Safety

Humira (adalimumab) injection

Detailed View: Safety Labeling Changes Approved By FDA Center for Drug Evaluation and Research (CDER) 

June 2016

Summary View

WARNINGS AND PRECAUTIONS

Malignancies

Malignancies in Adults

  • 39 global HUMIRA clinical trials replaces 37 global HUMIRA clinical trials
  • Addition of and uveitis (UV), following hidradenitis suppurativa (HS)
  • (95% confidence interval) of 0.7 (0.48, 1.03)(replaces 0.45m 1.01) per 100 patient-years among 7973 (replaces 7723) HUMIRA-treated patients versus a rate of 0.7 (0.41, 1.17)  (replaces 0.48 and 1.31) per 100 patient-years among 4848 (replaces 4598) control-treated patients.
  • In 52 (replaces 50) global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV (addition) the most frequently observed malignancies…

Non-Melanoma Skin Cancer

  • During the controlled portions of 39 (replaces 37) global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, (addition) the rate (95% confidence interval) of NMSC…

Lymphoma and Leukemia

  • In the controlled portions of 39 (replaces 37) global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV, (addition) 2 lymphomas occurred among 7973 (replaces 7723) HUMIRA-treated patients versus 1 among 4848 (replaces 4598) control-treated patients. In 52 (replaces 50) global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV (addition) with a median duration of approximately 0.7 years, including 24,605 (replaces 24,135) patients and over 40,215 (replaces 39,000) patient-years…

Neurologic Reactions

  • (addition) discontinuation of HUMIRA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and central demyelinating disorders.

Immunizations

  • (addition) 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 liveattenuated) exposed infants.

ADVERSE REACTIONS

Clinical Trials Experience

Infections

  • In the controlled portions of the 39 (replaces 37) global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC, Ps, HS and UV (addition), the rate of serious infections was 4.3 (replaces 4.4) per 100 patient-years in 7973 (replaces 7723) HUMIRA-treated patients versus a rate of 2.9 per 100 patient-years in 4848 (replaces 4598) control-treated patients.

Tuberculosis and Opportunistic Infections

  • In 52 (replaces 50) global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, UC, Ps, HS and UV (addition) that included 24,605 (replaces 24,135) HUMIRA-treated patients, the rate of reported active tuberculosis was 0.20 per 100 patient-years and the rate of positive PPD conversion was 0.09 (replaces 0.10) per 100 patient-years. In a subgroup of 10,113 (replaces 9959) U.S. and Canadian HUMIRA-treated patients, the rate of reported active TB was 0.05 per 100 patient-years and the rate of positive PPD conversion was 0.07 (replaces 0.8) per 100 patient-years.

Liver Enzyme Elevations

  • (addition) In controlled trials of HUMIRA (initial doses of 80 mg at Week 0 followed by 40 mg every other week starting at Week 1) in patients with uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and control-treated patients, respectively, ALT elevations = 3 x ULN occurred in 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients.

Immunogenicity

  • In patients with non-infectious uveitis, anti-adalimumab antibodies were identified in 4.8% (12/249) of patients treated with adalimumab. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 mcg/mL. Among the patients whose serum adalimumab levels were < 2 mcg/mL (approximately 23% of total patients studied), the immunogenicity rate was 21.1%. Using an assay which could measure an anti-adalimumab antibody titer in all patients, titers were measured in 39.8% (99/249) of non-infectious uveitis patients treated with adalimumab. No correlation of antibody development to safety or efficacy outcomes was observed.
  • The data reflect the percentage of patients whose test results were considered positive for antibodies to adalimumab or titers (addition), and are highly dependent on the assay.

Other Adverse Reactions

Uveitis Clinical Studies (addition)

  • HUMIRA has been studied in 464 patients with uveitis (UV) in placebo-controlled and open label extension studies. The safety profile for patients with UV treated with HUMIRA was similar to the safety profile seen in patients with RA.

DRUG INTERACTIONS

Biological Products
  • There is insufficient information regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, CD, UC, Ps, HS and UV. (addition)

USE IN SPECIAL POPULATIONS

  • PLLR Conversion; please refer to label.

MEDICATION GUIDE

What is HUMIRA?

HUMIRA is a medicine called a Tumor Necrosis Factor (TNF) blocker. HUMIRA is used:

  • To treat non-infectious intermediate, posterior and panuveitis (UV) in adults. (addition)

What should I tell my doctor before taking HUMIRA?

  • HUMIRA may not be right for you. Before starting HUMIRA, tell your doctor about all of your health conditions, including if you:
    • have a baby and you were using HUMIRA during your pregnancy. Tell your baby’s doctor before your baby receives any vaccines. (addition)

 

September 2015

Summary View

WARNINGS AND PRECAUTIONS

Malignancies
  • *changes in information about number of controlled portions of global Humira clinical trials

 

May 2014

Summary View

6 ADVERSE REACTIONS

6.2 Postmarketing Experience
  • Hepato-biliary disorders: … added … hepatitis
     

 

May 2013

Summary View

5 WARNINGS AND PRECAUTIONS

5.1 Serious Infections
  • Cases of reactivation of tuberculosis and new onset tuberculosis infections have been reported in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Reports included cases of pulmonary and extrapulmonary (i.e., disseminated) tuberculosis. Evaluate....
  • Despite prophylactic treatment for tuberculosis, cases of reactivated tuberculosis have occurred in patients treated with HUMIRA
5.2 Malignancies
  • The potential risk with the combination of azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered.
5.3 Hypersensitivity Reactions
  • Anaphylaxis and angioneurotic edema have been reported following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, ......
5.10 Immunizations
  • It is recommended that JIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization.....

6 ADVERSE REACTIONS

6.2 Postmarketing Experience
  • General disorders and administration site conditions: Pyrexia
  • Neoplasms benign, malignant and unspecified (incl cysts and polyps): Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin)

7 DRUG INTERACTIONS

7.2 Biologic Products
  • Concomitant administration of HUMIRA with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF blockers is not recommended based upon the possible increased risk for infections and other potential pharmacological interactions.

8 Use In Specific Populations

8.1 Pregnancy

Pregnancy Category B

  • see PI for extensive changes to all subsections
8.3 Nursing Mothers
  • Limited data from published literature indicate that adalimumab is present in low levels in human milk and is not likely to be absorbed by a breastfed infant.
8.4 Pediatric Use
  • Due to its inhibition of TNFα, HUMIRA administered during pregnancy could affect immune response in the in uteroexposed newborn and infant. Data from five infants exposed....

 

May 2012

Summary View

6 ADVERSE REACTIONS

6.2 Postmarketing Experience
  • added...liver failure, sarcoidosis, demyelinating disorders (e.g., optic neuritis, Guillain-Barré syndrome), cerebrovascular accident, pulmonary embolism, alopecia, and deep vein thrombosis.

  

November 2009 

Summary View 

BOXED WARNING

Malignancy
  • Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member.

WARNINGS and PRECAUTIONS

  • Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blocking agents (initiation of therapy ≤ 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin's and non-Hodgkin's lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports.
  • In the controlled portions of clinical trials of all the TNF-blocking agents, more cases of lymphoma have been observed among patients receiving TNF blockers compared to control patients. In controlled trials in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque psoriasis, 2 lymphomas were observed among 3853 HUMIRA-treated patients versus 1 among 2183 control patients. In combining the controlled and uncontrolled open-label portions of these clinical trials with a median duration of approximately 2 years, including 6539 patients and over 16,000 patient-years of therapy, the observed rate of lymphomas is approximately 0.11/100 patient-years. This is approximately 3-fold higher than expected in the general population.1 Rates in clinical trials for HUMIRA cannot be compared to rates of clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with rheumatoid arthritis, particularly those with highly active disease, are at a higher risk for the development of lymphoma. Cases of acute and chronic leukemia have been reported in association with postmarketing TNF-blocker use in rheumatoid arthritis and other indications. Even in the absence of TNF-blocker therapy, patients with rheumatoid arthritis may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia.

ADVERSE REACTIONS

Postmarketing Experience
  • Skin reactions: new or worsening psoriasis (all sub-types including pustular and palmoplantar)  

 

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