Drug Advisories

• 2/24/05: Medication & Advisory
  
  SMALL STUDY TIES RITALIN TO HIGHER CANCER RISK
  
  SCIENTIST HOPES A LARGER LOOK AT DRUGS THAT TREAT ATTENTION DEFICIT WILL REFUTE RESULTS
  
  by Todd Ackerman (todd.ackerman@chron.com)
  
  In a small but potentially alarming new study, local scientists have linked the most popular drug used to treat attention-deficit problems with increased risks of cancer.
  
  The study of 12 children on Ritalin found every one experienced a significant increase in their level of chromosome abnormalities -- occurrences associated with increased risks of cancer and other adverse health effects.
  
  "Assuming it holds up, this study doesn't mean these kids are going to get cancer, but it does mean they're exposed to an additional risk factor," said Marvin Legator, a professor of environmental toxicology at the University of Texas Medical Branch at Galveston and the study's principal investigator and senior author. "Smoking doesn't mean you'll get cancer. It's a risk factor."
  
  But Legator said the study was too small for Ritalin to be considered a risk factor for cancer yet. He said he hopes larger studies refute the finding.
  
  The study is the first to look at the potential chromosome-damaging effects associated with methylphenidate, the generic name for Ritalin, the most widely prescribed drug used to treat attention deficit/hyperactivity disorder (ADHD). Between 1991 and 1999, U.S. sales of Ritalin and its variants, including Concerta and Metadata CD, increased more than 500 percent.
  
  The study, conducted by researchers at UTMB and UT M.D. Anderson Cancer Center, will be published in an upcoming edition of the journal Cancer Letters. It was made available online Thursday.
  
  Other medications cited
  
  
  The study is just the latest to cast doubt on ADHD medication. Earlier this month, Canadian regulators suspended sales of Adderall amid reports of 20 deaths of patients, including 12 children, taking the drug between 1999 and 2003. In the same time period, American regulators logged seven sudden deaths of children taking Ritalin and Concerta. A third ADHD drug, Strattera, can cause severe liver injury.
  
  In the study, researchers drew blood from children diagnosed with ADHD before they began taking Ritalin and again three months after, then employed a method of analysis that has detected 48 of the 53 known carcinogens in humans. All the children -- 10 boys and 2 girls averaging 8.5 years old -- were taking normal doses.
  
  For all 12, blood analysis tests showed a twofold to threefold increase in abnormalities in the chromosomes, the bodies within cells that carry genes and genetic information. Most consisted of chromosome breaks, which are associated with an increased risk of cancer.
  
  All people have chromosome abnormalities, typically about 1 percent. The children in the study had levels increased to 2 to 3 percent.
  
  Legator said he was amazed by the consistency of the findings, that all 12 children showed the same result. But he and other investigators stressed that more research needs to be done -- for instance, researchers didn't follow up so it's not known whether the chromosome abnormalities are permanent or go into repair once the patient goes off the drug.
  
  Follow-up study planned
  
  
  Study investigators said parents should respond cautiously to the study and not take their child off Ritalin if he or she is doing well. But Melissa Bondy, an M.D. Anderson epidemiologist who was part of the study, said she understood parents' natural reaction.
  
  "My child was recently diagnosed with ADHD and it was very difficult to decide to use medication after knowing these results," said Bondy. "That's why we need to do further research."
  
  The investigators said they plan to propose a follow-up study with hundreds of patients, multiple sites and longer study periods. Although there are millions of children on Ritalin, participation is limited by the need to enroll patients before they start treatment.
  
  ADHD, the most common neurobehavioral disorder in childhood, affects 4 to 12 percent of U.S. school-age children. Symptoms include short attention span, impulsive behavior and difficulty focusing.
  
  Copyright 2005 Houston Chronicle

• 2/09/05 ADDERALL PULLED FROM CANADIAN MARKET (2/9/05)
  
  On February 9, the Canadian government banned the sale in Canada of the ADD drug Adderall XR.
  
  Regulators say the move stemmed from news that "there were 20 international reports of sudden death in patients" taking Adderall (the immediate-release form of the drug sold in the United States) or Adderall XR (the timed-release preparation sold in the US and Canada).
  
  They -- the Health Canada therapeutic products directorate -- continue: "These deaths were not associated with overdose, misuse or abuse. Fourteen deaths occurred in children, and six deaths in adults."
  
  Health Canada adds: "There were 12 reports of stroke, two of which occurred in children."
  
  And it advises: "Patients taking drugs of the same class for the management of ADHD should NOT discontinue their medication, and should consult with their physician if they have any concerns or questions."
  
  The decision prompted a statement from US regulators at the Food and Drug Administration. It reads: "FDA has been in close consultation with the Canadian authorities regarding the basis for their action. FDA does not feel that any immediate changes are warranted in the FDA labeling or approved use of this drug based upon its preliminary understanding of Health Canada’s analyses of adverse event reports and FDA’s own knowledge and assessment of the reports received by the agency."
  
  The FDA says nothing about the possibility of stroke, and -- for fatalities -- has a lower number: 12 in the five years from 1999 to 2003.
  
  Of these, "five occurred in patients with underlying structural heart defects (abnormal arteries or valves, abnormally thickened walls, etc.), all conditions that increase the risk for sudden death. Several of the remaining cases presented problems of interpretation, including a family history of ventricular tachycardia, association of death with heat exhaustion, dehydration and near-drowning, very rigorous exercise, fatty liver, heart attack, and type 1 diabetes mellitus. One case was reported three to four years after the event and another had above-toxic blood levels of amphetamine [Adderall]. The duration of treatment varied from one day to 8 years." During this time some 30 million Adderall prescriptions were written, according to the FDA.
  
  But it's not just Adderall; the FDA adds: "The number of cases of sudden deaths reported for Adderall is only slightly greater, per million prescriptions, than the number reported for methylphenidate products [Ritalin, Concerta, Metadate, Methylin, Focalin; generic methylphenidate preparations], which are also commonly used to treat pediatric patients with ADHD."
  
  The fatality total there is 7, all associated with either Ritalin or Concerta; or so the FDA's medical affairs director was quoted during a February 10 interview.
  
  Beyond the numerical discrepancy is a clash of attitudes. Here's the spokesman for the FDA:
  
  "There is a tendency to believe that sudden death doesn't occur in children. That is wrong....we don't think the [Adderall fatality] rate is clearly different from the rate that would be expected in an untreated population....Psychiatrists say that these drugs are needed. To get rid of them for something that may well be a background [general-population] rate of death is not responsible."
  
  And here's the head of Health Canada:
  
  "It's very difficult to generate a benefit-to-risk balance when the risk is sudden and unexpected death....at the recommended dosages of the product....The adverse events that were identified are very rare, but they are also catastrophic....And it was not possible for us to determine wording that would effectively caution individuals about sudden death if you take a recommended dose of this product."
  
  In other words, at the FDA, Adderall is presumed innocent until proven guilty; at Health Canada, it's the reverse.
  
  In August, the FDA did instruct the manufacturer to add the following to the Adderall insert: "MISUSE OF AMPHETAMINE MAY CAUSE SUDDEN DEATH AND SERIOUS CARDIOVASCULAR ADVERSE EVENTS....Sudden death has been reported in association with amphetamine treatment at usual doses in children with structural cardiac abnormalties. Adderall XR generally should not be used in children or adults with cardiac abnormalities."
  
  Signs of one type of adverse event, a heart attack, can include:
  
  -- chest discomfort. Most heart attacks involve discomfort in the center of the chest that lasts more than a few minutes, or that goes away and comes back. It can feel like uncomfortable pressure, squeezing, fullness or pain.
  
  -- discomfort in other areas of the upper body. Symptoms can include pain or discomfort in one or both arms, the back, neck, jaw or stomach.
  
  -- shortness of breath. May occur with or without chest discomfort.
  
  -- breaking out in a cold sweat
  
  -- nausea
  
  -- lightheadedness
  
  The American Heart Association adds: "Some heart attacks are sudden and intense -- the 'movie heart attack,' where no one doubts what's happening. But most heart attacks start slowly, with mild pain or discomfort. Often people affected aren't sure what's wrong and wait too long before getting help....If you or someone you're with has chest discomfort, especially with one or more of the other signs, don't wait longer than a few minutes (no more than 5) before calling for help. Call 911 and get to a hospital right away."
  
  Meanwhile, the onset of another type of adverse event, a stroke, can be signaled by a:
  
  -- sudden numbness or weakness of the face, arm or leg, especially on one side of the body
  
  -- sudden confusion, trouble speaking or understanding
  
  -- sudden trouble seeing in one or both eyes
  
  -- sudden trouble walking, dizziness, loss of balance or coordination
  
  -- sudden, severe headache with no known cause.
  
  The American Stroke Association adds: "Call 911 immediately if you experience symptoms! Time lost is brain lost!"
  
  It should be noted, though, that there are different types of stroke, some more treatable than others. More information here might come in handy.
  
  -- Paul Jaffe, MAADDSG@aol.com; coordinator, Manhattan Adult ADD Support Group
  
  ---------------------------------------------------------------------------------
  
  NOTE: The FDA has announced plans for a Drug Safety Oversight Board to monitor drugs once they've been approved. The Board will sponsor "a new 'Drug Watch' web page for emerging data and risk information and increased use of consumer-friendly information sheets written especially for healthcare professionals and patients." Until then, for more information:
  
  Health Canada statement on Adderall
  www.hc-sc.gc.ca/english/protection/warnings/2005/2005_01.html
  
  FDA statement on Adderall
  www.fda.gov/bbs/topics/news/2005/NEW01156.html
  
  FDA public health advisory on Adderall
  www.fda.gov/cder/drug/advisory/adderall.htm
  
  FDA healthcare sheet for professionals
  www.fda.gov/cder/drug/InfoSheets/HCP/adderalHCP.htm
  
  Adderall label www.fda.gov/cder/foi/label/2004/021303s005lbl.pdf
  
  American Heart Association americanheart.org
  
  American Stroke Association strokeassociation.org
  
  Public Citizen Health Research Group worstpills.org

• 12/17/04 STRATTERA ADVISORY
  
  Eli Lilly & Co., maker of the ADD medication Strattera, has issued the following patient advisory: "In rare cases, Strattera can cause liver damage. Call your doctor right away if you have itching, dark urine, yellow skin or eyes, upper right-side abdominal tenderness, or unexplained 'flu-like' symptoms. In all reported cases, the liver recovered upon discontinuation of Strattera."
  
  The government has added the following: "The Food and Drug Administration (FDA) is advising health care professionals about a new warning for Strattera, a drug approved for attention deficit hyperactivity disorder (ADHD) in adults and children. The labeling is being updated with a bolded warning about the potential for severe liver injury following two reports (a teenager and an adult) in patients who had been treated with Strattera for several months, both of whom recovered.
  
  "The labeling warns that severe liver injury may progress to liver failure resulting in death or the need for a liver transplant in a small percentage of patients. The labeling also notes that the number of actual cases of severe liver injury is unknown because of under-reporting of post-marketing adverse events.
  
  "The bolded warning indicates that the medication should be discontinued in patients who developed jaundice (yellowing of the skin or whites of the eyes) or laboratory evidence of liver injury.
  
  "Strattera has been on the market since 2002 and has been used in more than 2 million patients. In clinical trials of 6000 patients, no signal for liver problems (hepatotoxicity) had emerged.
  
  "FDA has asked the manufacturer to add a bolded warning about severe liver injury to the labeling. Eli Lilly has agreed to alert health care professionals about the new information in a Dear Health Professional letter. The company will also update the patient package insert with information about the signs and symptoms of liver problems ...."
  
  The FDA is asking health-care professionals to report adverse events associated with Strattera directly to Lilly (1-800-LILLYRX) or to them (1-800-FDA-1088). The FDA MedWatch form is available online (www.fda.gov/medwatch/safety/3500.pdf) and can be mailed to
  
  FDA MedWatch
  HFD-410
  5600 Fishers Lane
  Rockville MD 20857
  
  or faxed to 1-800-FDA-0178. The FDA can also be reached at 1-888-INFO-FDA or 1-888-463-6332.
  
  While this situation needs to be monitored, some perspective may come in handy. As one clinician notes, "two known cases of liver problems on Strattera among millions of treated cases is a very small percentage."

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