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Kiddie killers

MagazineApril 2009 (Vol. 20 Issue 1)Kiddie killers

On 12 October, three of the world's leading drug com-panies 'voluntarily' with-drew a clutch of cold and cough remedies for infants

On 12 October, three of the world's leading drug com-panies 'voluntarily' with-drew a clutch of cold and cough remedies for infants. This announcement was made immediately after a bombshell US Food and Drug Administration (FDA) report showed that everyday children's medications had caused over 120 deaths over the last 37 years in the US alone. Most of the victims were infants under the age of two. In its defence, the drug industry partly blamed parents for not reading labels, thus inadvertently overdosing their children.

At another extreme, parents have not only been blamed, but sent to jail because of drug side-effects (see box).

These two extremes are merely the twin peaks of a huge iceberg. Doctors have been warning us for years that there are major problems concerning children's medications in general, a situation that both the drugs industry and regulators have largely ignored.

ADRs in children

In the last few years, a slew of medical reports has revealed the damaging effects of prescription drugs on children. Paediatricians across the globe have become aware that children are at particularly high risk of so-called 'adverse drug reactions' (ADRs) from relatively common medications.

Among the first whistleblowers were British researchers from Nottingham University who, six years ago, complet-ed a major audit of the reasons given for children's hospital admissions. They found that a staggering one in 50 hos-pital admissions was because of ADRs, and nearly 40 per cent of these were "life-threatening reactions". As ADRs are often worse in children than in adults, they constitute "a significant public health issue" (Br J Clin Pharmacol, 2001; 52: 77-83).

It's a similar story in other countries, too. Three years ago, doctors did a six-year audit of paediatric admissions in Ohio hospitals. Again, a significant percentage was found to be due to ADRs, with antibiotics, anticonvulsants and narcotics being the main offenders. Ironically, to combat the ADRs, 73 per cent of cases were treated with even more drugs, according to the hospital records (Drug Saf, 2004; 27: 819-29).

Earlier this year, pharmaceutical chemists at the University of British Columbia, in Canada, audited toxic reactions to drugs among their nation's children. Their four-year survey revealed that 61 per cent of ADRs in children were "serious", with as many as 41 (out of 1193) children actually dying as a result of drug side-effects. The main culprits were isotretinoin (an anti-acne preparation), paroxetine (an antidepressant), methylphenidate (Rit-alin, the hyperactivity drug), amoxy-cillin (an antibiotic) and valproic acid (an anticonvulsant used in epilepsy) (Can J Clin Pharmacol, 2007; 14: e45-e57).

A considerably longer, 15-year sur-vey found that, in Swedish children, the most frequent causes of adverse reactions were vaccines and antibiotics. Again, children died-808 out of 5771-as a direct result of medication (Pharmacoepidemiol Drug Saf, 2005; 14: 493-9).

This survey came hard on the heels of a more intensive Swedish study that tried to measure the reliability of drug-reaction reporting in general. The researchers found that both doctors and the reporting system were particularly lax in recording serious drug side-effects. An intensive analysis of 1349 patient records from five Swedish hospitals revealed an under-reporting rate of as much as 86 per cent. Of 107 patients whose symptoms had probably been caused by drugs, only 15 had ever been recorded as an ADR; the other 92 cases of drug toxic-ity had been totally ignored-and this in spite of the efficient, state-run Swedish medical system (Pharmacoepi-demiol Drug Saf, 2004; 13: 483-7).

This suggests that the already substantial official rate of annual child-hood ADRs is very likely far below the true figures. Indeed, last year, researchers from the Drug Safety Unit at Southampton University completed a huge survey of ADRs across 12 countries, and found that ADRs were underreported by an average of an incredible 94 per cent (Drug Saf, 2006; 29: 385-96).

This means that, to get a real picture of the situation, any official ADR statistics should be multiplied by 20.

Yet, behind all these figures lies a stark and rather disturbing fact: most prescription drugs have never been tested to see if they are safe for children or, indeed, if they actually work for them. "Less than 25 per cent of drugs can be advertised as safe and effective [for children]", say the British Colum-bia pharmacologists.

How can the authorities-or doc-tors, for that matter-allow children to be given drugs that lack safety or efficacy data for such patients? It appears that as long as a drug has been approved by the regulatory authorities for at least one medical condition, it can be used for any other medical purpose. Doctors have carte blancheto prescribe any approved drug for conditions for which it hasn't been tested and for patients in whom it hasn't been studied.

The drug industry uses two relatively innocuous terms to describe this situation: 'off-label' and 'unlicensed'. The former refers to the use of drugs for conditions not indicated in the product's license, including dosage, type of medical condition and age of patient. 'Unlicensed' refers to prescrib-ing a drug for types of patients, suchas children or the elderly, for whom it has not been authorized.

Astonishingly, both uses are legal. In the UK and rest of Europe, they are permitted under the Medicines Act of 1968 and EU Pharmaceutical Directive 89/341/EEC. In the US, the Food and Drug Modernization Act of 1997 confirms the longstanding practice, even allowing drug makers to inform doctors of potential off-label uses.

Not surprisingly, some doctors are feeling increasingly uneasy about the impact this is having on children. "There have been numerous studies to show that many of the medicines used in children are used off-label or are unlicensed for use in children," says Professor Ian Wong, of the School of Pharmacy, University of London. "Some people may see these children as unknowing participants in informal and uncontrolled experiments" (Drug Saf, 2003; 26: 529-37).

For decades, the pharmaceutical industry has argued that children should be excluded from experimental premarketing clinical trials to protect them from possible harm. However, another motive may well be financial. Clinical trials involving children are both expensive and difficult to carry out and, yet, the market for children's drugs is much smaller than that for adults. The end result is that children given even ordinary drugs like pain-killers are likely to be exposed to substances with no objective evidence of safety or efficacy, or risk-benefit analysis.

One Swedish survey of its doctors' prescribing habits found that, on average, more than 40 per cent of the drugs prescribed to children were off-label and that these were more likely to cause serious ADRs than approved drugs. In this case, anti-asthmatics were the most frequent category of problem drug, causing almost one in every three ADRs (Pharmacoepidemiol Drug Saf, 2004; 13: 147-52).

The fact that GPs use drugs off-label is somewhat understandable, given that they are generally not in the vanguard of research. However, Italian research-ers found that hospitals, rather than GPs, are the chief offenders. After a worldwide data search going back to 1985, they found that up to 80 per cent of hospital drug prescriptionsfor children were either off-label or unlicensed. The drugs most commonly used were paracetamol (acetamino-phen), cisapride, chloral hydrate and salbutamol (Eur J Pediatr, 2005; 164: 552-8).

Small wonder, therefore, that children have been shown to be most vulnerable to ADRs in hospital. In fact, according to the Nottingham University researchers, as many as one in 10 children suffers ADRs as a direct result of drug treatment received at the hands of hospital doctors (Br J Clin Pharmacol, 2001; 52: 77-83).

Voices in the wilderness

None of this will come as a surprise to Dr Mohammed Al-Bayati, a toxicologist and pathologist, who fled Saddam Hussein's Iraq 30 years ago and settled in California. When he arrived in the US, he was shocked to find an almost equally repressive regime in the guise of Western medicine. He was confronted with case after case of parents being prosecuted for killing their children, with some parents in jail and others even facing the death penalty. Looking at these cases, one thing stood out clearly to Al-Bayati: doctors, hospitals, prescription drugs and vaccinations were almost always involved in the children's deaths. He soon found himself defending parents as an expert witness in the courts, sometimes the appeals courts (see box, page 6).

To date, Dr Al-Bayati has successfully defended over 20 cases in the US and Canada. His success has relied on exhaustive detective work, forensically drilling down into fine medical detail.

One of his latest cases was that of Patrick, a three-month-old baby boy. In November 2005, he became severely ill, and his parents took him to hos-pital. The hospital ran a battery of tests, and reported that the child had "sub-dural and subretinal bleeding, seven rib fractures in various stages of healing, severe anaemia, thrombocytosis, low blood creatinine levels, hyperglycaemia, and elevated neutrophils and monocyte counts". The hospital doctors decided the child was suffering from 'shaken baby syndrome', and accused the parents of having violently abused their child.

The parents' lawyers called in Dr Al-Bayati, who soon saw the gaping holes in the indictment. The underlying problem was that Patrick had always been a sick child-born prematurely, and prone to vomiting and feeding problems, leaving him malnourished. Two weeks before the hospital emer-gency, the child had developed a severe cough, for which he was prescribed Tylenol. Five days later, the boy had gastrointestinal reflux, for which he was given Zantac, the antiulcer drug.

The underlying culprit

For Al-Bayati, that was the root of the problem. "Patrick was treated with Tylenol," he says, "which contains acetaminophen, at a dose of 200 mga day-a high dose for such a young child-and one that could cause liver toxicity. The child was then treated with Zantac (ranitidine), despite the fact that ranitidine is known to potentiate the toxic effects of acetaminophen. Thus, liver poisoning partly explains the subdural and subretinal bleeding, which was exacerbated by the child's inherent vitamin K deficiency and anaemia."

But what about the rib factures? How could they be explained? "The child had a chronic cough," says Al-Bayati. "The child was already deficient in protein and vitamin K, which would cause weakening of the bones, and so the child's ribs would be vulnerable to any violent coughing" (Medical Veritas, 2006; 3: 1019-40).

Twenty years ago, Dr Al-Bayati was a lone voice in the wilderness but, today, there's now a huge groundswell of concern within the medical profession itself. It's begun to realize that few drugs have ever been tested for use in children-mainly because the official drug-approval process only requires evidence of safety and efficacy in adults. Many doctors are now clamouring for major reforms.

"The current situation regarding the licensing of medicines for children is a profoundly unsatisfactory state of affairs both for children and their doctors," says Professor Peter Hill, of the Great Ormond Street Hospital for Children (Arch Dis Child, 2005; 90: i17-8). The practice of giving children drugs meant for adults is being roundly condemned as unscientific guesswork.

Says Professor Andrew Bush, of London's National Heart and Lung Institute: ". . . the differences between adults and children, and at different stages of childhood development, mandate strategies to improve this situation rather than continually relying on extrapolation from adult studies . . . Disease phenotypes may be completely different in children . . . wheeze in infants is not miniature adult asthma"(Paediatr Drugs, 2006; 8: 271-7).

According to Professor Laura Cuzzolin, of the University of Verona, Italy, there is a need to take "immediate action for a more rational use of drugs in paediatrics, to avoid exposing child-ren and infants to unnecessary risks" (Fundam Clin Pharmacol, 2003; 17: 125-31).

Regulatory authorities have finally begun to act. In 2001, the US Food and Drug Administration (FDA) asked the drug industry to provide specific paediatric safety and efficacy data for any drugs prescribed to children, in return for which the FDA offered six extra months of drug-patent exclusivity.

Although the industry appeared to have embraced this enthusiastically,so far, virtually all the applications for extended patents have been for "cardiovascular and other drugs that are rarely prescribed in the paediatric population, but for which an extra six months of exclusivity is very lucrative in adults," wryly observe Dutch paedia-tricians at the Erasmus University Medical Centre in Rotterdam (Eur Respir J, 2004; 23: 310-3).

Changes: too little too late

Another major problem is that ADRs occur not just with prescription drugs, but with everyday over-the-counter (OTC) medicines, too, most marketed for relatively trivial conditions. On 1 October, the FDA issued a 356-page report on OTC decongestants (cough and cold medicines) which included the revelation that, between 1969 and 2006, 54 children died after taking these medicines, and 69 died after taking antihistamines. The report admits that, since ADRs are under-reported, those figures are likely to be significant underestimates (Nonprescrip-tion Drug Advisory Committee Meeting, 2007-4323b1-02-FDA 10-01-2007).

As we go to press, the FDA is reviewing whether the roughly 800 decongestants on the market are either safe or effective for children. It has already banned one group of cough medicines. Running for cover, manu-facturers have now voluntarily with-drawn another set marketed to infants (see box, page 7). In September, the Consumer Healthcare Products Asso-ciation (CHPA), the OTC trade associa-tion in the US, relabelled children's decongestants, advising against their use in the under-twos-almost certainly in response to a damning report seven months earlier from the US Centers for Disease Control and Prevention (CDC), which warned: "Caregivers and clinicians should be aware of the risk for serious illness or fatal overdose from administration of cough and cold medications to children aged under2 years" (CDC MMWR Surveill Summ, 2007; 56: 1-4).

But all this activity masks the underlying problem. With no safety or efficacy data, children's medications as a whole are in chaos, and yet, authorities appear to be paralyzed. In Europe in 2002, the EU published Better Medicines for Children as a 'prelude' to new regulations for children's medications, but has goneno further. In the US, the FDA is only shutting the proverbial stable door,and then only to address a tiny part of the problem.

This climate of regulatory dithering is deeply frustrating to many paedia-tricians. WDDTY has collated a dossier of over 30 medical reports about children's drugs written over the past decade. The pleas from doctors for the authorities to act are almost anguished-"undesirable situation", "requires action" and "irrational" are just a few of the comments. Doctors have rarely been so united against an industry they so often perceive as their life's blood.

Meanwhile, thousands of children are being injured by side-effects and, in some of them, fatally.

Tony Edwards

Who's the criminal?

In November 1997, two-month-old Alan Yurko, born in a weakened state after a difficult pregnancy, suddenly stopped breathing. His father rushed the infant to a Florida hospital, where he died two days later. The hospital accused the father of causing shaken baby syndrome (SBS); he was subsequently convicted and sentenced to life imprisonment.

Appeals court lawyers asked Dr Al-Bayati to investigate, who says, "The hospital was at fault on two main counts: it failed to review the child's medical notes, which showed a history of infections, and to take account of the side-effects of the vaccines the baby had already received from the family physician. Furthermore, the child was given high doses of sodium bicarbonate and heparin by the hospital itself, and it was those drugs which caused the cardiac arrest and internal bleeding. I was able to establish that these symptoms, which are similar to those of SBS, did not develop until after the baby was admitted to hospital" (Medical Veritas, 2004; 1: 201-31).

In August 2005, two-month-old Averial was rushed to hospital by her mother, and diagnosed as suffering from acute bronchopneumonia and respiratory distress syndrome. Blood analysis suggested major infection. Chest x-ray showed pneumonitis, and physical examination and body scans revealed no evidence of physical injury. The hospital gave her epinephrine (adrenaline), sodium bicarbonate, antibiotics and other drugs. It was only then that skull and rib fractures were seen on the scans. The baby died 11 days after admission. The post mortem found evidence of bleeding both inside and outside the skull which, taken with the rib fractures, was consistent with physical trauma. The girl's 27-year-old father was accused of shaking his daughter to death and is currently awaiting trial. Dr Al-Bayati was called in. "My investigation reveals that the infant's bleeding, brain oedema and necrosis, and skull and rib fractures occurred after she had been brought to A&E. These injuries were caused by the original infection and the medications she received in hospital" (Medical Veritas, 2007; 4: 1452-69).

The main culprits

- Decongestants

- Anything with codeine, dextromethorphan, carbinoxamine, ephedrine, pseudoephedrine, phenylephrine or brompheniramine (CDC MMWR Surveill Summ, 2007; 56: 1-4)

- Cough suppressants containing hydrocodone "can lead to serious illness, injury, or death", says the FDA, which has issued a formal ban on most (over 200) of these products (www.fda.gov/bbs/topics/NEWS/2007/NEW01713.html)

- Withdrawn drugs: Dimetapp Decongestant Infant Drops, Robitussin Infant Cough DM Drops, Little Colds Decongestant Plus Cough, Pediacare Infant Drops Decongestant, Tylenol Concentrated Infant Drops Plus Cold and Cough, Triaminic Infant & Toddler Thin Strips Decongestant.

- Antihistamines

- Anything with diphenhydramine, brompheniramine or chlorpheniramine (Nonprescription Drug Advisory Committee Meeting, 2007-4323b1-02-FDA 10-01-2007).

- Asthma drugs

- Inhaled corticosteroids can stunt growth, and may cause osteoporosis

(J Allergy Clin Immunol, 2003; 112 [3 Suppl]: S1-40).

- NSAIDs

- Ibuprofen, aspirin and paracetamol (acetaminophen) are "a significant cause of morbidity in children" (Br J Clin Pharmacol, 2005; 59: 718-23).

- Antibiotics

- More than half of all antibiotics cause ADRs (Biomedica, 2007; 27: 66-75)

- These drugs are one of the leading causes of fatal ADRs in children (Arch Dis Child, 2002; 87: 462-6)

- Amoxycillin is one of the most common causes of ADRs (Can J Clin Pharmacol, 2007; 14: e45-57).

- Behavioural drugs

- Ritalin causes headache, insomnia, anorexia and tachycardia (Curr Opin Pediatr, 2002; 14: 219-23).

- Vaccines

- The most recent CDC report records 11.4 ADRs per 100,000 doses, primarily in children under six, and 14.2 per cent of all reports were "serious"-including life-threatening illness, hospitalization, permanent disability and death (MMWR Surveill Summ, 2003; 52: 1-24).

Non-drug treatments of childhood problems

Many children suffer adverse reactions when given drugs for problems that can be treated with safer alternatives. But, do consult a qualified practitioner before taking this route.

Infections

- Bacterial and fungal

- Colloidal silver. Take care not to overdose: 100 mcg/day is safe for a child weighing 20 kg (Curr Probl Dermatol, 2006; 33: 17-34)

- Tea tree oil. As effective as standard antibiotics for skin infections, including MRSA (J Antimicrob Chemother, 2003; 51: 241-6), although it may cause skin reactions.

- Colds

- Echinacea (Lancet Infect Dis, 2007; 7: 473-80) and vitamin C (Cochrane Database Syst Rev, 2007; 3: CD000980)

- Saltwater nose drops

- Inhaling steam from water containing Friars Balsam, a 600-year-old herbal remedy.

- Coughs

- EPs 7630, a herbal medicine from geranium (Pelar-gonium sidoides) roots (Phytomedicine, 2007; 14 [Suppl 6]: 69-73), made by Schwabe Pharmaceuticals, Karlsruhe, Germany; www.schwabepharma.com

- CORSHE-E, an Ayurvedic herbal linctus (J Herb Pharmacother, 2004; 4: 1-12). A similar product is Olbas Cough Syrup.

- Urinary and bladder

- Cranberry or blueberry juice (N Engl J Med, 1991; 324: 1599).

- Diarrhoea

- Individualized homeopathic medicine (Pediatr Infect Dis J, 2003; 22: 229-34).

- Inner ear

- Naturopathic herbal ear drops containing tea tree oil, garlic and other herbs (Cochrane Database Syst Rev, 2006;

3: CD005657)

- Individualized homeopathic medicine (Pediatr Infect Dis J, 2001; 20: 177-83)

- Homeopathic Pulsatilla (J Am Inst Homeop, 1986; 79: 3-4).

- Sore throat

- Throat spray containing 15-per-cent sage (Salvia officinalis) extract (Eur J Med Res, 2006; 11: 20-6); a similar product is Echinacea Throat Spray, made by A. Vogel, Switzerland

- Slippery elm, as a pre-drug therapy

- Do nothing, rather than use drugs like penicillin (BMJ, 2003; 327: 1324-7).

Pain

- Headache

- Peppermint oil applied to the forehead and temples (Nervenarzt, 1996; 67: 672-81)

- Acupressure (Digital Dissertation Abstracts, 1990; DAI-B 50/

12: 5890)

- Self-hypnosis (Pediatrics, 1987; 79: 593-7)

- Check for food allergy (J Pediatr, 1989; 114: 51-8)

- Feverfew may work (Lancet, 1988: ii: 189-92), although a recent survey casts some doubt (Curr Opin Neurol, 2005; 18: 289-92)

- Homeopathy (although there are no clinical trials).

- Toothache

- Oil of cloves

- Activated charcoal compress

- Tincture of Plantago major (plantain)

- Purple passion flower (Passiflora incarnata) for hyper-sensitive teeth

- Prickly ash (Zanthoxylum americanum) bark tinctureto numb teeth and gums.

- Colic

- See Q&A, page 19, for treatment alternatives.

Bad Behaviour

- Remove additives from the child's diet (Lancet, 2007;

epub ahead of print; DOI:10.1016/S0140-6736(07)61306-3)

- Check for food allergy in general (J Pediatr, 1989; 114: 51-8)

- Pycnogenol, the extract from the bark of the French maritime pine tree (Eur Child Adolesc Psychiatry, 2006; 15: 329-35)

- Omega-3 and -6 supplements (Pediatrics, 2005; 115: 1360-6).


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