Health Canada: Safety Update on TNF Blockers and Risk of Cancer in Children and Young Adults

August 29, 2009 – As recent as on August 21, 2009, Health Canada released the following Safety Update Information:

Health Canada is informing health care professionals and Canadians that it is working with manufacturers to further strengthen product labelling for the class of drugs known as tumour necrosis factor (TNF) blockers with respect to an increased risk of cancer in children and young adults.

This communication comes in light of similar labelling updates undertaken by the U.S. FDA following their review, which concluded that there is an increased risk of lymphoma and other cancers associated with the use of TNF blocker drugs in children and adolescents. Health Canada has also been reviewing this issue and is currently working with the manufacturers to strengthen existing warnings in the prescribing information for these drugs.

TNF blockers are used to treat patients with chronic inflammatory diseases including juvenile idiopathic arthritis (JIA), rheumatoid arthritis, psoriatic arthritis, plaque psoriasis, Crohn’s disease, and ankylosing spondylitis (a type of arthritis). They suppress the activity of tumour necrosis factor, a protein that, when overproduced in the body, can cause inflammation and damage to bones, cartilage and tissue, and lead to immune system-related diseases. There are currently five prescription TNF blockers authorized in Canada: Enbrel (etancercept) , Remicade (infliximab), Humira (adalimumab), Simponi (golimumab), and Cimzia (certolizumab pegol).

Currently the labels for all TNF blockers include warnings and precautions on the risk of lymphomas and other cancers. The labels will be updated to highlight the risk of specific cancers, particularly in the younger patient groups. As well, the label updates will include other new safety information based on reviews conducted by Health Canada , including the risk of new-onset psoriasis in patients treated with TNF blockers. Health Canada will inform health care professionals and Canadians again once these updates are complete.

The role of TNF blockers in the development of cancer is not known. Health Canada has communicated in the past on the risk of the development of certain types of cancers, including lymphoma, associated with the use of these drugs.

Health Canada recommends that patients should not stop taking their TNF blocker without first speaking to their doctor. Patients should contact their health care professional if they have any concerns about any medicines they are taking.

You can report any adverse reactions associated with the use of health products to the Canada Vigilance Program by one of the following three ways:

• Report online at the MedEffect ™ Canada Web site
• Call toll-free at 1-866-234-2345
• Complete a Canada Vigilance Reporting Form and either:
  • Fax toll-free to 1-866-678-6789
  • Mail to: Canada Vigilance Program
    Health Canada
    AL 0701C
    Ottawa , ON K1A 0K9

To have postage pre-paid, download the postage paid label from the MedEffect ™ Canada Web site. The Canada Vigilance Reporting Form and the adverse reaction reporting guidelines may also be obtained via this website.

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Etravirine [Intelence]: Association with fatal cases of Stevens Johnson Syndrome (SJS)

August 28, 2009 – As we have learned today, Tibotec Therapeutics and  the American Food and Drug Administration (FDA) notified healthcare professionals of revisions to the WARNINGS AND PRECAUTIONS section of the prescribing information for Etravirine [Intelence].  Etravirine [Intelence] (for chemical structure see graphic provided) is a human immunodeficiency virus type 1 (HIV-1) specific, non-nucleoside reverse transcriptase inhibitor (NNRTI) indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in treatment-experienced adult patients, who have evidence of viral replication and HIV-1 strains resistant to an NNRTI and other antiretroviral agents.

There have been postmarketing reports of cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme, as well as hypersensitivity reactions characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. Etravirine [Intelence] therapy should be immediately discontinued when signs and symptoms of severe skin or hypersensitivity reactions develop.

The new Warnings and Precautions Section (i.e., the Section 5 of that document) of the drug labeling document for Etravirine [Intelence] reads as follows:

5 WARNINGS AND PRECAUTIONS

5.1 Severe Skin and Hypersensitivity Reactions

Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome, toxic epidermal necrolysis and erythema multiforme. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including hepatic failure. In Phase 3 clinical trials, Grade 3 and 4 rashes were reported in 1.3% of subjects receiving INTELENCE™ compared to 0.2% of placebo subjects. A total of 2% of HIV-1-infected subjects receiving INTELENCE™ discontinued from Phase 3 trials due to rash [see Adverse Reactions (6)]. Rash occurred most commonly during the first 6 weeks of therapy.

Discontinue INTELENCE™ immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia). Clinical status including liver transaminases should be monitored and appropriate therapy initiated. Delay in stopping INTELENCE™ treatment after the onset of severe rash may result in a life-threatening reaction.

5.2 Fat Redistribution

Redistribution/accumulation of body fat, including central obesity, dorsocervical fat enlargement (buffalo hump), peripheral wasting, facial wasting, breast enlargement, and “cushingoid appearance” have been observed in patients receiving antiretroviral therapy. The mechanism and long-term consequences of these events are currently unknown. A causal relationship has not been established.

5.3 Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including INTELENCE™. During the initial phase of combination antiretroviral treatment, patients whose immune system responds may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium complex, cytomegalovirus, Pneumocystis jiroveci pneumonia, and tuberculosis), which may necessitate further evaluation and treatment.

Read here the  “Dear Healthcare Professional Letter” sent out by Tibotec Therapeutics in accordance with the FDA.

Orlistat (Marketed as Alli and Xenical): Early Communication About an Ongoing Safety Review with Respect to Serious Liver Injury

August 25, 2009 – From a safety information release of today, we learn that  FDA notified healthcare professionals and patients that it is reviewing new safety information regarding reports of liver-related adverse events in patients taking Orlistat. Orlistat, is marketed in the United States, as a prescription product, Xenical, and as an over-the-counter (OTC) product, Alli. (See the furnished graphic for product names in some other important  (European) markets. Between 1999 and October 2008, 32 reports of serious liver injury, including 6 cases of liver failure, in patients using orlistat were submitted to FDA’s Adverse Event Reporting System. The most commonly reported adverse events described in the 32 reports of serious liver injury were jaundice, weakness, and abdominal pain. FDA is reviewing other data on suspected cases of liver injury submitted by the manufacturers of orlistat, analysis of these data is ongoing and no definite association between liver injury and orlistat has been established at this time. FDA is not advising healthcare professionals to change their prescribing practices with orlistat. Consumers currently taking Xenical should continue to take it as prescribed and those using over-the-counter Alli should continue to use the product as directed.

FDA urges both healthcare professionals and consumers to report side effects from the use of orlistat (Alli and Xenical) to FDA’s MedWatch Adverse Event Reporting Program.

Health Canada: Important New Safety Information on Potential Interactions of Proton Pump Inhibitors (PPIs) with Clopidogrel [Plavix]

August 21, 2008 –  From a new posting on Health Canadas’s website, we learn that in collaboration with Health Canada,  Sanofi-Aventis Canada Inc. and Bristol Myers Squibb Canada Co. have informed Canadian healthcare professionals and patients alike of important new safety information regarding the potential interaction of Proton Pump Inhibitors (PPIs) with Clopidogrel [Plavix]. This potential interaction could lead to a reduction in the level of Clopidogrel’s [Plavix] active metabolite and therefore, it is conceivable that the therapeutic response to Clopidogrel [Plavix ] may be affected. This information is summarized as follows:

Clopidogrel [Plavix] is a prodrug metabolized by the liver, partly by cytochrome P450 2C19 (CYP2C19), before it can be biologically active in preventing atherothrombotic events. Healthcare professionals should be aware of a potential interaction between PPIs or other drugs that inhibit CYP2C19 and Clopidogrel [Plavix] leading to a potential reduction in the clinical activity of Clopidogrel [Plavix].

Administration of PPIs or of other drugs that inhibit CYP2C19 should be discouraged in patients taking Clopidogrel [Plavix]. The risk-benefit relationship of continuing treatment with a PPI should be considered by the prescribing physician taking into account that other gastro-protective agents are available.

Healthcare professionals should continue to prescribe and patients should continue to take Clopidogrel [Plavix] as directed, because Clopidogrel [Plavix] has demonstrated benefits in preventing life-threatening atherothrombotic events that could lead to myocardial infarction or stroke.

PPIs are drugs used to prevent and treat peptic ulcer and gastroesophageal reflux and may inhibit, to some degree, the activity of CYP2C19. Recent reports in the literature suggest a potential interaction with PPIs through CYP2C19 that may reduce the efficacy of Clopidogrel [Plavix]. Although the evidence for CYP2C19 inhibition varies within the class, the effect is possibly related to all members of the PPI class.

Sanofi-Aventis Canada Inc. and Bristol Myers Squibb Canada Co. are currently working with Health Canada on this topic to integrate the new safety information in the Canadian Product Monograph. In addition to updating the Product Monograph for Clopidogrel [Plavix], Sanofi-Aventis and Bristol Myers Squibb are currently conducting studies to further characterize this potential interaction to provide additional information to healthcare professionals.

Managing marketed health product-related adverse reactions depends on healthcare professionals and consumers reporting them. Reporting rates determined on the basis of spontaneously reported post-marketing adverse reactions are generally presumed to underestimate the risks associated with health product treatments. Any case of serious drug interaction with a PPI or a drug known to inhibit CYP2C19 or other serious or unexpected adverse reactions in patients receiving Clopidogrel [Plavix] should be reported to Sanofi-Aventis Canada Inc. or Health Canada at the following addresses: sanofi-aventis Canada Inc., 2150 St. Elzear Blvd. West Laval, Quebec, H7L 4A8, Telephone: 1-800-265-7927.

The Product Monograph and a copy of this Important Safety Information can be accessed online at  sanofi-aventis Canada Inc. or at Bristol-Myers Squibb Canada Co.

Gene May Predict Response to Hepatitis C Therapy

August 18, 2008 – A slight difference in a person’s genetic code could determine whether they respond to a grueling round of treatment for hepatitis C infection or not.

Chronic infection with hepatitis C virus (HCV) affects 170 million people worldwide and is the leading cause of cirrhosis in North America. Although the recommended treatment for chronic infection involves a 48-week course of Peginterferon-2b (PegIFN-2b) or Peginterferon-2a (PegIFN-2a) combined with ribavirin (RBV), it is well known that many patients will not be cured by treatment, and that patients of European ancestry have a significantly higher probability of being cured than patients of African ancestry. In addition to limited efficacy, treatment is often poorly tolerated because of side effects that prevent some patients from completing therapy. For these reasons, identification of the determinants of response to treatment was and continues to be a high priority. A recent study, led by D.B. Goldstein and published in the Journal Nature reported that a genetic polymorphism near the IL28B gene, encoding interferon-3 (IFN-3), is associated with an approximately twofold change in response to treatment, both among patients of European ancestry (P = 1.06 x 10-25) and African-Americans (P = 2.06 x 10-3). Because the genotype leading to better response is in substantially greater frequency in European than African populations, this genetic polymorphism also explains approximately half of the difference in response rates between African-Americans and patients of European ancestry.

Genetic tests looking for that particular genetic variant could be used to help treating physicians decide which patients are most likely to benefit from the current PegIFN-2b or PegIFN-2a based therapies. Of course, the findings of this study do not mean poor responders should not be offered therapy but it may alter their decision-making.

Increased Risk for Lymphoma and Other Malignancies in Children and Adolescents Treated with Tumor Necrosis Factor – α (TNF – α) Blockers (marketed as Remicade, Enbrel, Humira, Cimzia, and Simponi)

August 9, 2009 –  On August 4, 2009, the US Food and Drug Administration (FDA) posted the following Safety Alert for Human Medicines (graphic added by the author of this blog post):

The U.S. Food and Drug Administration is requiring stronger warnings in the prescribing information for a class of drugs known as TNF blockers. The warnings, which include an updated boxed warning, highlight the increased risk of cancer in children and adolescents who receive these drugs to treat juvenile rheumatoid arthritis, the inflammatory bowel disorder, Crohn’s disease, and other inflammatory diseases.

In addition, the FDA is working with manufacturers to explore new ways to further define the risk of cancer in children and adolescents who use these drugs.

TNF blockers target and neutralize tumor necrosis factor-alpha (TNF-α), a protein that, when overproduced in the body due to chronic inflammatory diseases, can cause inflammation and damage to bones, cartilage and tissue. The drugs in this class include Remicade (infliximab), Enbrel (etancercept), Humira (adalimumab), Cimzia (certolizumab pegol) and Simponi (golimumab).

Today’s action is based on the completion of an investigation first announced by the FDA in June 2008. An analysis of U.S. reports of cancer in children and adolescents treated with TNF-blockers showed an increased risk of cancer, occurring after 30 months of treatment on average. About half of the cancers were lymphomas, a type of cancer involving cells of the immune system. Some of the reported cancers were fatal.

Additional required updates to the prescribing information include incorporation of reports of psoriasis associated with the use of TNF blockers.

For more information see:

• Update to June 2008 Early Communication about an Ongoing Safety Review of TNF Blockers
• Information for Healthcare Professionals
• June 2008 Early Communication about an Ongoing Safety Review of TNF Blockers

If you experience a serious problem with one of the medicines dicussed here, please report it to FDA by means of the MedWatch Online reporting system.

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