Healthy Skepticism International News

March 2008

The ADHD drug Strattera – actions needed now

This article gives updated information about the harmful effects of the ADHD drug Strattera.

For the years 2004-2006, 31,835 adverse reactions for Strattera were reported to the FDA where Strattera was the primary suspect drug in 9,250 individual cases (with duplicate reports excluded) [1]. This puts Strattera as number three among most reported psychiatric drugs. For the purpose of causality assessment it should be observed that Strattera is in the lead in reports to the FDA about psychiatric drugs as regards positive dechallenge/rechallenge. (Positive dechallenge refers to the partial or complete disappearance of an adverse event after withdrawal of a product from the patient’s therapeutic regimen; positive rechallenge to the reoccurrence of similar signs and symptoms upon reintroduction of product.) [2] “Recovery after medicine withdrawal [dechallenge] is an important pointer to a causal relationship…recurrence on rechallenge is strongly suggestive that the medicine was responsible.” [3] In 1,562 unique cases (17%) it was noted the subsequent disappearance of the adverse reaction(s) when medication was ceased (1,556 cases) and/or a reappearance of the adverse reaction(s) when medication was resumed (227 cases) [4].

Internationally between November 2002 (when Strattera was approved) and March 2006 “a total of 23,132 spontaneous adverse event reports of atomoxetine [Strattera], representing 58,048 adverse events, were collected by the MAH [Market Authorization Holder; Eli Lilly].” [5] Updating this figure with the number of reports mentioned in Periodic Safety Update Reports number 7-8, covering the periods May 2006 – May 2007, one gets a total of 61,220 adverse events in 25,034 reports for Strattera [6]. Only a fraction (1-10 percent) of adverse events occurring are reported. [11]

“Compelling evidence” for a causal association between Strattera and treatment emergent symptoms of psychosis or mania

The British Medicines and Healthcare products Regulatory Agency (MHRA) is leading the “safety work” for Strattera in Europe. The following promise is given : “…we take any necessary action to protect the public promptly if there is a problem.” [7] In January 2006 MHRA described “a problem” of magnitude with Strattera. The agency had found out that there was a “large number of psychiatric reactions reported” for the drug [8]. The conclusion in the Strattera – Risk: Benefit Assessment Report (p. 23) was: “Due to the large number of psychiatric reactions reported (the majority of which are unlisted), in September 2005 the MHRA requested the MAH [Market Authorization Holder] to perform a cumulative review of all psychiatric disorders reported for atomoxetine. The MAH is currently performing the review and it is anticipated that it will be available during [deleted in document].” The actual number of “psychiatric reactions reported” was at that time 10,988 (as stated in Annex 4 to the report) [9].

A cumulative review was however never done. But in March 2006 the FDA published its report of some of the psychiatric reactions reported from ADHD drugs, Psychiatric Adverse Events Associated with Drug Treatment of ADHD: Review of Postmarketing Safety Data, for the Pediatric Advisory Committee meeting, March 22, 2006 [10]. In that report it is stated that Eli Lilly (for the period January 2000 – June 2005; recall, Strattera was marketed November 2002) had received 360 reports of psychosis or mania (p. 14). The conclusion was reached that the FDA review “presents compelling evidence for a likely causal association between each of these four drugs [Strattera/amphetamine drugs] and treatment emergent onset of signs and/or symptoms of psychosis or mania, notably hallucinations, in some patients.” (p. 17) It is stated: “These data show that some patients, including some with no identifiable risk factors, can develop drug-related signs or symptoms of psychosis or mania, such as hallucinations, at usual doses of these drugs.” “Positive rechallenge (i.e., recurrence of symptoms when drug is re-introduced) is considered a hallmark for causality assessment of drug-induced adverse effects. Cases which include a positive rechallenge were reported by the Sponsors for each of the drugs included in this analysis.” “a substantial proportion of psychosis-related cases were reported to occur in children age ten years or less, a population in which hallucinations are not common.”

The MHRA did not in any visible way act on the data in the FDA report. But the agency finally found that Eli Lilly had not done or submitted the requested “cumulative review over psychiatric disorders reported for atomoxetine”, and in August 2006 the agency requested Eli Lilly to submit the same data set that, more than one year earlier, was submitted to the FDA and formed the basis for the FDA report (part Strattera) presented in March 2006. But rather than analysing these data the agency later wrote: “The safety of Strattera, including review of all serious psychiatric reactions, is considered on an ongoing basis in the periodic safety update reports… Our own assessment of subsequent periodic safety updates satisfied us that the issue of psychiatric reactions could be appropriately monitored through these updates and there was not a requirement for a separate and cumulative review of psychiatric reactions with Strattera.” [12]

And so we come to March 2007, when the Periodic Safety Update Report (PSUR) for Strattera, for the period May 27, 2005 – November 26, 2005, was finalized. In the PSUR it is stated (p. 61) under the heading Conclusions: “the MAH [Marketing Authorization Holder; Eli Lilly] is requested … to perform cumulative reviews of all reported cases of hallucinations, mania, agitation, and psychotic reactions with a view to adding these to section 4.8 of the SPC [Summary of Product Characteristics] should there be evidence of a causal association between these events and atomoxetine treatment.” [13]

The question was sent to the MHRA: How come the MHRA is not accepting the conclusions of the FDA assessors in the report presented March 2006, but instead requests Eli Lilly to do a cumulative review of basically the same data already reviewed by the FDA? And the answer was: “Changes to European product information are based on assessment by EU regulators, agreement between members states and in line with legal requirements about product information, not on conclusions of FDA assessors.” [14]

And now we have arrived at the time for the publication of the latest Periodic Safety Update Report (number 8) for the period 27/11 2006-26/5 2007 – the 4th of December 2007. It’s two years after the MHRA published its finding about the “large number of psychiatric reactions reported” for Strattera, it’s almost two years after the FDA report was published, and it’s one and a half year after the MHRA got the full data set that the FDA report was based on. What do we find about hallucinations, mania and psychotic reactions in this recently finalized report? We find on page 12 the assessor’s comment: “The MAH has recently been asked to perform a cumulative review of all spontaneously reported cases of 1) mania, 2) psychotic disorders and 3) hallucinations.” [6] This means that parents and doctors in Europe are still not told about “the compelling evidence” for drug induced hallucinations and mania. The FDA approved label for Strattera, in place since August 2006, states under the heading Emergence of New Psychotic or Manic Symptoms: “Treatment emergent psychotic or manic symptoms, e.g., hallucinations, delusional thinking, or mania in children and adolescents without a prior history of psychotic illness or mania can be caused by atomoxetine at usual doses. If such symptoms occur, consideration should be given to a possible causal role of atomoxetine, and discontinuation of treatment should be considered.” [15] The UK SPC for Strattera says nothing about the fact that Strattera can cause hallucinations, delusional thinking, or mania [16]. It is notable that the MHRA in this case falls far behind the FDA in ability and willingness to protect patients, even though he FDA is subject to Congressional investigations for its lack of ability to protect US citizens from serious harmful effects of prescription drugs.

The forgotten 700 cases of psychomotor hyperactivity

In PSUR 5 (finalized in the beginning of 2007) the MHRA assessors took up the subject of Movement Disorders, and included psychomotor hyperactivity (pages 54-55). The assessors criticize Eli Lilly and note: “… the MAH is requested to provide further clarification as to the criteria used for determining that the 700 reported cases of psychomotor hyperactivity were related to an exacerbation of the underlying ADHD which resulted in exclusion of these cases from this review.” [13]

What could be understood from this was that Eli Lilly had received 700 reports that the company classified as reports of “psychomotor hyperactivity” and that these were excluded from the analysis, with the explanation that they only were a sign of “exacerbation of the underlying ADHD”. This was remarkable in several ways. First of all the 700 reports would, considering the accepted rate of underreporting, represent an actual incidence of between 7000 and 70 000 cases. Secondly, this would mean that Lilly said that Strattera worsened the hyperactivity it was supposed to positively affect. Thirdly, these cases may have been another example of misclassification by the MAH (as in the example where pharmaceutical companies misled medical agencies and the public about the suicide risk with antidepressant drugs – classifying suicidal behaviour as “emotional lability”, thus hiding the actual drug induced suicidality). What Eli Lilly classified as “psychomotor hyperactivity” (an exacerbation of ADHD) in many cases, might be re-classified as drug induced agitation, mania or hypomania.

The MHRA asked Eli Lilly to do an analysis of these 700 reported cases, after the company had withheld this obviously sensitive information. A better solution would have been for the agency to request all data about this security risk, followed by an independent review of the data. But this was not done – and as expected nothing is mentioned in the later PSURs – finalized December 4, about this matter.

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Finally it should be noted that a total of 870 reported cases of suicidality and self-injurious behaviour in connection with Strattera “treatment” have been collected internationally, up to May 2007, according to data in PSURs. And the response from the MHRA assessor in the latest PSUR (p. 22)? “Suicide-related events are listed reactions. These reports do not raise any new issues…” [6a]

Janne Larsson

Reporter – investigating psychiatry

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