Understanding Humira

Humira (also known as adalimumab) is a Tumor Necrosis Factor (TNF) Inhibitor that is indicated for the treatment of the following autoimmune diseases: rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease, and plaque psoriasis.

Humira is administered subcutaneously and works by blocking tumor necrosis factor, a protein that is naturally released by certain cells of the immune system. TNF’s primary roll in the body is to regulate immune responses in order to defend the body against infectious diseases and foreign materials. TNF promotes an inflammatory response, which initiates the healing process.

People with autoimmune disease produce extra amounts of TNF, leading to pain, inflammation and cell damage as the immune system mistakenly starts attacking healthy tissue. Humira blocks the TNF, which might help relieve the symptoms of the underlying disease, but at the same time compromises the immune system and its ability to do its job.

Consequently, Humira has been associated with a plethora of devastating, even deadly, side effects.

Humira was approved by the FDA in December 2002, and launched by Abbott Laboratories in 2003 with a label, designed for physicians, that warned of little more than the risk of tuberculosis. Since that time, the label has been changed and warnings and risks added, as mandated by the FDA, over 20 times and the length of the label has grown 4-fold. The Black Box warnings have greatly expanded. A guide for patients was finally added, but with only limited information.

Unlike the warnings in 2003, Humira’s label now warns of serious opportunistic infections, malignancies, nervous system disorders including multiple sclerosis, heart failure, and a multitude of problems with drug-interactions.

Humira Timeline

December 2002
Humira is approved by FDA. (link to FDA)

May 2006
The Journal of the American Medical Association (JAMA) reports 3-fold increased risk of cancer in people taking TNF-blockers such as Humira. (JAMA Article)

February 2007
Humira introduces a new label design as ordered by the FDA for the benefit of physicians that identifies the current changes to the label. (February 2007 Label)

February 2008
Humira introduces a Patient Medication Guide – separate from the label and for the benefit of the patients (Patient Medication Guide)

June 2008
The FDA releases an Early Communication letter regarding the possible association between the use of Humira and the development of lymphoma and other cancers in children and young adults. (link to FDA)

September 2008
The FDA orders stronger warnings for Humira and the risk of opportunistic infections, including histoplasmosis. Included in their requirement that the Black Box be changed to include these warnings, Abbott Labs was ordered to comply with a Risk Evaluation Mitigation Strategy (REMS) due to the seriousness of the risk. (link to FDA)

December 2008
The FDA reprimands Abbott Labs for airing a misleading advertisement for treatment of plaque psoriasis with Humira.  Abbott is accused of misbranding Humira and misleadingly minimizing the serious risks associated with Humira. (link to FDA)

August 2009
The FDA orders a Black Box warning for the increased risk of lymphoma and other cancers in children and young adults. (link to FDA)

November 2009
November 2009 marked some of the most serious changes in the Humira label.

Black Box of the label was strengthened to include a serious risk of opportunistic infections including histoplasmosis and bacterial sepsis, and the risk of lymphoma and other cancers in children and young adults. (Nov 2009 Label)

In the Warnings Section under Full Prescribing Information, after years of stating that taking Humira concomitantly with Methotrexate and other immunosuppressants was just fine, the increased risk of infection leading to hospitalization and even death in those that do so is added. (Nov 2009 - Methotrexate & Histoplasmosis Warning)  

Also in the Warnings Section under Full Prescribing Information, the seriousness and difficulty in diagnosing histoplasmosis and other opportunistic infections is highlighted, as well as the recommended treatment.(Nov 2009 - Methotrexate & Histoplasmosis Warning)  

The risk of acute or chronic leukemia is added to Section 5.2 Malignancies.(Nov 2009 - Leukemia Warning) 

Under Adverse Events, incidences of patients reporting new onset or worsening psoriasis is added to Section 6.2 Postmarketing Experience. (Nov 2009 - Psoriasis)

April 2010
Abbott implements the REMS requirement for Humira, as ordered by the FDA for a drug that poses a potential serious safety risk (link to REMS)

May 2010
Abbott releases the Dear Healthcare Provider letter (6 months after adding the risk to the Black Box) outlining the serious risk of histoplasmosis and other opportunistic infections. (Dear Doctor Letter)

July 2010
Under Section 5.5 Neurological Reactions, the risk of demyelinating disease is expanded to include multiple sclerosis, peripheral demyelinating disease, and Gullain-Barre syndrome. (July 2010 Label) (July 2010 - Section 5.5)

March 2011
Abbott updates the REMS and the Invasive Fungal Infection Educational Pamphlet. (March 2011 Label - REMS)

The risk of hepatosplenic T-cell lymphoma (HSTCL), an extremely rare cancer, is added to the Black Box.(March 2011 Label - Black Box)

Section 2.5 Monitoring And Assessing Safety was added, advising that patients should be tested for TB before and during treatment with Humira.(March 2011 Label - Section 2.5)

Sections 5.1 and 5.11 were strengthened to include the risk of increased serious infection when taking Humira concomitantly with Abatacept in patients with RA.(March 2011 Label - Section 5.1)

The statement that had been included in all previous labels, “the role of TNF and cancer is not know,” is removed in Section 5.2 Malignancies.  The malignancy risk is now outlined to include lymphoma, non-melanoma skin cancer, and cancer risk in children and young adults. (March 2011 Label - Section 5.2)

The risk of acute liver failure is added to Section 6.1 Adverse Reactions – Clinical Studies Experience. (March 2011 Label - Section 6.1)

April 2011
The FDA issues a Drug Safety Communication Letter warning of the serious risks of Humira and the development of the rare T-cell lymphoma, HSTCL. (link to FDA)

September 2011
The risks of Legionella and Listeria are added to the Black Box. (link to FDA) (September 2011 Label) (September 2011 Label - Legionella)

November 2011
The FDA issues a Drug Safety Update and the announcement of enhanced surveillance regarding the risks of Humira and people under 30 years of age. (link to FDA)

December 2011
The risk of optic neuritis is added to the Neurological warnings in the label.(December 2011 Label) (December 2011 Label - Optic Neuritis)

Humira Safety Information and Links

Full Prescribing Information:
http://www.rxabbott.com/pdf/humira.pdf

Important Update to the Prescribing Information:
http://www.humirapro.com/Utility/LabelUpdate.aspx

Current Medication Guide:
http://www.rxabbott.com/pdf/humira_medguide.pdf

Important Changes to the Medication Guide:
http://www.humiramentor.com/Main/ImportantUpdates

REFERENCES:

* Bongartz, T, and AJ Sutton, and MJ Sweeting, and I Buchan, and EL Matteson, and V Montori. "Anti-TNF antibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials." JAMA : The Journal of the American Medical Association 295 (2006): 2275-2285