Crohn's Disease + Ulcerative Colitis Medication
FDA Drug Safety Communication: New risk factor for Progressive Multifocal Leukoencephalopathy (PML) associated with Tysabri (natalizumab)
The U.S. Food and Drug Administration (FDA) is informing the public that testing positive for anti-JC virus (JCV) antibodies has been identified as a risk factor for progressive multifocal leukoencephalopathy (PML). PML is a rare but serious brain infection associated with use of Tysabri (natalizumab) for the treatment of multiple sclerosis (MS) or Crohn's disease.
The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more of the other known risk factors for PML. Patients with all three known risk factors have an estimated risk of PML of 11/1,000 users. The risk factors are:
- The presence of anti-JCV antibodies.
- Longer duration of Tysabri treatment, especially beyond 2 years.
- Prior treatment with an immunosuppressant medication (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, or mycophenolate mofetil).
A patient's anti-JCV antibody status may be determined using an anti-JCV antibody detection test that has been analytically and clinically validated, and has been ordered by a healthcare professional. The Stratify JCV Antibody ELISA test was cleared by FDA on January 20, 2012. Testing positive for anti-JCV antibodies means that a person has been exposed to JCV in the past.
PML is a rare disorder in which the coating (myelin) of some brain nerve fibers gets damaged. Although JCV is a common virus that is generally harmless and does not cause symptoms in people whose immune systems function normally, it can cause PML in people with weakened immune systems. Causes of a weakened immune system may include human immunodeficiency virus (HIV) infection, leukemia or lymphoma, or taking a medication such as Tysabri.
The FDA issued two previous Drug Safety Communications (DSCs) on the risk of PML with the use of Tysabri on February 5, 2010 and on April 22, 2011.
Additional Information for Patients
- As a result of this new information, your healthcare professional may recommend a blood test to see if you have ever been exposed to JCV, the virus that causes PML. This test measures antibodies to the virus, which are often referred to as "anti-JCV antibodies."
- The risk of developing PML increases if you have tested positive for anti-JCV antibodies and have one or two of the other known risk factors.
- The risk of PML is greatest if you have all three known risk factors.
- Discuss any questions or concerns about Tysabri and the risk of PML with your healthcare professional.
- Report any side effects you experience to your healthcare professional and the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- Inform your patients that PML continues to occur in patients treated with Tysabri.
- The Tysabri label has been updated with information about a newly identified third risk factor for PML (see Data Summary).
- For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered to be anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody test.
- Consideration should be given to testing patients prior to treatment or during treatment if antibody status is unknown.
- Patients who test negative for anti-JCV antibodies are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. Consideration should be given to periodic re-testing of patients previously determined to be anti-JCV antibody negative.
- When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay.
- Tell your patients to contact you if they develop any symptoms suggestive of PML. Symptoms of PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory and orientation, leading to confusion and personality changes. The progression of deficits can lead to death or severe disability over weeks or months.
- Monitor your patients and withhold Tysabri immediately at the first sign or symptom of PML.
- Report adverse events involving Tysabri to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
201 cases of PML have been reported among approximately 96,582 patients treated with Tysabri worldwide through January 4, 2012.
New data have identified the presence of anti-JCV antibodies as a risk factor for developing PML in Tysabri-treated patients. The Stratify JCV Antibody ELISA test, which can detect these antibodies, was cleared by FDA on January 20, 2012.
The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000. (See Table 1).
The PML incidence information in Table 1 below is being added to the Tysabri label:
Table 1: Estimated PML Incidence Stratified by Risk Factor
Anti-JCV Antibody Positive* Anti-JCV Antibody Positive* Tysabri Exposure† No Prior Immunosuppressant Use Prior Immunosuppressant Use 1-24 months <1/1,000 2/1,000 25-48 months 4/1,000 11/1,000
Notes: Based on postmarketing PML data and Tysabri use data as of September 1, 2011.
†Data beyond 4 years of treatment are limited.
* Risk in anti-JCV antibody positive patients was estimated based on the assumptions that 18% of Tysabri-treated MS patients have a history of prior immunosuppressant treatment and that 55% of Tysabri-treated MS patients are anti-JCV antibody positive.
* The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with a false negative rate of 3%.
FDA continues to evaluate the reports of PML and consider new ways to help patients and healthcare professionals understand the risk.
- U.S. National Library of Medicine. National Institutes of Health. Health Topics-Progressive multifocal leukoencephalopathy. Available at http://www.nlm.nih.gov/medlineplus/ency/article/000674.htm Accessed January 11, 2012.
Source : FDA (January 2012)
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FDA Drug Safety Communication: Safety Review update on reports of Hepatosplenic T-Cell Lymphoma in adolescents and young adults receiving tumor necrosis factor (TNF) blockers, azathioprine and/or mercaptopurine
The U.S. Food and Drug Administration (FDA) is informing the public that it continues to receive reports of a rare cancer of white blood cells (known as Hepatosplenic T-Cell Lymphoma or HSTCL), primarily in adolescents and young adults being treated for Crohn’s disease and ulcerative colitis with medicines known as tumor necrosis factor (TNF) blockers, as well as with azathioprine, and/or mercaptopurine.
Crohn's disease and ulcerative colitis cause inflammation of the digestive system. Common symptoms are pain in the abdomen, cramps, and diarrhea. Bleeding from the rectum, weight loss, joint pain, skin problems and fever also may occur. Children with the disease may have growth problems, develop intestinal blockage, and experience malnutrition.1
HSTCL is an aggressive (fast-growing) cancer and is usually fatal. The majority of cases reported were in patients being treated for Crohn’s disease or ulcerative colitis, but also included a patient being treated for psoriasis and two patients being treated for rheumatoid arthritis. FDA is now updating the number of reported cases of HSTCL.
Although most reported cases of HSTCL occurred in patients treated with a combination of medicines known to suppress the immune system, including the TNF blockers, azathioprine, and/or mercaptopurine, there have been cases reported in patients receiving azathioprine or mercaptopurine alone.
FDA believes the risks and benefits of using TNF blockers, azathioprine, and/or mercaptopurine should be carefully weighed when prescribing these drugs to children and young adults, especially for the treatment of Crohn’s disease and ulcerative colitis. Patients should continue to talk to their Healthcare Professionals about the potential risk of HSTCL with use of these medications in order to make the best decision about their medical treatment.
FDA previously communicated about the increased risk of lymphomas and other cancers associated with the use of TNF blockers in children and adolescents in June 20081 and in August 20092 when warnings3 were added to the TNF blocker labels.
The product labels for Remicade (infliximab) and Humira (adalimumab) have been updated and the product labels for azathioprine and mercaptopurine are being updated to include warnings about HSTCL that have been reported in patients treated with these products.
FDA will continue to communicate any new safety information to the public as it becomes available.
Additional Information for Patients
• Be aware that taking TNF blockers, azathioprine, and/or mercaptopurine may increase the risk of HSTCL.
• Review the Medication Guide that accompanies a prescription for TNF blockers.
• Do not stop taking TNF blockers, azathioprine, and/or mercaptopurine without talking to your healthcare professional.
• Discuss any questions or concerns about these medications with your healthcare professional.
• Report any side effects you experience to the FDA MedWatch program using the information in the “Contact Us” box at the bottom of the page.
Additional Information for Healthcare Professionals
• Discuss with patients and caregivers the increased risk of developing HSTCL, especially in adolescents and young adults, taking into account the risks/benefits of TNF blockers, azathioprine, and/or mercaptopurine, and other immunosuppressive therapies.
• Educate patients and caregivers about the signs and symptoms of malignancies such as HSTCL so that they are aware of and can seek evaluation and treatment of any signs or symptoms. These may include splenomegaly, hepatomegaly, abdominal pain, persistent fever, night sweats, and weight loss.
• Monitor for the emergence of malignancies when a patient has been treated with TNF blockers, azathioprine, and/or mercaptopurine.
• Know that people with rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis may be more likely to develop lymphoma than the general U.S. population. Therefore, it may be difficult to measure the added risk of TNF blockers, azathioprine, and/or mercaptopurine.
• Report adverse events involving TNF blockers, azathioprine and/or mercaptopurine to the FDA MedWatch program, using the information in the “Contact Us” box at the bottom of the page.
FDA is updating the public about the number of reported cases of Hepatosplenic T-cell Lymphoma (HSTCL). From initiation of TNF blocker marketing to December 31, 2010, the following HSTCL cases have been identified in the Adverse Event Reporting System (AERS) database (de-duplicated), the literature, and the HSTCL Cancer Survivors' Network in association with the following agents (mutually exclusive): Infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), and mercaptopurine (3). Of note, in the 20 cases identified with infliximab use, 18 of the patients also were using concomitant mercaptopurine or azathioprine (for the remaining two patients, concomitant drug use was not reported). Of the 5 cases identified with infliximab/adalimumab use, 4 patients were using concomitant mercaptopurine or azathioprine (for the remaining patient, concomitant drug use was not reported). Complete medical histories have not been obtained on some cases to exclude a history of exposure to a potential confounder/co-factor. See Table 1 for the list of cumulative cases associated with selected immunosuppressant use reported as of December 31, 2010.
Due to the potential increased risk for cancers, including HSTCL, the risks and benefits of using TNF blocker products, azathioprine and/or mercaptopurine should be carefully weighed when prescribing these drugs especially in adolescents and young adults.
- U.S. National Library of Medicine. National Institutes of Health. Crohn's Disease health topic. Available at http://www.nlm.nih.gov/medlineplus/crohnsdisease.html4 Accessed March 1, 2011.
FACTS ON TNF BLOCKERS
- TNF blockers suppress the immune system by blocking the activity of TNF, a substance in the body that can cause inflammation and lead to immune-system diseases, such as Crohn’s disease, ulcerative colitis, rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and plaque psoriasis. The drugs in this class include Remicade (infliximab), Enbrel (etanercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab).
Azathioprine (also known as Imuran) and mercaptopurine (known as
Purinethol) also suppress the immune system. They are commonly used
as part of a combination regimen or used alone to treat Crohn’s
disease and ulcerative colitis, although they are not approved for
is approved for the prevention of rejection following renal
transplantation and for the reduction of signs and symptoms of
- Mercaptopurine is approved to treat acute lymphatic leukemia.
1 Zeidan A, Sham R, Shapiro J, et al. Hepatosplenic T-cell lymphoma in a patient with Crohn's disease who received infliximab therapy. Leuk Lymph 2007: 48(7): 1410-3.
2 Wijeratne R, Teller T, Sekhon H, et al. Hepatosplenic T cell lymphoma following exposure to infliximab in a patient with ulcerative colitis. Inflamm Bowel Dis 2009; 5 (S2): S11.
3 Drini M, Prichard PJ, Brown GJE, et al. Hepatosplenic T-cell lymphoma following infliximab therapy for Crohn's disease. Med J Austral 2008; 189(8): 464-5.
4 Kotlyar D, Blonski W, Porter DL et al. Hepatosplenic T-cell lymphoma (HSTCL) and inflammatory bowel disease (IBD): A rare complication after long-term thiopurine exposure: Case report and systematic review of the literature. Gastroenterology 2009; 36(1): S1133.
5 Thayu M, Markowitz JE, Mamula P, et al. Hepatosplenic T-cell lymphoma in an adolescent patient after immunomodulator and biologic therapy for Crohn's disease. J Pediatr Gastroenterol 2005; 40(2): 220-2.
6 Gumbs AA, Zain J, O'Connor OA. Importance of early splenectomy in patients with hepatosplenic T-cell lymphoma and severe thrombocytopenia. Ann Surg Oncol 2009; 16 (7): 2014-7.
7 Bernheim O, Scherl E, Bosworth B, et al. Hepatosplenic T-cell lymphoma after sequential infliximab, adalimumab, and natalizumab therapy for Crohn's Disease. Abstract #P1146 at 74th meeting of the American College of Gastroenterology.
8 Beigel F, Jurgens M, Tiliack C, et al. Hepatosplenic T-cell lymphoma in a patient with Crohn's disease. Nat Rev Gastroenterol Hepatol 2009; 6: 443-6.
9 Grimpen F, Yeung D, Joseph J, et al. Hepatosplenic T cell lymphoma, immunosuppressive agents and biologicals: What are the risks? J Gastroenterol Hepatol 2009; 24: A311.
10 Rosh J. T-cell hepatosplenic lymphoma in an adolescent on azathioprine montherapy for ulcerative colitis and autoimmune hepatitis (abstract). North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NSAPGHAN) 2006 annual meeting.
11 Navarro JT, Ribera JM, Mate JL, et al. Hepatosplenic T-gamma delta lymphoma in a patient with Crohn's disease treated with azathioprine. Leuk Lymphoma 2003; 44: 531-3.
12 Mittal C, Milner BJ, Johnston PW, et al. A case of hepatosplenic gamma-delta T-cell lymphoma with a transient response to Gludarabine and Alemtuzumab. Eur J Haematol 2006; 76: 531-4.
13 Lemann M, el La Valussiere G, Bouhnik Y, et al. Intravenous cyclosporine for refractory attacks of Crohn's disease (CD): Long-term follow-up of patients (abstract). Gastroenterology 1998; 114(4): A 1020.
14 Humphreys MR, Cino M, Quirt I, et al. Long-term survival in two patients with hepatosplenic T cell lymphoma treated with interferon-alpha. Leuk Lymph 2008; IFirst article, pp 1-4.
15 HSTCL Cancer Survivors Network, csn.cancer.org/node/136135, accessed on June 25, 2010 (search identified 2 patients treated for UC and 1 patient treated for CD; note that these cases have not been verified by a health care professional).
16 Keller KM, Magdefrau C, Bohl J, et al. Hepatosplenic T-cell lymphoma in a 15-year-old boy with ulcerative colitis treated with azathioprine for 9 years. J Pediatr Gastroenterol Nutr; 44(6): abstract PG6-12.
17 Vega F, Medeiros LJ, Gaulard P. Hepatosplenic and other γδ T-cell lymphomas. Am J Clin Pathol 2007; 127: 869-80.
18 Moran G, Dillon J, Green J. Crohn's disease, hepatosplenic T-cell lymphoma and no biological therapy: Are we barking up the wrong tree? Inflam Bowel Dis 2008 Dec 9 [Epub ahead of print].
19 Ochenrider MG, Patterson DJ, Aboulafia DM. Hepatosplenic T-cell lymphoma in a young man with Crohn's Disease: Case report and literature review. Clin Lymphoma Myeloma Leuk 20100; 10(2): 144-8.
20 Fowler S, Beyak M, Depew WT, et al. Hepatosplenic T-cell lymphoma in Crohn's disease. Where does the risk lie? Gastroenterology 2010; 138(5): Suppl 1 p. 675.
- Information on Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)5
to the June 4, 2008 Early Communication about the Ongoing Safety Review
of Tumor Necrosis Factor (TNF) Blockers (marketed as Remicade, Enbrel,
Humira, Cimzia, and Simponi)6
- FDA: Cancer Warnings Required for TNF Blockers7
Communication About an Ongoing Safety Review of Tumor Necrosis Factor
(TNF) Blockers (marketed as Remicade, Enbrel, Humira, and Cimzia)8
- Report a Serious Problem
- 1-800-FDA-0178 Fax MedWatch Online9
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