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Follow-up UCB’s promotion of Atarax (hydroxyzine)

August 1998

Vol 16 Issue 7/8 Follow-up UCB's promotion of Atarax (hydroxyzine) MaLAM apologises but we remain concerned about the promotion of Atarax Welcome baby Adelaide MaLAM Inc Annual General Meeting

MaLAM apologises to UCB and to our readers…

When MaLAM wrote to UCB in March 1998 about the promotion of Atarax (hydroxyzine) in the Ivory Coast we believed incorrectly that UCB had promoted that antihistamine as global therapy for cardiovascular, gastrointestinal, dermatological and/or respiratory problems. This was because we had received a copy of a brochure as depicted in illustration-1. In April 1998, UBC sent us a colour copy of the original advertisement (as depicted in illustration-2) which promotes Atarax as a global treatment for Anxiety with somatic manifestations in the cardiovascular, gastrointestinal, dermat-ological and respiratory systems. We have discovered that the error arose when the word “Anxiety” was lost during photocopying to make the copy that was sent to our office. This occurred because that word had been printed in light green in the original advertisement unlike the rest of the text. MaLAM apologises to UCB, and MaLAM subscribers for the error. We will improve our procedures to ensure that similar errors cannot occur in the future.

UBC have told us that the brochure depicted in illustration 2 was used from May 1990 until October 1993. We have checked back with our source for the brochure. Our source has told us that the brochure was obtained during a visit to the Ivory Coast during late 1996 to early 1997. It was obtained from a medical doctor at the Hôpital Prostestant de Dabou who had collected promotional brochures since he commenced his post in 1989. He had accumulated the brochures as a source of drug information in a country with very limited resources. Our source exchanged a pharmacology textbook for 50 promotional brochures. We do not know how many other countries were targeted with the brochure by UBC.

In April we decided to publish an apology as soon as we could determine where the error occurred. Unfortunately there was a delay because our source was visiting several African countries again. On 28 May we received the following “Cease and desist letter” from UCB.

26 May 1998

Dear Sir,

Re: Promotion of Atarax in Ivory Coast

We refer to our letter dated 22 April 1998 in reply to your letter of March 1998 with the there enclosed copy of the MaLAM International News-bulletin, Vol. 16 No 1 /2 of January/February.

In our letter we refuted your allegations that UCB would carry on a campaign in Ivory Coast for the promotion of its Atarax drug in an unlimited area of indications. The promotional material in question explicitly limited the use of Atarax to anxiety.

Not only have we never received a reply from MaLAM to our letter, we have also received over two hundred (identical) letters from doctors world-wide requiring information from UCB on its alleged false promotion of Atarax. Some of these letters were sent in February, thus even before MaLAM had notified UCB of the publication. Moreover, we have discovered an article in the Dutch Journal “Pharmaceutisch Weekblad” (1998, nr. 20) covering this matter and causing great damage to UCB’s reputation as an ethically conducted pharmaceutical company. UCB expressly reserves its rights in relation to any damages or other actions under applicable Australian law to which it would be entitled as a result of MaLAM’s actions.

We hereby demand from MaLAM and its Directors the following undertakings:

(i) to immediately cease any and all action with respect to spreading by any means whatsoever and using in any way whatsoever the statement that UCB would have promoted or would still be promoting Atarax in the Ivory Coast or elsewhere for drug indications without limitation to anxiety; and

(ii) to publish on the front page of the next issue of MaLAM’s International News-bulletin a half-page corrective advertisement of a statement of public apology to UCB, in accordance with UCB’s 22 April letter; and

(iii) to publish an identical announcement as under (ii) above in all journals, magazines, and other publications where the false information on UCB’s promotion of Atarax has been published either directly through MaLAM or indirectly through journalists or other intermediate persons; and

(iv) to communicate in writing the message described under (ii) above to all doctors and other destinees of the letter which MaLAM addressed to UCB in March 1998.

We demand that MaLAM and its directors provide the above listed undertakings by no later than 5:00 pm on Friday 29 May 1998 (CET). This may be done by signing, dating and returning to us a copy of this letter.

If MaLAM and its directors fail to give the undertakings sought, or if having given them to honour them, we will take such steps as we may be advised without notice to MaLAM.

Further, this letter has put MaLAM and its directors on notice of UCB’s rights, and, should legal proceedings ensue, this letter will be used as evidence of MaLAM’s knowledge of those rights for the purposes of these proceedings.

Yours sincerely,

Christian Matton
Legal Counsel

As already decided in May we apologise.

…but we remain concerned

Firstly, the illustrations are the most influential component of a brochure. The pictures used in the Atarax brochure do not illustrate anxiety alone. They illustrate cardiovascular, gastrointestinal, dermatological and respiratory problems. We are concerned that the impression made by the illustrations may lead to the same misunderstanding in the minds of some health professionals as occurred to us when the word “anxiety” was lost.

Secondly, contrary to UBC’s letter above, the brochure promoted Atarax for more than anxiety. One of the indications listed for Atarax was “tachycardie paroxystique” or paroxysmal tachy-cardia. As we pointed out in our January/February edition the only evidence to support such an indication comes from case series reports. Case series can be a very valuable tool in suggesting beneficial effects of a drug, but by themselves they cannot form the basis for treatment, unless there is no other alternative for a condition. Clearly this is not the situation for cardiac arrhythmias. UBC have not provided any evidence to support the paroxysmal tachycardia indication and have implied that they no longer support that indication. We hope they will agree to provide corrective information for all the doctors who were exposed to this unjustified promotional claim.

Thirdly, we are concerned about the quality of the evidence that UBC is using to support the promotion of Atarax for anxiety. The original reply from UCB, dated 23 April, asserts that:

“This concept of anxiety is central to Atarax (hydroxyzine) and as opposed to a widening of the indications, which we do not claim at all, we are currently precising [sic] our indication in anxiety, namely in the specific diagnosis of Generalised Anxiety disorder (GAD) as defined in the latest version of the DSM (DSM IV, 1994).”

UCB has provided MaLAM with reports of two trials of hydroxyzine for Generalised Anxiety Disorder (GAD) as defined in DSM 3R (the pre-1994 version of the DSM). The DSM IV definition of GAD can be summarised as significant or disabling anxiety, for more days than not, for at least 6 months, without the features of other specific diagnoses such as Panic Disorder. (See box 1 for the full DSM IV definition.)

Box 1: Diagnostic criteria for 300.02 Generalized Anxiety Disorder

A. Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance).

B. The person finds it difficult to control the worry.

C. The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms present for more days than not for the past 6 months). Note: Only one item is required in children.

    1 restlessness or feeling keyed up or on edge
    2 being easily fatigued
    3 difficulty concentrating or mind going blank
    4 irritability
    5 muscle tension
    6 sleep disturbance (difficulty falling or staying asleep, or restless unsatisfying sleep)

D. The focus of the anxiety and worry is not confined to features of an Axis 1 disorder. e.g., the anxiety or worry is not about having a Panic Attack (as in Panic Disorder). being embarrassed in public (as in Social Phobia), being contaminated (as in Obsessive-Compulsive Disorder), being away from home or close relatives (as in Separation Anxiety Disorder). gaining weight (as in Anorexia Nervosa). having multiple physical complaints (as in Somatization Disorder). or having a serious illness (as in Hypochondriasis), and the anxiety and worry do not occur exclusively during Post-traumatic Stress Disorder.

E. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.

F. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) and does not occur exclusively during a Mood Disorder, a Psychotic Disorder, or a Pervasive Developmental Disorder.

Generalising from GAD, which is a specific severe disorder, to promote a drug for the very common symptom of anxiety with somatic manifestations is still an example of widening the indications even though it is not as severe an example as we first thought.

The two reports provided by UCB do not disclose the method used for concealment of allocation during randomisation. (see box 2 for definitions of terms in bold.) Consequently we do not know if the methods used for concealment of allocation were adequate or not. According to a study published in JAMA, trials with clearly inadequate concealment if treatment allocation exaggerate the treatment benefit by 41% on average. [1] Trials where the method of concealment of allocation is simply not reported, exaggerate the treatment benefit by 30% on average. Concealment of allocation is more important than double-blinding. Lack of double blinding leads to an exaggeration of treatment benefit by only 17% on average. However even that is enough to make an ineffective treatment appear effective.

Box 2: Definitions


- Allocation refers to the process of choosing subjects to go into the different groups in a comparative trial.

Concealment of allocation

- Ensuring that the investigators who are responsible for enrolment and allocation can not know which group the subject will go into. This is to prevent them from biasing allocation consciously or unconsciously in anyway.

Efficacy trial

- A trial that tests whether a therapy works under ideal conditions, e.g. rigid inclusion/exclusion criteria, close follow-up, encouraging compliance.

Effectiveness trial

- A trial that tests whether a therapy works in the real world where all sorts of patients will be receiving the therapy, where compliance will not necessarily be great, etc.

Type II (b ) error

- Treating a difference as insignificant when in reality there is a difference, a false negative finding. One important cause of type II errors is insufficient sample size.

Furthermore “in anxiety disorders, the cognitive behavioural range of treatments are mostly superior to therapy with drugs, both in short term effectiveness and in the long term after treatment has concluded.” [2] The 2 trials supplied by UCB did not compare hydroxyzine with any of the established psychological therapies. (See box 3.)

Box 3: Psychological therapy for GAD [2]

    1 Education about the nature of the disorder.
    2 Progressive muscle relaxation.
    3 Structured problem solving.(see below)
    4 Graded exposure to difficult situations.
    5 Cognitive behavioural program for non-responders.

Structured problem solving.

Step 1: What is the problem/goal?

Step 2: List all possible solutions.

Step 3: Assess each possible solution.

Step 4: Choose the “best” or most practical solution.

Step 5: Plan how to carry out the best solution.

Step 6: Review progress and be pleased with any progress.

One of the trials compared hydroxyzine with placebo. The report suggests that this trial by Ferreri, two UBC staff members and the “French study group for hydroxyzine” (1995) [3] was a well designed and conducted study except, as noted above, the method for concealing allocation was not disclosed. The main endpoint of the trial was changes in the Hamilton Anxiety Rating Scale (HAM–A) after four weeks of therapy and one week without. Average HAM-A scores improved by 24% in the placebo group and by 42% in the hydroxyzine group. Trials without disclosure of the method of concealment of allocation exaggerate the benefit of treatment by 30% on average but the exaggeration could be more or less than that. Consequently, we do not know how large the difference between placebo and hydroxyzine really is so we cannot judge whether or not the difference is clinically important.

Furthermore, we note that this study was an efficacy trial rather than an effectiveness trial. We base this conclusion on the exclusion criteria which included: panic attacks, obsessive-compulsive disorder, pregnancy, use of benzodiazepines (verified by urine tests), physical ill-health due to significant cerebral, cardiovascular, hepatic or renal disease, and a history of alcohol abuse or recent use

of neuroleptics, antidepressants, antihistamines or opiates. These rather restrictive exclusion criteria limit the generalizability of this study. However this criticism needs to be seen in perspective. Smilar criticism applies to most trials for many drugs.

The other trial compared hydroxyzine with lorazepam 4 mg per day in divided doses. (The dose of lorazepam recommended for anxiety in Australia is 2-3 mg per day in divided doses.) This study by Samuelian and two UBC staff members (1995) [4] is a much weaker study in our opinion. Again the method of concealment of allocation is not stated.

Exclusion criteria for the Samuelian et al trial are much more vague (i.e. patients were excluded who had “any other pathology liable, by its nature or treatment, to interfere with the treatments tested and their evaluation.”[4])

There was no significant difference in anxiety scores but this could have arisen from a type 2 error because there were only 14 patients in the hydroxyzine group and only 16 patients in the lorazepam group. On day 28 of the study the hydroxyzine group did 7.6% better than the lorazepam group on cognitive tests. This was statistically significant but it is not clear whether or not it was a clinically important difference. Moreover, the absence of a placebo control group makes it difficult to evaluate the response because there is a significant placebo effect in this condition.


UCB’s advertisement in the Ivory Coast promoted Atarax for anxiety (rather than for GAD) and for paroxysmal tachycardia but the company has not provided any evidence to support those indications. UBC has provided one placebo-controlled trial suggesting that hydroxyzine may be superior to placebo for Generalised Anxiety Disorder. However, no high quality trials comparing hydroxyzine with recommended psychological therapies have been done. Consequently, MaLAM believes that UCB’s should provide corrective information for all health care workers who were exposed to the Atarax brochure.

Welcome baby Adelaide

We congratulate MaLAM’s drug information pharmacist, Agnès Vitry and her husband, John-Christophe Xerri, on the birth of their daughter on 7/7/98. They have named her Adelaide in honor of her city of birth. She arrived a little earlier and more quickly than anyone expected but parents and baby are now doing extremely well. Adelaide has been growing at up to 19% per week so we look forward to receiving her assistance with achieving high growth rates for MaLAM!

MaLAM Inc Annual General Meeting

MaLAM Inc’s AGM is held via mail and will commence soon. If you would like to receive the AGM mailings then please contact MaLAM, PO Box 172, Daw Park SA 5041, Australia or E-mail: .(JavaScript must be enabled to view this email address) or fax +61 8 83742245. Please let us know if you are interested in serving on the MaLAM Inc Board.

The current Board consists of:

President - Prof Tariq Iqbal Bhutta (Lahore), Secretary and Treasurer - Associate Professor Joel Lexchin (Toronto),
Board members - Prof Les Irwig (Sydney), Dr Bernard Topuz (Paris), Dr Zafar Mirza (Islamabad).


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