, weight loss, abdominal pain or tenderness, intermittent nausea or vomiting without obstruction), or significant anemia.

§Persistent symptoms despite corticosteroids or biologics; high fevers, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or abscess.

Assessing Crohn's disease activity

Crohn's Disease Activity Index (CDAI) is a tool used to quantify the signs and symptoms of adult patients with CD. CDAI score is calcuated by adding the following weighted variables18:

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. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med. 2009;361(21):2066-2078. 3. Kornbluth A, Sachar DB; 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. Friedman S, Blumberg RS. Inflammatory bowel disease. In: Kasper D, Fauci A, Hauser S, Longo DL, Jameson JL, Loscalzo J, eds. Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill Education; 2015:1947-1964. 5. Panaccione R, Rutgeerts P, Sandborn WJ, et al. Review article: treatment algorithms to maximize remission and minimize corticosteroid dependence in patients with inflammatory bowel disease. Aliment Pharmacol Ther. 2008;28(6):674-688. 6. Torres J, Billioud V, Sachar DB et al. Ulcerative colitis as a progressive disease; the forgotten evidence. Inflamm Bowel Dis. 2012;18(7):1356-1363. 7. Ordás I, Eckmann L, Talamini M, et al. Ulcerative colitis. Lancet. 2012;380(9853):1606-1619. 8. Yarur AJ, Strobel SG, Deshpande AR, et al. Predictors of aggressive inflammatory bowel disease. Gastroenterol Hepatol (NY). 2011;7(10):652-659. 9. Blonski W, Buchner AM, Lichtenstein GR. Clinical predictors of aggressive/disabling disease: ulcerative colitis and Crohn disease. Gastroenterol Clin North Am. 2012;41(2):443-462. 10. Data on file, AbbVie Inc. 11. Stone CD. Sequential and combination therapy for small bowel Crohn’s disease. In: Bayless TM, Hanauer SB, eds. Advanced Therapy in Inflammatory Bowel Disease. 3rd ed. Shelton, CT: People’s Medical Publishing House—USA; 2011:625-630. 12. 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. 13. 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. 14. 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. 15. Lichtenstein GR, Hanauer SB, Sandborn WJ; and the Practice Parameters Committee of the American College of Gastroenterology. Management of Crohn’s disease in adults. Am J Gastroenterol. 2009;104(2):465-483. 16. Thia KT, Sandborn WJ, Harmsen WS, et al. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology. 2010;139(4):1147-1155. 17. Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology. 2011;140(6):1785-1794. 18. Sands BE, Siegel CA. Crohn’s disease. In: Feldman M, Friedman LS, Brant LJ, eds. Sleisenger and Fordtran's Gastrointestinal and Liver Disease: Pathophysiology/Diagnosis/Management. 9th ed. Philadelphia, PA: Saunders Elsevier; 2010:1941-1973.

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