Rheumatology Advance Access originally published online on November 20, 2006
Rheumatology 2007 46(2):368-370; doi:10.1093/rheumatology/kel384
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"To do no harm"
1SDGH, Rheumatology, Southport, 2Liverpool University, Rheumatology, Liverpool, 3Medicines Information, Pharmacy, Southport, UK
Correspondence to: K. A. Binymin. E-mail: kbinymin2001{at}yahoo.co.uk
SIR, We read with interest the article by Walker and Moots [1]. We share their apparent frustration with the recent withdrawal of rofecoxib, valdecoxib and co-proxamol. However, we feel in order to reach a balanced view in this argument, we need to explore the logics and reasoning behind the decision to withdraw these drugs.
The first question we should ask ourselves surely is, would any pharmaceutical company of world renown, simply withdraw a universally acclaimed product and relinquish a market worth billions without clear and compelling reasons for doing so? We agree that the industry feared an unacceptably high level of future litigations, which forced immediate drug withdrawal. This fear was based on an in-depth knowledge of the anticipated size of the cardiovascular and cerebrovascular side effect profile related to COX-2 inhibitors if their use was allowed beyond that time. Furthermore, following the voluntary withdrawal of rofecoxib by Merck Sharp & Dohme (MSD), the Food and Drug Administration (FDA) reviewed the available evidence and asked Pfizer to withdraw valdecoxib and revise labelling for all non-steroidal anti-inflammatory drugs (NSAIDs) to highlight the potential increased risk of cardiovascular events [2].
Dr Walker and Moots downplayed the size of the risk attached to the use of these drugs. We doubt very much that the decision to withdraw the three drugs was made hastily nor was it a commercial decision by the drug industry. The decision to withdraw was based on high quality data [3, 4, 5] and a prolonged monitoring campaign. We always believe that prospective, randomized, controlled clinical trials are the best way to evaluate the safety of medicines. The voluntary withdrawal of rofecoxib (Vioxx) by MSD in September 2004 was based on 3-yr data from a prospective, randomized, placebo-controlled clinical trial, the APPROVe (Adenomatous Polyp Prevention on VIOXX) trial [6]. In this study, the risk of myocardial infarction is doubled in patients on rofecoxib compared with those taking placebo. Rofecoxib's cardiovascular toxicity was highlighted soon after its launch in 2000 based on the VIGOR (VIOXX GI Outcomes Research) study [4]. The Arthritis Advisory Committee added ‘increased cardiovascular side effects’ to the labelling for rofecoxib in April 2002. Withdrawal then became inevitable in 2004, following the overwhelming data that eventually confirmed the long-suspected unacceptable increase in the morbidity and mortality associated with the use of rofecoxib.
It has been known for over 20 yrs that co-proxamol (combination of dextropropoxyphene and paracetamol) is unique amongst paracetamol-containing analgesics in that it can cause death within 1–2 h (coma, severe respiratory depression, convulsions and cardiac arrest may occur within 30 min [7]). Symptoms occur so rapidly, that the majority of deaths (
80%) with this agent occur before patients reach hospital. The Committee on Safety of medicines (CSM) first warned prescribers about the risks of co-proxamol in 1985, but despite being rated as ‘less suitable for prescribing’ by the British National Formulary (BNF) it is still widely used. There has been no reduction in toxicity and fatal overdose [8]. The national statistic report for 2006 estimates deaths related to co-proxamol poisoning for England and Wales between 2000–2004 at 300 deaths per year [9], which is several times more than deaths due to ecstasy. Many of these deaths (1/5) are due to accidental overdose. Co-proxamol overdose is associated with a 10-fold excess mortality compared with other paracetamol combination analgesics such as co-codamol and co-dydramol [10]. This was attributable to inherent toxicity and not to increased use in overdose. In view of the high toxicity of co-proxamol, especially when combined with alcohol, and the fact that the risk of overdose extends beyond the person the drug is prescribed for (particularly in young people), phased withdrawal from the market was considered the most appropriate option, especially if less dangerous alternatives are available. (The Medicines and Healthcare products Regulatory Agency (MHRA) issued CSM pain management guidance to help doctors find suitable alternatives for individual patients [11].
The authors attempted to exaggerate the void left in pain and inflammation treatment as a result of withdrawal of these drugs. They cited an anecdotal report ‘Many patients "swear by" the effect of one drug and not that of another’ and ignored a large volume of class one data [12, 13], which does not support a superior analgesic or anti-inflammatory effect for rofecoxib or valdecoxib over any other NSAIDs. A Drug and Therapeutics Bulletin (DTB) reviewed the use of coxibs and concluded that there are few, if any, situations in which a COX-2 inhibitor is indicated [14]. The efficacy of co-proxamol is poorly established. There is no evidence that suggests co-proxamol is actually more effective as an analgesic than paracetamol alone at its standard dose of 1 g [15]. Furthermore, 25 different equally effective NSAIDs, three of which are COX-2 inhibitors, and a similar number of simple analgesics are available in the market and are listed in the BNF/2006. Other useful modalities of treatments include topical NSAIDs and analgesics as well as intra-articular injections. All are safer and proven to be effective in various arthritic disorders.
The use of the term ‘unilateral withdrawal’ rather than the standard phrase ‘voluntary withdrawal' seems to reinforce the thrust of the article that the action of removing these drugs was made arbitrarily and without detailed analysis and serious debate and with little thought for patients and their pains. The FDA's safety review process states that manufacturers and/or distributors may initiate a recall at any time to fulfil their responsibility to protect the public health from products that present a risk of injury.
In deciding what might be the most effective strategy for future drug withdrawal one needs to consider the variability in characteristics of those at risk, efficacy as well as the level of risk. Doubling the risk of myocardial infarction and stroke in order to control chronic dull ache and stiffness due to arthritis seems a logically unacceptable practice especially when alternative therapies—not proven as toxic as the drugs in question—are readily available.
We believe that in this instance the pharmaceutical industry and the regulatory bodies have fulfilled their contractural and moral duties towards patients and the public at large, putting patient interest and safety at the centre of their policies.
Following the COX-2 withdrawals, A Drug Watch Program and New Drug Safety Initiative was introduced by the regulatory bodies FDA and MHRA. Patients are taking a more active role in their healthcare provisions and play a major role in decision-making. Easier access to information on drugs licenced and deemed safe by the pharmaceutical industry will only benefit this process.
We strongly endorse the current regulatory measures that allow immediate drug withdrawal and recall. Though the shared model of medical decision-making has been proposed as the preferred method of determining patients’ treatment, agreement is often difficult to achieve if patients’ and clinicians’ preferences are polarized [16]. This is true when significant risk is well-established in terms of size and direction (end organ toxicity).
The authors have declared no conflicts of interest.
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[Free Full Text] - FDA announces series of changes to the class of marketed Non-steroidal Anti-inflammatory Drugs (NSAIDs). FDA News ( April 7, 2005).
- Hedner T and Himmelmann A. (2004) Cardiovascular complications of COX2 selective inhibitors cause considerable concern. Blood Press 13:260–1.[CrossRef][ISI][Medline]
- Bombardier C, Laine L, Reicin A, et al. (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR study group. N Engl J Med 343:1520–1528.
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- Health Statistics Quarterly. (2006) Spring Table 2.
- Afshari AM, Good SRJ, Maxwell , Bateman DN. (2005) Co-proxamol overdose is associated with a 10-fold excess mortality compared with other paracetamol combination analgesics. Br J Clin Pharmacol 60:444–7.[CrossRef][ISI][Medline]
- Advice from the CSM expert working group on analgesic options in treatment of mild to moderate pain. ( January 23, 2006).
- Pavelka K, Recker DP, Verburg KM. (2003) Valdecoxib is as effective as diclofenac in the management of rheumatoid arthritis with a lower incidence of gastroduodenal ulcers: results of a 26-week trial. Rheumatology 42:1207–15.
[Abstract/Free Full Text] - Garner SE, Fidan DD, Frankish RR, et al. Rofecoxib for rheumatoid arthritis (Cochrane Review). The Cochrane Database of Systematic Reviews 2005 Issue 1. Art. No.: CD003685. doi:10.1002/14651858.CD003685.
- Taking stock of coxibs. DTB (2005) 43:1–6.[Medline]
- The Oxford League Table of Analgesics. (2003) Bandoliers Little Book of PainOxford University Press.
- Charles C, Whelan T, Gafni A. (1999) What do we mean by partnership in making decisions about treatment? Br Med J 319:780–2.
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