Formulations for children: problems and solutions

Abstract

Paediatric formulation design is complex as there is a need to understand the developmental physiological changes that occur during childhood and their impact on the absorption of drugs. Paediatric dose adjustments are usually based on achieving pharmacokinetic or pharmacodynamic profiles equivalent to those achieved in adult populations. However, differences in the way in which children handle adult products or the use of bespoke paediatric formulations can result in unexpected pharmacokinetic drug profiles with altered clinical efficacy. Differences in drug formulations need to be understood by healthcare professionals involved in the prescribing, administration or dispensing of drugs to children such that appropriate advice is given to ensure that therapeutic outcomes are achieved. This issue is not confined to oral medicines but is applicable for all routes of administration encountered in paediatric therapy.

Introduction

Development of age appropriate medicines for children requires not only an understanding of their preferences for different formulations, flavours and textures of products but also an understanding of the physical and biochemical differences between children and adults. The most obvious difference between adult and paediatric drug therapy is the complexity of dose adjustment and the algorithms used to calculate dosages relevant to sub-populations within the overall paediatric population. There is much emphasis on the idiom that ‘children are not just small adults’ in terms of drug therapy 1. Indeed, growth and development are two major aspects of children not readily apparent in adults. The topic of human growth and development is extensive with many detailed dedicated reference works (e.g. 2,3).

There are several reviews that detail formulation options and their suitability for children across a range of ages 4–8. There is also regulatory guidance on formulation preference with age within a paediatric population 9–11. However, there is a still a need for evidence based information to guide the development of formulations that are appropriate and acceptable to children and young people.

Owing to the wide age range of the paediatric population, it is unlikely that a single formulation will be appropriate across this range, necessitating multiple product variants. The design of an ideal paediatric formulation needs to consider the following factors: (i) producing minimal impact on the lifestyle of the child, manifesting as the lowest dosage frequency and a palatable product, (ii) provision of individualized dosing or dose banding appropriate for effective therapy, (iii) sufficient bioavailability, (iv) non-toxic excipients in the formulation, (v) convenient and reliable administration and (vi) robust production process at minimal cost 12.

Barriers to using existing formulations

The use of unlicensed and off-label medicines for treating children is widespread with associated risks as these products have not been properly studied in paediatric populations. Healthcare professionals and parents or caregivers are often required to manipulate an adult medicine to obtain an appropriate dose for a child, for example, by splitting a tablet to provide a smaller dose or in more complex cases preparing a suspension from a crushed tablet. Such manipulations increase the variability in the product by inaccurate measurement, issues with stability or errors in instruction for manipulation 13. There are currently regulatory and financial drivers to develop age-appropriate medicines for new drugs, yet there is a significant number of existing drugs where age-appropriate formulations are needed. There are priority lists for such medicines (e.g. 14,15).

Formulations and pharmacokinetics

Pharmaceutical formulation can affect the performance of a drug, particularly with extemporaneously prepared products that are administered to children. One reported case study 16 described significant underdosing of clobazam in a 3-year-old child with epilepsy. In this case the extemporaneous preparation, although prepared as the correct nominal concentration, was not fit for purpose as the active drug was not homogeneously suspended. The correct administered volume did not contain the correct dose resulting in sub-therapeutic treatment.

Ideally, any paediatric formulation should be bioequivalent to an adult product to minimize errors in prescribing and to enable simple switching of formulations at the relevant age. Bioequivalence is usually assessed in terms of peak plasma concentration (C_max), time to C_max (t_max) and area under the absorption time curve (AUC) in a plot of plasma concentration against time. Differences in the rate of absorption (faster or slower) will alter t_max yet are unlikely to affect C_max or AUC. Differences in the extent of absorption will affect C_max and AUC which typically have greater clinical significance compared with changes in t_max. In terms of regulatory guidance, a significant difference is defined as one where the 90% confidence interval fails to meet the limits of 80–125% for either C_max or AUC of the reference product's profile 17. Bioequivalence studies are typically conducted in adult populations. A literature search was conducted to identify bioequivalence studies undertaken using paediatric formulations. The search terms ‘pediatric’ OR ‘paediatric’ AND ‘bioequivalence’ OR ‘bioavailability’ were used. The search was limited to those where these terms appeared in the title, abstract or keywords of articles within both Scopus (http://www.scopus.com) and Pubmed (http://www.pubmed.com) databases up to January 2013. Table 1 reviews bioequivalence studies reported in the literature and the resulting differences in pharmacokinetic profile compared with adults.

Table 1.

Pharmacokinetic studies comparing paediatric formulations

In total, 45 reports of bioequivalence studies of paediatric formulations were found. Of these 15 were conducted within a paediatric population, 29 within adults and one in both paediatric and adults. The paediatric formulation was not equivalent to the reference adult product in 40% of cases included in this review. There were 10 instances where the paediatric product showed higher bioavailability and 11 where the bioavailability was reduced. These findings highlight the need to understand the influence of formulation design on pharmacokinetic performance in paediatric populations. Typically liquids have a rapid onset compared with tablets as there is no disintegration step to retard absorption. Since paediatric products tend to be liquids it is unsurprising that the bioavailability is different in so many cases. Perhaps it is more surprising that there were 11 cases where bioavailability was reduced in the paediatric formulation. However, as several formulations listed within Table 1 were extemporaneously prepared rather than a bespoke paediatric formulation, it may be expected that these may not perform in a similar way to the adult product.

Differences in paediatric physiology and anatomy can also influence the absorption, distribution, metabolism and elimination of drugs. Therefore it is important to understand not only the formulation but how this may interact with the site of absorption to understand whether differences in pharmacokinetics relate to formulation, age or a combination of formulation and age for paediatric medicines.

Routes of administration and formulation considerations relating to pharmacology

There have been some excellent reviews on selection of paediatric formulations based on paediatric preferences (for example 4,9,64) as well as reviews on physiological and anatomical differences in paediatric populations and the consequences in drug therapy (e.g. 65,66). However, this review brings together these aspects to identify issues in paediatric formulations for alternative routes of administration.

Oral drug delivery

Drugs given orally include liquid dosage forms (solutions, suspensions, syrups and emulsions) as well as solid dosage forms including tablets, capsules, granules/sprinkles, chewable tablets, orodispersible tablets and controlled release tablets. The oral route of administration is the preferred route for patients of all ages for reasons of convenience and stability.

Oral liquids

The bitter taste associated with many drugs is thought to have evolved as a deterrent against ingesting toxic substances 67. The major barrier in development of oral liquid formulations is taste-masking of drugs as more than 90% of paediatricians in the US reported that a drug's taste and palatability were the greatest barriers to completing treatment 68. In some cases simple taste-masking is insufficient and more complex formulations are required to encapsulate the drug providing taste-concealing properties. The excipients used in the development of a product need to be safe and acceptable for use in children. Excipients are typically used to optimize the formulation of the medicine to improve palatability, shelf-life and/or manufacturing processes. There are certain excipients that should not be used in childrens' medicines as they can retard on-going organ development, for example, ethanol, propylene glycol, benzyl alcohol and parabens 65. It is also important to consider the electrolyte concentration when developing medicines for neonates where renal function may be immature.

The maximum recommended single dosing volume is 5 ml for children aged below 4 years and 10 ml for children aged between 4 and 12 years according to EMA draft guidance 11. Oral liquid drops provide a mechanism to deliver small volumes or low doses of a drug to children and are particularly useful in very young children. The use of appropriate measuring devices with oral medicines is encouraged, particularly the use of oral syringes as they have superior accuracy compared with graduated pipettes or measuring spoons 9.

Liquids provide maximal dosing flexibility and it is possible to use a single formulation over a wide age range (including neonates). However the volume used must be acceptable to the patient and the dosing device must be fit for purpose.

Solids for reconstitution

The use of dispersible tablets, powders, granules, pellets or sprinkles for reconstitution is a popular strategy in paediatric formulation development as the solid product typically has better stability compared with a formulated liquid. However, these reconstituted products also need to be taste-masked. Reconstitution can occur either at the point of dispensing or at the point of administration depending on the product. The instructions for reconstitution can be complicated for untrained individuals, yet it is important that the final product contains the correct dosage for the patient. If these solids for reconstitution are administered in the absence of water they are only appropriate for infants who are accepting solid food (typically >6 months). For solids of a larger particle size the minimum age range may be higher owing to the risk of aspiration or choking.

If dispersible products are not reconstituted in an appropriate volume of liquid then there is a risk of local tissue injury (similar to when tablets adhere to the oesophagus 69) and a delay in the onset of action, since the solid material needs to dissolve prior to absorption. Therefore, it is important to consider the overall solubility of any drug and how this may affect biopharmaceutical performance.

The volume of liquid used for administration of dispersible tablets is larger (up to 20 ml) than volumes typically used for conventional oral liquids, with volumes up to 20 ml considered (by the EMA) to be appropriate for children below the age of 4 years and volumes of 50 ml for those over 4 years old 11.

Oral solid dosage forms – conventional tablets and capsules

Conventional tablets are limited by their rigid dose content and the ability of the child to swallow a tablet. The general thinking is that children will accept tablets based on size, where a smaller tablet is more likely to be acceptable. Tablets can be scored to allow splitting to reduce their size yet this can result in inaccurate dosages within the fragmented tablets 70. Draft EMA guidance proposed that, ‘small tablets (i.e. tablets from 3 to 5 mm diameter, width or length whichever is the longest) will not be considered acceptable for children below the age of 2 years, medium sized tablets (i.e. tablets from 5 to 10 mm) for children below the age 6 years, large tablets (i.e. tablets from 10 to 15 mm) for children below the age of 12 years and very large tablets (i.e. tablets from 15 mm) for children below the age of 18 years’ 11, however, this recommendation was removed from the updated guidance document 7. Studies that investigated the use of mini-tablets (tablets ≤3 mm) found that mini-tablets were a potential dosage form suitable for 2–6 year olds (based on placebo tablets 3 mm in diameter) 71. Additionally Spomer and co-workers found that very young children (6–12 months) were fully capable of swallowing mini-tablets of 2 mm diameter, often accepting them in preference to sweet liquid formulations 72.

Standardized capsule sizes range from 11.1 mm (size 5) to 23.3 mm (size 00) in length. There are no data on acceptability of capsule size in children although this should be considered to be equivalent to tablets. Capsules can be opened and the contents taken to improve acceptability in children. However this should only be undertaken when justified. However, the capsule contents may taste unpleasant and the bioavailability of the opened capsule may differ from that of the intact product.

In adults the recommended volume of water taken with tablets and capsules is 250 ml based on clinical study protocol used during development of such products 73. The use of smaller volumes can delay onset of absorption and reduce the overall bioavailability of a product, particularly drugs that are poorly water soluble 74,75. There are no literature reports that provide a similar volume of water to be used in children. Therefore water ingestion may increase the variability in exposure observed following tablet administration in children.

Chewable tablets and orodispersible formulations

Chewable tablets and orodispersible formulations need to possess good organoleptic properties including a good mouth feel which is influenced by the drug's crystalline structure and solubility. The consequences of swallowing such tablets whole should be considered and it is preferable that their bioavailability is unaffected. WHO guidance suggests that they should be developed such that the label can state, ‘tablets that may be chewed or swallowed whole’ 9.

Orodispersible tablets, oral lyophilisates and oral films are solid products that are designed to dissolve within the oral cavity. These products dissolve and disperse within the saliva for absorption either directly from the oral cavity or for absorption from the gastrointestinal tract following ingestion. The ratio of absorption from each of these sites can be important, particularly for drugs that show differences in bioavailability from each route, for example desmopressin 76.

These products offer the level of pharmaceutical stability associated with solid dosage forms and are acceptable to even very young patients. However, they are limited by dose rigidity in the same way as conventional tablets. They are most suited to highly soluble drugs, although the solubility of the drug needs to be balanced with taste-masking as highly soluble drugs will activate taste receptors on the tongue if they dissolve in saliva within the oral cavity 77. The volume of liquid taken with such products should also be considered, particularly for poorly water soluble drugs as described previously.

Nasal drug delivery – formulation considerations

Intranasal drug administration is convenient with fast onsets of action approaching that of intravenous therapy and so nasal drug formulations are used within paediatric populations routinely. Intranasal medications can be delivered using several methods. Drops can be instilled from a syringe or drugs can be nebulized or given through a pressurized aerosol. All of these delivery methods have been demonstrated to be effective 78. While it is believed that metered-dose systems provide the greatest dose accuracy and reproducibility, their ease of use can vary significantly. There are no reports on the differences in nasal mucus, nasal pH or mucociliary clearance in paediatric patients compared with adults. Therefore it is assumed that these properties remain the same in children as in adults. There are no reported paediatric specific nasal formulations that differ from adult products. However, the similarities in anatomy and physiology ensure that products are likely to perform in the same way in adults compared with children with few reported adverse effects following nasal drug delivery.

Ocular drug delivery – formulation considerations

Many ocular medications, as drops, ointments, gels and inserts, are used in children to treat common bacterial and viral infections, inflammation and allergy, uveitis and glaucoma, as well as other conditions including myopia, amblyopia and strabismus. Eye conditions are prevalent in paediatric populations. Within the United Kingdom more than 5% of children have had at least one eye condition by the age of 3 years 79.

The eye of the newborn is roughly two thirds of its adult size, reaching an adult size around ages 3 to 4 years 80. In the eye, membranes are thin in neonates and infants, so drug absorption and corneal permeation may be more rapid in these groups 81,82. The cornea of the neonate has 70% of the absorptive surface of the adult cornea, but the total intraocular volume is barely one third of the adult eye 83. The area of contact between the posterior conjunctiva and the eye globe has been approximated to 4 cm² in adults 84. This surface area would be reduced in children. Consequently, the ratio of surface area to internal volume could lead to drugs becoming somewhat concentrated within the eye of paediatric patients.

Basal tear volume increases with age. Typical volumes reported are 0.5 μl (range 0.6–2 μl) for neonates, 2.5 μl (range 1.4–7.75 μl) for infants (mean age 7 weeks) at an older age, and 6 μl (range 2.73–12.75 μl) in adults 85. The age-related reduction in tear volume can lead to topically applied medications becoming concentrated in younger patients.

Topical application of ocular drugs may cause serious adverse ocular or systemic side effects. Children are at greater risk of systemic side effects because ocular dosing is not weight-adjusted, and infants are especially vulnerable particularly in cases where drug metabolism is reduced in the young and/or an immature blood–brain barrier 86.

There are examples where topical administration of ophthalmic medicines in children has led to elevated systemic drug concentrations or systemic side effects. Examples include:

• elevated plasma concentrations of brimonidine 1459 pg ml⁻¹ and 700 pg ml⁻¹ following instillation by eye (compared with reported adult studies that show a maximum concentration of 60 pg ml⁻¹) leading to somnolence or coma 86,87.

• blood concentrations of timolol in five small children ranged from 3.5 to 34 ng ml⁻¹, in contrast to 2.45 ng ml⁻¹ in adults following topical ocular administration 88.

• systemic exposure of latanoprost ophthalmic solution 0.005% once daily was higher in a <3 year age group (166 pg ml⁻¹) vs. other groups (49, 16 and 26 pg ml⁻¹ for the 3– <12 year, 12–<18 year, and ≥18 year age groups, respectively 89.

The increased systemic exposure observed in paediatric patients has been attributed to absorption of eye drops into the systemic circulation where the reduced size of the patient results in higher plasma concentrations of circulating drug.

Calculating dosages for paediatric patients is complex. Body weight, surface area, development, metabolism, other medications taken and physiologic function can all affect the dosage. Pharmacokinetic models that adjust dosage based on aqueous humour volume have previously been proposed for topical pilocarpine 90. It is estimated that a newborn requires only one half of the adult dosage of eyedrops to obtain an equivalent ocular concentration; two thirds of the adult dosage is required at age 3 years and 90% of this dosage at age 6 years 83

Anatomical and physiological differences in the eyes of neonates and infants leave them vulnerable to systemic effects of topically administered ocular drugs. Further studies are required to understand how formulations behave in a paediatric population. In addition, there may be a need for a bespoke paediatric delivery device to provide a smaller dose of topically applied medicines.

Otic drug delivery – formulation considerations

Drugs that act on the ear in paediatric populations include therapies for otitis externa, otitis media and the removal of ear wax. These medicines are most frequently applied as ear drops and sprays. A small volume is generally used as excess will be lost out of the ear passage.

The outer ear in humans is not completely mature at birth and various anatomical and physiological changes occur with age. The external auditory canal (EAC) of an infant is straighter, narrower and much shorter than in the adult. EAC volume increases with age from a mean value of 0.56 ml 91 at 4–5 years of age up to 0.70–0.98 ml in adults 92. Dosing devices allow smaller doses to be administered in paediatric patients and as there is no significant systemic uptake from medicines administered aurally there are little anticipated differences in treatments in paediatric patients compared with adults.

Otic drug formulations are used within paediatric populations routinely. There are no reported paediatric specific formulations that differ from adult products. However, the similarities in anatomy and physiology ensure that products are likely to perform in the same way in adults compared with children with few reported adverse effects following otic drug delivery

Rectal drug delivery – formulation considerations

Rectal preparations are used to treat both local and systemic disorders in children. These are typically delivered as creams, ointments, suppositories, foams, sprays and enemas. The rectal route of administration is particularly useful for infants and children who have difficulty in swallowing oral medicine. This route is also useful in cases of nausea and vomiting or where upper intestinal disorders present may affect oral drug absorption.

The diameter, length and volume of the rectum changes during development, with adult dimensions being reached at about 10 years of age 93. The rectal length increases with age from 4 cm as a neonate, 6 cm at 1 year, 7 cm at 5 years, 9 cm at 10 years, 10 cm at 15 years and 10.5 cm as an adult 94. The diameter of the rectum in children age 7 years was approximated as 21 mm by Joensson and co-workers 95.

Rectal delivery of paracetamol in pre-term infants was investigated by van Lingen and co-workers. Their results showed that there was rapid absorption with higher concentrations attained in patients aged from 28–32 weeks compared with those over 32 weeks although the dose administered was calculated on a mg kg⁻¹ basis 96. The greater absorption in the youngest patients may be a factor of both reduced thickness of the rectal wall akin to reduced thickness of external skin observed in preterm infants. Increased plasma concentrations may also be influenced by the developmental immaturity of hepatic metabolism in younger individuals 66.

Historically oral liquid preparations or injectable solutions have been administered rectally when oral administration was not appropriate and no specific rectal preparation was available. The rectal delivery of oral liquid preparations of antiepileptic agents was investigated by Graves & Kriel 97. They found that most were well tolerated and demonstrated clinical efficacy. A diazepam rectal solution provided rapid systemic concentrations and improved clinical outcomes compared with a diazepam suppository in children 98.

Dose adjustments in paediatric patients are typically made based on weight, height or body surface area. In terms of rectal drug delivery for systemic effects, the rectal absorptive surface area is an important factor to consider. Although dose adjustments are relatively simple for solutions and suspensions, the use of suppositories restricts simple dose adjustment in many cases. Paediatric suppositories are typically manufactured as an appropriate size for children (1 g nominal weight). Where necessary, portions of adult suppositories are used in paediatric patients as it is assumed that there is a uniform distribution of the active substance in the suppository matrix. However, there is unlikely to be any accuracy or stability data for such practices and the resulting shape may not be optimal for rectal insertion.

The formulation of paediatric dosage forms for rectal administration follows the same principles as for adult products. Dosage adjustments in paediatric populations need to be considered carefully for systemically absorbed rectal products. The dimensions of paediatric suppositories should be considered to maximize patient and carer acceptability.

Parenteral drug delivery

Intravenous injections are prepared using the same principles as for adult products, although there may be a need to consider the excipient load to ensure that this is appropriate for children. The main drawback of intravenous administration in the paediatric patient is associated with the use of needles and the pain and fear associated with needles.

Intramuscular injections can provide a depot of active drug that reduces the frequency of injections although the limited muscle mass in neonates and preterm neonates restricts wide use of this type of administration within this population. However, in developing countries i.m. administration is common owing to the difficulties associated in obtaining i.v. access and maintaining the i.v. line in children 99.

Neonates have reduced skeletal muscle blood flow and inefficient muscular contractions due to their limited movements which may reduce the rate of absorption of drugs following intramuscular administration 100. However, neonates and infants have a higher density of skeletal muscle capillaries compared with older children which explains the greater efficiency in intramuscular absorption observed for amikacin 101 and cephalothin 102 in younger paediatric populations.

The subcutaneous route is used routinely with children to administer a wide variety of pharmacological preparations including vaccinations, anticoagulants, analgesics, insulin, growth hormones and some anti-cancer agents 103. Typical subcutaneous administration volumes are limited to <2 ml in adults and <1 ml in children 104. An alternative to subcutaneous injections includes the use of needle free injection devices such as jet injectors 105 that deliver drugs through the skin using high pressure or through the use of microneedles 106. However, there are very limited studies that report on the use of these technologies in children. A commonly listed advantage lies in the reduced pain offered by such devices yet no significant differences in pain between insulin administration by needle and liquid-jet using the Vitajet II® device were reported in a study in patients aged 9–21 years 107.

For parenteral administration the dose volume needs to be considered to ensure that this can be accurately measured, rather than relying on serial dilution where errors are more likely to occur with serious consequences 108.

Dermal and transdermal delivery

The skin undergoes many changes during development. This needs to be considered when paediatric formulations are applied to the skin for both local and systemic action. The stratum corneum is intact shortly after birth (<1 month), yet the way it stores and transports water becomes adult-like only after the first year of life 109. The ratio of surface area to body weight is much higher in a neonate compared with an adult. Therefore the volume of distribution is lower per unit area of skin within the paediatric population 110.

Preparations for dermal (or cutaneous) administration include liquid preparations (lotions and shampoos), semi-solid preparations (ointments and creams) and solid preparations (powders). Although these products are typically considered safe in terms of absorption, higher levels may be reached in paediatric patients or where skin is broken.

Newborn infants are regularly exposed to a wide variety of topical agents, including treatments for rashes, antimicrobial agents, solvents and skin barriers or moisturizers. The excipients used within such products need careful consideration as transdermal absorption of propylene glycol from an antiseptic dressing used in a preterm infant resulted in the infant going into a state of coma. Complete recovery occurred following cessation of topical treatment 111.

Dose adjustments for children for topical products are usually relatively simple owing to the nature of the product that does not link to rigid dose units. However, establishing a dose unit can be difficult.

The paediatric population is an inviting target for effective transdermal medication administration as their skin is comparatively thin and well perfused. Transdermal patches have been used to deliver drugs such as scopolamine, fentanyl, oxybutynin and methylphenidate to children. Regulatory guidance states that, ‘the size and shape of transdermal patches and medicated plasters should be tailored to the size and shape of the child body and should not interfere with daily routines’ 11. Patches and plasters are usually developed for use as a single dose/strength. Although some patches can be cut for partial patch administration, cutting others destroys the release of the medication.

The formulation used in transdermal patches can be similar for adult and paediatric populations provided that excipient usage is appropriate for the youngest infants to be treated.

Pulmonary drug delivery

Inhaled medications are commonly administered to infants and small children with asthma and cystic fibrosis. Airway size, respiratory rate, inspiratory/expiratory flow rates and breathing patterns, as well as lung volumes and capacities, change dramatically during the first months and years of life. For example, obligate nose breathing is common at birth and may persist to the age of 12 months, resulting in substantial differences in the route taken for inhaled material to reach the lungs 112.

Delivery devices used in paediatric populations are the same as those used in adults although they are frequently modified by attaching a small infant or child sized mask. There is no clinical evidence demonstrating better clinical response with or across interfaces (for example, mask vs. mouthpiece) 113,114. Therefore, selection of interfaces is more dependent on age, tolerance of the device and preference of the patient. Nebulized liquids are potentially suitable for young children who cannot use metered dose inhalers (MDIs) and dry powder inhalers (DPIs). MDIs may be suitable for children from birth when combined with a spacer. The spacer eliminates the need for the patient to co-ordinate actuation with inhalation. A facemask is required until the child is able to manage with a mouthpiece. DPIs may be used for children from the age of 4–5 years, as minimum inspiratory flow is required. DPIs and MDIs are preferred for older children because of their portability and convenience.

Dose adjustment for inhaled medications is typically based on body weight where extrapolation from adult doses is acceptable for children from 3 to 12 years of age 112. For inhaled medicines it is the delivery device that controls the dosage and this is critical for paediatric populations. However, the devices used are typically the same as those used in adults, adapted to control the dose delivered.

Conclusions

Paediatric formulations need to be appropriate for the child in terms of dose, convenience and acceptability to ensure compliance with the medication. There are differences in paediatric anatomy and physiology that can impact upon the performance of a drug that is different from that observed in adults. The design of a paediatric formulation needs to take these differences in physiology into account to ensure that the pharmacokinetic profile of the drug is not compromised. This is of particular relevance to neonates and infants who are furthest in development terms from an adult.

Formulation can lead to differences in pharmacokinetic profiles for a drug, highlighting the risks associated with using off-label medicines that are manipulated to enable administration to children. Prescribers need to be aware of the consequences of manipulating medicines formulations, particularly for drugs with a narrow therapeutic index, even in extemporaneous compounding by a pharmacist where there is insufficient evidence on product quality. In addition, healthcare professionals should be aware that patients and their carers often further manipulate medicines to aid in compliance, particularly within a paediatric population where 19% of all medicines administered to children were manipulated 115.

The excipients used in paediatric formulations need to be appropriate for the age group 116–118 to avoid the consequences of excipient toxicity. Acceptability of medicines to paediatric patients is also of great importance in the child receiving adequate therapy. Palatable formulations are known to achieve greater compliance. Therefore this is critical in the design of a new paediatric formulation 119.

Competing Interests

Both authors have completed the Unified Competing Interest form at http://www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare HKB had support from National Institute for Health Research Medicines for Children Research Network for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years and no other relationships or activities that could appear to have influenced the submitted work.

The author (HB) would like to thank the National Institute for Health Research Medicines for Children Research Network for their support for this research.