Not again
It seems ironic that it was in October 2004 that the P.I.L.S Compliance Column covered the latest United States Food and Drug Administration (FDA) Public Health Advisory alerting healthcare professionals to reports of increased suicidal thoughts and behavior in children and adolescents being treated with antidepressant medications. Now here we are in October 2005 and the FDA has issued another Public Health Advisory to alert physicians of reports of suicidal thinking in children and adolescents. This time the problem is associated with a drug approved to treat attention deficit hyperactivity disorder (ADHD).
The “safe” alternative
The drug at the center of concern is Strattera® (Atomoxetine Hydrochloride) manufactured by Eli Lilly & Co. Strattera® was launched in the United States in 2003 and was heralded as a safer alternative to existing ADHD treatments. Many parents welcomed the drug as it was the first and only non-stimulant medication approved by the FDA for the treatment of ADHD in children and adolescents. Strattera® is a norepinephrine reuptake inhibitor, and although the precise mechanism by which atomoxetine produces its therapeutic effects in ADHD is unknown, it is thought to be related to selective inhibition of the pre-synaptic norepinephrine transporter, as determined in ex vivo uptake and neurotransmitter depletion studies. Improved efficiency in the norepinephrine system appears to be associated with improvement in the symptoms of ADHD.
Until the approval of Strattera®, parents had to rely on amphetamine-like medicines, such as Ritalin® (Novartis), Concerta® (Johnson & Johnson) and Adderall® (Shire Pharmaceuticals) to treat their children’s ADHD and many were concerned about the potential risk of substance abuse that these types of drugs pose.
So what happened?
A variety of anecdotal data had emerged linking Strattera® with increased irritability and mood swings. In September 2004, Theodore A. Henderson, MD, PhD and Keith Hartman, MD noted their concerns in a Letter to the Editor of Pediatrics – an official peer-reviewed journal of the American Academy of Pediatrics. In their correspondence the doctors concluded:
“Our collective experience argues that caution should be used in selecting atomoxetine as a treatment in children with a personal history of mood dysregulation or mood disorder or who have a family history of mood disorders. Moreover, mania/hypomania induction or mood dysregulation can occur in a percentage of patients (4% of our total sample) who have no family or personal risk factors for mood disorder.”
That anecdotal data now appears to be supported by results from a review and analysis of 11 clinical trials conducted in children with ADHD and of an additional trial in children with enuresis that identified an increased risk of suicidal thinking for Strattera®. As part of a larger evaluation of psychiatric drugs and suicidality, FDA had requested that Eli Lilly conduct a review of its database and clinical trials, which included more than 2200 patients - 1350 patients receiving Strattera® and 851 receiving a placebo. The analysis showed that 0.4% of children treated with Strattera® reported suicidal thinking compared to no cases in children treated with the placebo. A similar analysis in adult patients treated with Strattera for either ADHD or major depressive disorder (MDD) found no increased risk of suicidal ideation or behavior with the use of Strattera.
In response to the latest data, Eli Lilly has added a warning to Strattera® labels worldwide highlighting that the drug increases the risk of suicidal thinking in children and adolescents with ADHD. In the United States, the information will appear as a black boxed warning to the product label and Eli Lilly is working with the FDA to finalize the product label content as well as information for healthcare professionals. In Europe, the information will be provided under the special warnings and precautions section of the product label and in Australia, it will appear as a precaution. In addition, a Medication Guide will be prepared to provide patients, their families, and caregivers, information concerning the potential risks associated with Strattera®. This guide will be distributed by the pharmacist with each prescription or refill of Strattera®.
Not the first time
This is not the first time that the spotlight has been on potential Strattera® side-effects and Eli Lilly has always been quick in informing the public of any potential risks. Last December the company added a bolded warning to the product label saying that that the drug should be discontinued in patients with jaundice or laboratory evidence of liver injury. This label change was a result of two reported cases of severe liver injury. Both patients recovered with normal liver function after discontinuing the medication.
And not the last
Dr. Thomas Laughren, head of the FDA's psychiatric drug unit stresses that the agency still regard Strattera® as an effective drug and emphasizes that the “actual risk is very low”. Dr. Laughren also commented that the agency plan to ask Eli Lilly to include a stronger caution on the product label about its risk of inducing mania and similar mood destabilization, along with the new "black box" warning out this week. The new warning will focus on the drug's risk for children with undiagnosed bipolar illness. The potential risk for children with undiagnosed bipolar illness is not surprising. The active substance in Strattera®, atomoxetine, is chemically similar to a class of drugs known as tricyclic antidepressants (TCA’s). These drugs are a subclass of antidepressants and have long been known to occasionally induce mania in people with bipolar illness. The increased frequency of extreme mood swings that seems to be linked to post-approval Strattera® use may be a reflection of the prevalence of undiagnosed bipolar disorders among children and adolescents.
Parents and physicians are faced with difficult choices in determining appropriate drug therapy for children with ADHD. What is clear is that all clinical trials for psychiatric drugs must include a carefully monitoring of possible mood destabilization and suicidal thoughts.
Worldwide concern
There is increased concern worldwide pertaining to the use of medication in children with ADHD.
In Britain, the National Health Service’s Institute for Health and Clinical Excellence (NICE) has just issued guidelines for doctors on non-psychiatric remedies for children, including regular sleep, exercise and nutrition. These guidelines were issued following a June 2003 British Medical advisory warning doctors that anti-depressants can pose suicidal risks for young people.
The Commission of the European Communities, representing 25 countries throughout Europe has issued the strongest warnings to date by any medical agency against child antidepressant use. In this case, the Commission recommended against the prescription of these drugs for anyone under 18.
In Canada, Health Canada took dramatic action in February, ordering that the ADHD drug Adderall XR® be taken off pharmacy shelves after learning that Adderall® and the once-daily version Adderall XR® had been linked to 20 sudden deaths and 12 strokes worldwide. The drug was eventually reinstated, but Health Canada has asked the makers of Concerta, Adderall XR, Dexadrine, Ritalin and Attenade to submit data from all clinical trials and post-marketing reports to the agency by the end of this year for detailed review.
In a landmark report, the United Nations Committee on the Rights of the Child, has also issued a strong warning against the use of ADHD medication. In its Concluding Observations on reports by Australia, Finland and Denmark regarding their compliance to the U.N. Convention on the Rights of the Child, the Committee expressed concern that “[ADHD] and Attention Deficit Disorder (ADD) are being misdiagnosed and therefore psycho-stimulant drugs are being over prescribed, despite growing evidence of the harmful effects of these drugs.”
Meeting the challenge
So the international spotlight is on all involved with planning, conducting, analyzing, reporting and reviewing clinical trials of psychiatric drugs in children. The bar has been raised - let’s hope we can all meet the challenge – and find ways to develop safe and effective treatment options for those who really need them. Whereas Eli Lilly acted swiftly and appropriately in addressing the problem with Strattera® and the Regulatory and Government bodies must be commended for their actions in tackling the wider issue, parents and doctors are left in a quandary. Are these medications safe? When and how should they be prescribed? What alternatives are available? Let’s hope that in a year’s time the P.I.L.S Compliance Column can report that we have found at least some of the answers.
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