In a supplementary "Question and Answer" document released yesterday, the FDA provided more information on the types of cancers seen in children and teens treated with TNF blockers. According to the document, the following types of pediatric malignancies were reported between 2001 and 2008:
Hepatosplenic T-cell lymphoma, 10 cases
Non-Hodgkin’s lymphoma, 7 cases
Hodgkin's lymphoma, 6 cases
Leukemia, 6 cases
Malignant Melanoma, 3 cases
Thyroid cancer, 3 cases
Basal cell carcinoma, 1 case
Lymphoma and AML, 1 case
Leiomyosarcoma, 1 case
Nephroblastoma, 1 case
Renal cell carcinoma, 1 case
Metastatic hepatocellular cancer, 1 case
Malignant mastocytosis, 1 case
Neuroblastoma, 1 case
Colorectal cancer, 1 case
Yolk sac tumor, 1 case
Myelodysplasia, 1 case
Bladder cancer, 1 case
These 48 cases of pediatric cancers included both U.S. (32) and non-U.S. (16) cases. According to the document, 31 cases of malignancy were reported in children taking Remicade, including 10 cases of hepatosplenic T-cell lymphoma in patients with inflammatory bowel disorder; 15 cases of malignancy in children receiving Enbrel were reported; and two cases of malignancy in children receiving Humira were reported. The FDA also said that the 48 cases of pediatric cancers did not confirm a dose association with malignancy.
Last month, the FDA had said that there were 11 deaths among the 48 cases of cancer. The causes of death included hepatosplenic T-cell lymphoma (9 cases) and T-cell lymphoma (1 case). In the remaining case, the patient died from sepsis after achieving remission of the lymphoma.
In children, TNF blockers are used to treat rheumatoid arthritis, inflammatory bowel disorder and Crohn’s disease. They are also approved to treat a variety of chronic, inflammatory and autoimmune system diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF blockers work by neutralizing a protein that, when overproduced, causes inflammation and damage to bones, cartilage and other tissue.
The FDA had been studying the link between the pediatric uses of TNF blockers and cancer since 2008.
The FDA had been studying the link between the pediatric uses of TNF blockers and cancer since 2008. The safety review was prompted by approximately 30 reports of cancer in children and adolescents treated with TNF blockers.
According to a notice posted on the FDA's Website on yesterday, the agency has identified 48 cases of malignancies in children and adolescents treated with TNF blockers. Approximately half were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. Other malignancies reported include leukemia, melanoma, and solid organ cancers. Malignancies such as leiomyosarcoma, hepatic malignancies, and renal cell carcinoma, which are rare in children, were also reported.
Of the 48 cases of cancer, there were 11 deaths, the FDA said. The causes of death included hepatosplenic T-cell lymphoma (9 cases) and T-cell lymphoma (1 case). In the remaining case, the patient died from sepsis after achieving remission of the lymphoma.
Cimzia, approved in April 2008, and Simponi, approved in April 2009, were not included in the FDA’s review because they are not approved for use in children and were minimally used during the review period.
The FDA is requiring manufacturers of TNF blockers to update the Boxed Warning in the prescribing information to alert healthcare professionals of an increased risk of lymphoma and other malignancies in children and adolescents treated with TNF blockers. Along with updating the drugs' labels, the FDA is requiring companies to add information about cancer risks to patient medication guides. The FDA said it is also working with the manufacturers to further define the scope of the cancer risk.
In addition to the updated Boxed Warning, the FDA also required several other changes to the prescribing information for TNF blockers to warn of and mitigate the risks associated with these drugs. These changes are based on additional safety reviews and include:
* Update to the Warnings section describing reported cases of leukemia in adults, adolescents, and children. Changes to the Warnings section of the labeling will also include additional information on malignancies in children and adolescents (see also Boxed Warning information above).
* Update to the Adverse Events section to include information on reported cases of new-onset psoriasis.
* Revised Medication Guide to reflect this new safety information.
In children, TNF blockers are used to treat rheumatoid arthritis, inflammatory bowel disorder and Crohn's disease. They are also approved to treat a variety of chronic, inflammatory and autoimmune system diseases including juvenile idiopathic arthritis, rheumatoid arthritis, psoriatic arthritis, plaque psoriasis and ankylosing spondylitis. TNF blockers work by neutralizing a protein that, when overproduced, causes inflammation and damage to bones, cartilage and other tissue.
Humira, Kineret, and Remicade each increased the risk of developing shingles by 80 percent according to Anja Strangfeld, MD from the German Rheumatism Research Center in Berlin, "We compared these different types of TNF inhibitor with conventional disease-modifying anti-rheumatic drugs and we found there is an increased risk of herpes zoster in patients treated with the monoclonal antibodies." The drugs are also used in the treatment of ankylosing spondylitis, psoriatic arthritis, and Crohn’s disease because they quiet unmanageable immune responses common with these diseases, said Web MD.
The Guardian explained that rheumatoid arthritis occurs when the body’s immune system attacks joint linings, causing stiffness, swelling, and pain. Shingles occurs when the herpes zoster virus—the virus that causes chickenpox—is activated in people who have already suffered from chickenpox. Shingles cause severely painful blisters, headache, flu-like symptoms without fever, itching, tingling, pain, dizziness, weakness, vision changes, and changes in thought processes
Unfortunately, said Richard J. Whitley, MD, professor of pediatrics, microbiology, medicine, and neurosurgery at the University of Alabama, Birmingham, the drugs can not only prompt shingles in patients taking Humira, Kineret, and Remicade, the risk increases in those patients who have already suffered from shingles, reported Web MD. "It's pretty clear that if you have had previous zoster and take these anti-TNF monoclonal antibodies, you are going to reactivate it," Whitley told WebMD.
About one in five—or 25 percent—of the participants who developed shingles also suffered complications, which was more than expected, said Robert F. Betts, MD, professor of medicine at the University of Rochester, New York, according to WebMD. The risk of shingles appeared to be highest in older patients and those also taking steroids, said HealthDay News. And while a vaccine for shingles exists, it cannot be administered when anti-TNF drugs—which are immune system suppressants—are being taken as the shingles medication contains a live virus.
HealthDay News reported that severe cases of shingles—a viral infection—have been reported in patients being treated with TNF blockers and that there is an established link between the medications and fungal and bacterial infections. As a matter-of-fact, late last year, the U.S. Food and Drug Administration (FDA), urged the makers of Humira, Cimzia, Enbrel, and Remicade to increase safety warnings regarding the risk of developing opportunistic fungal infections; all of the medications carried black-box warnings concerning other safety issues, said HealthDay News.
The study was conducted at the German Rheumatism Research Centre in Berlin, Germany and its findings appear in today’s issue of the Journal of the American Medical Association, said the Guardian.
The FDA said the Humira ad indicates the medication’s risks in "extremely" small type that “fails to adequately convey the serious risks connected to the product.” Of note, Humira carries a black-box warning, the FDA's strongest, which discusses the risk of serious—some fatal—side effects such as tuberculosis and other infections, said Dow Jones. The FDA wants Abbott to stop the ad and respond to the agency by January 2 explaining if it intends to comply with the FDA request, said Dow Jones.
Meanwhile, two years ago, a study revealed that patients taking Humira faced a three-fold risk of developing several kinds of cancer and a two-fold risk of getting severe infections. Humira is in the same class of drugs as Enbrel and Remicade, which are anti-TNF drugs or TNF blocker drugs. TNF is a small protein called a cytokine, which has a major role in the regulation of the immune system. Anti-TNF drugs confine TNF and obstruct the reaction, which causes the abnormal joint inflammation. Humira is approved for the treatment of rheumatoid arthritis and in rheumatoid arthritis, TNF levels are very high, resulting in inflammation, swelling, pain, and joint damage.
A Mayo Clinic study published in the May 17, 2006 issue of the Journal of the American Medical Association, found an apparent link between Humira and other cancers, including skin, gastrointestinal, breast, and lung tumors. According to study author Eric Matteson, a professor at the Mayo Clinic in Rochester, Minnesota, physicians might well expect to see one additional case of cancer developing within six to 12 months of treatment for every 154 patients who take the drugs and could expect to see one serious infection, such as pneumonia, within three to 12 months for every 59 patients treated. Anti-TNF antibody drugs are one of the fastest-growing prescription classes in the nation. Humira was granted FDA approval on December 31, 2002.
Dow Jones noted that Humira is also approved to treat adult patients with moderate to severe chronic psoriasis, a skin disease characterized by red patches and flaky and scaly skin, who don't generally respond to topical medications and is also approved to treat Crohn's disease, a chronic infection of the intestines.
In September, we reported that Federal regulators ordered the makers of Humira, Cimzia, Enbrel, and Remicade to strengthen the existing warnings about opportunistic fungal infections linked to the drugs. At least 45 people are known to have died from such infections.
Biological drugs are defined as medicines whose active substance comes from a biological source. The first biological approved by the U.S. Food and Drug Administration was recombinant insulin in 1982. Such drugs affect the body’s immune system, and relieve symptoms by suppressing that system.
Many had once thought that that biological drugs might be safer than traditional chemical-based medicines. A new study conducted by Dutch researchers, and published in The Journal of the American Medical Association, shows that assumption to be wrong. The study examines biological drug safety actions taken by the FDA and its European counterpart from January 1995 to June 2008. In that time period, US and European regulators approved 174 biological drugs to treat a wide range of conditions.
According to the study, a quarter of those drugs -- 41 out of 174 -- together had 82 safety-related regulatory actions: 46 letters from the FDA to US doctors, 17 letters from European regulators to doctors in Europe, and 19 "black box" warnings -- the FDA's sternest warning. Researchers found that most of the warnings came within five years of a drug's approval.
Many biological drugs have been linked to opportunistic infections and other disorders associated with a suppressed immune system. For instance, just this week, the psoriasis drug Raptiva received a new black box warning because of its link to progressive multifocal leukoencephalopathy, or PML, a serious, often fatal brain infection. Other biological drugs linked to PML include Tysabri, and Rituxan.
Humira, Remicade, Enbrel and Cimizia have all been associated with opportunistic fungal infections, as well as leukemia, lymphoma and other cancers in children and young adults. Enbrel has also been linked to deadly infections, including tuberculosis.
The researcher who conducted the study say their findings indicate that biological drugs need to be subject to greater scrutiny. An editorial accompanying the study calls for improvements to the FDA's system of collecting reports of adverse drug reactions.
Humira, Cimzia, Enbrel and Remicade are known as tumor necrosis factor (TNF) blockers. They are used to treat rheumatoid arthritis, Crohn's disease and other conditions. The drugs work by suppressing the immune system. It has long been known that people taking TNF blockers run a risk of developing opportunistic infections, and the prescribing information for the drugs has included this information. But now the FDA says that current warnings are inadequate.
The FDA's order came after the agency reviewed 240 reports of histoplasmosis, an infection caused by the fungusHistoplasma capsulatum, in patients being treated with Enbrel, Humira, or Remicade. The majority of the reports involved people in the Ohio River and Mississippi River valleys (the fungus is commonly found in those areas). In at least 21 of the reports, histoplasmosis was initially not recognized by health care professionals, and antifungal treatment was delayed. Twelve of those patients died.
The FDA reviewed one reported case of histoplasmosis in a patient taking Cimzia. The FDA also has received reports of cases of coccidioidomycosis and blastomycosis, including deaths, in patients treated with TNF blockers.
The agency has given the makers of Humira, Cimzia, Enbrel and Remicade 30 days to submit the required safety labeling changes, including strengthened warnings and revisions to the Medication Guides, or to provide a reason why they do not believe labeling changes are necessary. If they do not submit new language, or if the FDA disagrees with the new language the company proposes, the Food and Drug Administration Amendments Act of 2007 provides strict timelines for resolving the labeling changes and allows the agency to issue an order directing the labeling change as deemed appropriate to address the new safety information.
The FDA is also reviewing TNF blockers over a possible link to cancer. In June, the agency said it was investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin’s and non-Hodgkin’s based.
In April, the FDA had Amgen and Wyeth include a new black box warning on the Enbrel label stating that the drug has been associated with serious infections, including tuberculosis in some patients. The Enbrel black box warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.
In addition to Humira, which is made by Abbott Laboratories, four other TNF blockers are currently on the market in the US. They are Enbrel, marketed by Wyeth and Amgen; Remicade sold by Schering-Plough; and Cimizia, made by UCB of Belgium. TNF blockers impede the action of a substance made by the body’s immune system called TNF. People with an autoimmune disease, such as rheumatoid arthritis, have too much TNF in their bodies.
The FDA said its review will focus on Humira, Enbrel and Remicade. Remicade is approved for use in children with Crohn's disease. Enbrel and Humira are approved to treat children with juvenile rheumatoid arthritis, according to the FDA. The FDA is requiring the maker of Cimzia to conduct a study to assess long-term risks of the product, including lymphoma and other cancers. This study will begin in 2009 and take about 10 years to complete.All of the labels for the drugs currently address the possible risk of cancer when taking the drug.
The FDA is investigating about 30 reports of leukemia, lymphoma and other cancers in children and young adults submitted between 1998, after the approval of the first TNF blocker, through April of this year. Approximately half of the reports were lymphomas, cancer of the immune system cells, that were both Hodgkin's and non-Hodgkin's based.
The FDA has requested that makers of TNF blockers approved for use in children and young adults supply information about all reported cases of cancer among patients in these age groups taking the drugs. The FDA has also asked health-care professionals to weigh the possible risks against the benefits when prescribing TNF blockers.
In addition to the possible cancer risk, TNF blockers have been associated with an increased risk of some infections. In May, Enbrel had its label modified to include a black box warning - the FDA's strictest safety alert - about its association with serious infections, including tuberculosis. The warning was prompted by global studies of over 20,000 patients taking Enbrel, where tuberculosis was observed in about 200 people.