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Paediatric issues in the 21st century


Laurence A Goldberg
HPE Editorial Consultant
E:[email protected]

Unlicensed medicines and off-label use of medicines are major problems in paediatrics. Up to 65% of medicines used for children in hospitals are not licensed for the purpose, according to Tony Nunn (Clinical Director Pharmacy, Royal Liverpool Children’s NHS Trust and Associate Director, Medicines for Children Research Network, University of Liverpool).

Medicines for children are often extemporaneously dispensed, but this is not always satisfactory. If only adult doses are available, it may be complicated to make a suitable paediatric dosage form and there is significant risk of error. For example, the dose of morphine for a 1kg neonate is 100μg, but the lowest commercially  available product is 10mg, equivalent to 100 neonatal doses. A tenfold overdose can easily occur, said Mr Nunn. Using laboratory-grade chemicals instead of licensed medicines is risky because quality is not assured in the same way, he continued. Another solution is to import a foreign, licensed product. This is always preferable, although there may be language problems with the packaging and labelling.

Further problems arise with off-label use; for example, parents may be confused or alarmed by the manufacturer’s information if it advises against use of a product in young children. There can also be difficulties in communicating accurately with other healthcare professionals.

Several factors have contributed to the absence of suitable medicines for children, the largest of which being the lack of commercial incentive to produce paediatric medicines. Patient numbers are relatively small, representing 20–25% of the EU population, the formulations are potentially costly, and the organisation of clinical trials in the paediatric field is fraught with difficulties.

Recently the problems have been recognised and regulators have sought to provide some incentives for the pharmaceutical industry. In the USA in 2005, the Paediatric Formulations Initiative provided a six-month patent extension for products if research in children was included. In Europe the Orphan Drugs Regulations have been in force for six years and have helped some products for rare diseases to become available, but the European Parliament and Council regulation on medicinal products for paediatric use, known as Better Medicines for Children, will have a wider impact. The objectives of the regulation are to increase the ­quality of research, availability of medicines and information about medicines for children. All of this is to be achieved without unnecessary studies in children and without delaying authorisation of medicines for adults. New rewards, incentives and requirements are envisaged, and a Paediatric Committee has been created at the European Medicines Evaluation Agency (EMEA) to support these developments.

Paediatric formulations
Some 25% of products licensed for children are only available in dosage forms that are unsuitable for the intended age group, and finding a suitable paediatric formulation is far from straightforward, Antje Neubert (Centre for Paediatric Pharmacy Research, London School of Pharmacy), told the audience. Moreover, reputable journals often provide inadequate formulation information in paediatric trials, and 70–80% of products that are suitable for children have inadequate dosing information. A recent EMEA report summarises what is available (see Resources).

Taste, smell and texture are important issues in ­paediatric formulation, said Dr Neubert. Taste cells develop at the seventh or eighth week of gestation, whereas olfaction does not develop until after birth. Children may have difficulties in recognising tastes and can, for example, confuse flavours such as strawberry and chocolate. For this reason it is generally best to avoid complex or unusual flavours. Social and cultural influences also play a part; for example, bubblegum flavour is popular in the USA, she noted. Assessment of taste can be done using a taste panel, ideally involving children, and also by using a taste sensor known as the “e-tongue”. This can mimic the response of the human tongue and also compare taste quality and intensity to known standards in a reproducible way.

The formation of the Task Force in Europe on Drug Development for the Young (TEDDY) has facilitated the development of a network of excellence across Europe (see Resources). The organisation now comprises 17 research institutions from 11 countries. Initiatives so far have included commenting on EMEA documents, a survey of paediatric pharmacological and clinical databases in Europe and a pharmacoepidemiological study of medicines for attention-deficit hyperactivity disorder (ADHD) in Europe.

Cystic fibrosis
Cystic fibrosis is caused by a mutation in a single gene that results in the production of a defective protein, cystic fibrosis transmembrane regulator (CFTR), explained Sara Arenas-Lopez (Specialist Paediatric Pharmacist, Evelina Children’s Hospital, London).  Numerous mutations have been documented, but the most common is that in which a phenylalanine molecule is missing at position 508, usually described as “ΔF508 CFTR”. Cystic fibrosis is an autosomal recessive disorder so only homozygotes have the disease, but heterozygotes are carriers. About one in 20 Caucasians carry a mutated CFTR gene. CFTR is a cyclic adenosine monophosphate (cAMP)-regulated chloride channel. In the normal situation, rising cAMP levels in cells open the CFTR chloride channel, but when the mutant protein is present there is excessive absorption of water, sodium and chloride, leading to dehydration of epithelial surfaces.

CFTR is found throughout the body on the epithelial cells of pancreas, lungs, kidneys, intestine, gallbladder, sweat and salivary glands, testis and uterus. Although many organs are affected, deteriorating lung function accounts for most of the morbidity and mortality. The main cause of death is respiratory failure following chronic pulmonary infection. In affected children, the bronchial secretions are thicker and stickier than usual and readily trap bacteria. The lungs are usually infected shortly after birth, and many patients will experience chronic infection, at first with Staphylococcus aureus, then Haemophilus influenzae and, by the time they reach adolescence, Pseudomonas aeruginosa. During the past decade, Burkholderia cepacia complex has emerged as a major pathogen in cystic fibrosis, said Ms Arenas-Lopez. Factors that contribute to the development of chronic infection include decreased ­mucociliary clearance, adherence of bacteria to the pulmonary epithelium and the ability of Staphylococcus aureus to inhibit phagocytic activity. Another important aspect is the ability of Pseudomonas aeruginosa to develop into a mucoid form in which organisms are grouped together in ­alginate-coated biofilms and are resistant to ­antibiotics and phagocytes but continue to cause lung damage through secretion of proteases.

Early intervention with antibiotics is essential to delay chronic infection and to improve long-term survival. However, the pharmacokinetics of antibiotics are different in people with cystic fibrosis, and careful monitoring is always required because these patients are repeatedly exposed to high doses of toxic drugs over many years. The development of resistant organisms and the development of hypersensitivity in the patients are two common problems.

Patients may also need treatment with mucolytic agents such as dornase, N-acetylcysteine or nebulised saline to reduce sputum viscosity, bronchodilators and, in some cases, steroids.

Both the exocrine and endocrine functions of the pancreas are affected in cystic fibrosis. The result is malabsorption of fat and the risk of fat-soluble vitamin deficiency. Enzyme supplements need to be given with each fat-containing food, and the dose should be titrated according to the child’s age and the fat intake. There have been reports of fibrosing colonopathy in children taking very large doses of enzymes, and for this reason a maximum dose of 10,000IU lipase/kg is now recommended, said Ms Arenas-Lopez. About a quarter of people with cystic fibrosis will develop diabetes by the age of 20 years and will require insulin treatment. Dose adjustment can be complicated because children with cystic fibrosis have higher calorific requirements than normal children, and many will have high-carbohydrate diets.

Another important area of treatment is nutrition. The energy requirements of children with cystic ­fibrosis are high because of the effort involved in breathing. These can be 150% of normal, rising to 200% during episodes of acute infection and, therefore, they often need nutritional supplements for normal growth and development. Short- and long-term nocturnal enteral feeding is common for this group. Future developments will include a polyvalent antipseudomonal vaccine and lung transplants.

Inger de Silva (Paediatric pharmacist, Evelina Children’s Hospital, London) presented a case history that illustrated the role of the pharmacist in the management of people with cystic fibrosis. A 13-year-old girl with cystic fibrosis was admitted for intravenous antibiotic treatment. She had complained of feeling unwell for the past four to six weeks and had developed a productive cough with exertional dyspnoea and chest tightness in the past few days. Her previous history included osteopenia, reactive airways disease and a gastrostomy. She also had a Portacath(™) in place. She was allergic to clavulanic acid, Tazocin, ­cyclizine, meropenem and ceftazidime. Her drug treatment is listed in Box 1. On examination, she had decreased air entry on the left side of her chest compared with the right but was alert and well.


The treatment plan was to give intravenous ­fosfomycin and Colistin for three weeks and then to resume nebulised gentamicin. Treatment was given for the first 48 hours in hospital and then the patient was discharged to continue treatment at home.

A number of pharmaceutical interventions were made. On admission, an accurate drug history was taken and a number of discrepancies were identified. While she was in hospital the supply of fosfomycin (which is unlicensed in the UK) was organised and information was provided in English. At discharge, the discharge prescription was prepared, arrangements were made with a homecare company to deliver intravenous administration equipment in time for discharge and the patient’s mother was educated about all medications, including IV administration.

Reflection paper: Formulations of choice for the paediatric
population. June 2005. Available from the EMEA at:
Task Force in Europe on Drug Development for the Young (TEDDY)

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