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Unlicensed and off label drug use in neonates
  1. E HEY
  1. Department of Child Health
  2. Royal Victoria Infirmary
  3. Newcastle upon Tyne NE1 4LP

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Editor—Most papers in this journal have a commendable clear “take home” message, but this was not really true of the recent paper by Conroy et al. 1 They described a 13 week, one unit study in Derby as finding that two thirds of all neonatal prescriptions (294 out of 455) involved the use of a drug in a way that the manufacturers had no license to recommend. The authors do not say what should be done about it.2

They note that 84 prescriptions for vitamins and 77 for penicillin or an aminoglycoside used a dose other than the one mentioned in the drug data sheet. But they must be aware, surely, that data sheet information is advisory in nature. Secondly, an immense amount of information has been published on these issues since the data sheets were first prepared. Thirdly, many UK college and American academy guidelines recommend doses that differ from those in the data sheets. The authors note that 36 prescriptions for caffeine, morphine, or parenteral nutrition had to be made up in the local pharmacy aseptic service unit, and the products were therefore classes as unlicensed. They do not suggest, however, how they would prefer to see the prescribing and dispensing of these drugs handled.

What was the intended message when arrangements were made for the news media to latch on to this report before most clinicians had had their chance to read the paper for themselves? Were headlines such as “Doctors raise alarm over drugs given to babies,” and “Babies used as drug guinea pigs” really what you hoped to generate? Coming only a week after an article in the New Scientist,3 inspired by a steer from the Derby clinicians, the journal article led the BBC to report that “Doctors are calling for stricter controls to ensure children are not given dangerous doses of adult drugs.” Such manipulation of the news media does a serious disservice to a serious subject. Professor Anysley-Green's subsequent letter,4 contrasting the lack of support for paediatric pharmacology in the UK with the establishment of 13 such centres in North America, rather suggests that it was a simple bid for money.

Readers who turned to Professor Sir David Hull's commentary in the same issue will have found little enlightenment. His main message seemed to be that everyone should buy Medicines for Children. However, any suggestion that this would be the first reference text to clearly identify unlicensed and off label paediatric drug use in the UK would be misleading. Even should that be the case, it wouldn't get us very far: the new consensus driven text may tell us what most people currently do, but what most do is not necessarily right.

The neonatal use of gentamicin typifies some of the key issues, as Conroy has herself highlighted.5 The drug has been in neonatal use for over 30 years, but the best dose is still a matter for debate. High trough concentrations frequently cause concern, but there are actually very few reports of neonatal renal or ototoxicity. Low peak concentrations, on the other hand, often go unremarked.

Six separate papers have been published over the past 10 years, which show that a therapeutic peak concentration will not be acheived for 12 to 24 hours using any standard policy, unless an initial loading dose is given—the volume of distribution being particularly high at birth—but such a strategy is still only recommended in a few reference texts.

This is not an area where more money is needed for research. More than 200 papers have already been published on this topic over the past decade. There is no commercial pressure on the manufacturer to modify the data sheet: they are generic products unprotected by patents. Nor does the Medicines Control Agency believe that it should take the intiative over this, although it would be very willing to review the case for voluntary modification with manufacturers if approached by an appropriate and responsible professional body. Why, then, does the Royal College of Paediatrics and Child Health not do this?

For most of the drugs listed by Conroy, there is no need for further research, or more papers stating that drug data sheets are out of step with current practice. Nor do “they” need to tighten the prescribing rules and restrict what “we” can do. What is needed is sensible, sustained, and constructive dialogue between the profession, the licensing authorities, and the manufacturers, to get drug sheets revised at regular intervals, so that they reflect all the additional information that becomes available in the years after the product first comes on the market. My message is, that it is up to the profession to start the ball rolling.

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Drs Conroy et alrespond: We welcome the opportunity to clarify our “take home” message. This is actually very simple: drugs used in children should be tested scientifically to ensure that age dependent changes in pharmacokinetics and pharmacodynamics are known, the likely side effects are anticipated, and that the minimum effective dose can be given.

We expect the Medicines Control Agency to ensure that neonates receive drugs that are as carefully evaluated for efficacy, safety, and quality as the drugs given to adults. We also expect the pharmaceutical industry to provide drugs that are appropriate for use in neonates and children as well as in adults. We accept that health professionals involved in the care of neonates have a responsibility to contribute to this process. It requires a joint effort between healthcare staff caring for children, the industry, and the government. Dr Hey states that data sheet information is “advisory,” but this is the only information that the pharmaceutical manufacturer will take responsibility for, anything else is on the head of the prescriber.

There may be few published reports of renal or ototoxicity following the use of gentamicin in neonates, as it is difficult to definitely attribute such problems to the drug. However, this does not mean that gentamicin does not cause such problems. We note that renal insufficiency is not uncommon in acutely ill preterm infants and that long term hearing problems occur in babies who have been through neonatal intensive care. We do not know how many of these problems are associated with gentamicin use because the babies have many other potentially contributory problems. Research is needed to establish the dose and frequency required to provide therapeutic, non-toxic serum concentrations of this drug for babies of all gestations.1-1

We were surprised by the media interest in our paper and responded to requests for interviews accordingly. Unfortunately, we cannot be held responsible for the headlines or tone of the published newspaper reports.

The extent of drug toxicity from unlicensed and off label drug use in neonates is unknown. We know that severe adverse drug reactions in children are more likely to occur with unlicensed and off label treatment than licensed drugs.1-2 The scientific study of drug treatment in neonates has been relatively neglected by both doctors and pharmacists in the UK and Europe. However, there are positive developments: the British Forum for the Use of Medicines in Children and the European Network for Drug Investigation in Children are trying to both encourage and coordinate clinical trials in this area.1-3

It is clear that many health professionals now accept the need for research in paediatric therapeutics. We are not simply bidding for money but trying to raise the profile of a neglected area of research. Historically, research has been centred on disease in specific areas—for example, cystic fibrosis, leukaemia, cardiac defects, etc. When seeking funding for research on the extent and risk of unlicensed and off label drug use in children1-2 1-4 we were told by a major children's charity that they did not consider it an appropriate area for research and that they would not even consider an application for funding. We hope that the studies documenting the extent of unlicensed and off label prescribing1-4 1-5 and the consequences of such prescribing7 will convince the Department of Health and the major charities that this is an important area of research, and that the use of drugs in the neonate should be evidence based.

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Editors' comments

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