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- A third of neonates who experience seizures will develop epilepsy;
- Non-compliance with antiepileptic drug therapy increases the chance of seizure recurrence;
- Parents’ and patients’ understanding of medication should be confirmed, especially when doses are increased;
- Awareness of the use of ketogenic diets to treat refractory epilepsy in children is important because many medicines contain carbohydrates.
In the UK there are an estimated 58,000 under-18-year-olds with epilepsy. The incidence has increased in recent years due to the development of sophisticated imaging equipment and clarification of terminology.
There are a number of epilepsy syndromes in children and symptoms can vary with the age of the child. The neonatal period is the most vulnerable stage of life for developing seizures. The prevalence of neonatal seizures is
approximately 1.5 per cent and the causes are extensive and diverse.
Hypoxic-ischaemic encephalopathy (HIE) is the most common cause, accounting for 80 per cent of all seizures within the first two days of life.
Prognosis depends on the underlying cause rather than the type of seizure but mortality and morbidity are high (15 per cent and 30 per cent, respectively). It is thought that half of neonates who experience seizures will achieve a normal or near-normal state but a third will develop epilepsy.
Some types of epilepsy can be inherited. Examples include juvenile myoclonic epilepsy and epilepsy associated with inherited medical conditions such as tuberous sclerosis. The risk of inheriting epilepsy is thought to be greater if the sufferer is the mother rather than the father.
Febrile convulsions are often mistaken for epileptic seizures and generally occur in infants between the age of six months and three years. They are triggered by a rapid increase in temperature early in an infection. Only 15 per cent of infants will experience recurrence of a seizure within the same illness. There is no confirmed link with epilepsy and it is thought that by the age of eight years only 3 per cent of children who have had a febrile convulsion will have developed epilepsy.
Febrile convulsions are managed without antiepileptic drugs (AEDs), by reducing the infant’s temperature and keeping him or her cool — giving an antipyretic, removing clothes, and using wet cloths are usually adequate.
It should be noted that epilepsy can impact profoundly on social, behavioural and educational outcomes of children.
Antiepileptic drug therapy in children
As with adults AED treatment should be individualised according to the seizure type, epilepsy syndrome, co-medication and any comorbidities. Monotherapy is generally preferred and is successful in controlling seizures in most children.
The start low, go slow approach to initiating treatment is important to reduce the incidence of adverse effects and ensure that the lowest effective dose is used. The older, more established drugs tend to be prescribed first-line because there is more evidence available on their use in children.
Special considerations for prescribing
Most AEDs used for children are licensed for some age groups but they are also widely used off-label for neonates, infants and younger children.
The variety of formulations available is an important consideration when deciding which drug to prescribe. The introduction of appropriate dosage forms for children is improving, with many of the widely prescribed AEDs now available in liquid, granule or powder forms. Not only can these make taking the medicine easier but they assist in the accurate administration of doses prescribed on a mg/kg basis.
Children, especially neonates and infants, gain weight rapidly and drug doses per kilogram body weight need to be reviewed (and their doses adjusted accordingly) at regular intervals. This is particularly important for drugs with a narrow therapeutic window.
For example, neonates prescribed phenytoin should have regular plasma level checks. This is because the metabolism of the drug in this age group increases over the first five to seven weeks of life along with changes in protein binding. Numerous dose increases are required to maintain plasma levels in the desired therapeutic range.
In addition, target serum levels of phenytoin are different in neonates and infants up to three months of age (6–15mg/L rather than 10–20mg/L in older
children and adults) due to their inherently low albumin levels and the poor binding capacity of albumin, which leads to greater amounts of free (active) phenytoin.
Frequency of dosing of AEDs in children may be different from that in adults due to pharmacokinetic differences. For example, extensively liver metabolised drugs, such as phenytoin and phenobarbital, may need to be administered more frequently in young children due to their efficient livers metabolising the drug at a faster rate than in adults.
Drugs with wide therapeutic windows do not need to have as accurate doses as those with narrow windows.When determining the doses for these drugs it is often more appropriate to ensure the dose is easily measurable for the parent or carer, to minimise dosing errors.
For example a 100mg/kg/day dose of vigabatrin for a 9.5kg child could safely be rounded to 500mg bd to enable a whole sachet to be administered at each dose.
Choosing suitable formulations for children isimportant with all conditions, but there aresome issues particularly relevant to AEDs.
Differences in bioavailability of different formulations are particularly important when drugs have narrow therapeutic windows.
The bioavailability and pharmacokinetics can vary when switching between brands of AEDs but also formulations. For example phenytoin is available as liquid, capsules, tablets and an intravenous solution.
The main differences are due to different salts. Chewable tablets and liquid are phenytoin where as capsules are phenytoin sodium. Although 90mg of phenytoin is considered to be approximately equivalent to 100mg of phenytoin sodium, care should be taken when switching between salts and serum levels should be checked where possible.
It is important to consider the excipients present in all drug formulations to be administered to children. One relatively common unsuitable drug formulation sometimes dispensed to infants and children is phenobarbital elixir BP 15mg/5ml.
The British Pharmacopeia endorsement can often mislead pharmacists into believing they are supplying the best formulation but this elixir contains 38 per cent alcohol — giving a 10kg one-year old 60mg per day can be approximately equated to giving the child a measure of vodka each day.
Numerous specials manufacturers now produce an alcohol and sugar free formulation which, although unlicensed, is far more suitable and should be sourced for infants and young children.
Strengths of formulations
Liquid products — particularly manufactured specials and extemporaneously prepared liquids — are often available in a number of strengths. This can cause dosing errors if labels are not explicit regarding the number of millilitres required per dose and if parents or carers are not properly educated on the dangers.
Because AEDs are often initiated at small doses and titrated until the desired effect is seen it is important to confirm parents’, carers’ and, where possible, patients’ understanding, especially if different strength preparations are to be used to make up the dose. This is often the case with topiramate and levetiracetam, where different strength tablets are supplied to increase dose regimens.
Palatability is an important factor incompliance with long-term medication. Knowledge of flavours of AEDs can often be helpful when patients have a preference for certain flavours. Many parents disguise medicines in milk or soft food. This can cause problems if the child develops food aversions where they associate the unpalatable medicine taste with that particular food. Moreover, if the food, milk or drink the medicine is disguised in is not finished, the full dose may not have been ingested.
It should be suggested that the smallest amount of food or drink is used to prevent these problems. If a child vomits or spits out a dose it is difficult to know how much of the intended dose will be absorbed. A pragmatic approach needs to be taken and it is suggested that if a child vomits within 30 minutes of a dose, or seems to have spat out a significant amount of the original dose then the whole dose can be repeated.
For once daily doses, the missed dose should be given as soon as remembered within same the day but double doses should not be administered the following day if not remembered until then.
Non-compliance with AED therapy can increase the chance of seizure recurrence. Factors thought to be related to poor compliance with AED regimens include:
- Teenage age;
- Four times per day dosing regimens;
- Feeling stigmatised;
- Experience of adverse effects.
Teenagers with epilepsy can feel isolated and stigmatised, and can feel that their ability to join in with their peers is threatened. These feelings can affect compliance and they may stop taking their AEDs as a result.
Research in Finland with 13- to 17-year-olds revealed that only 22 per cent fully complied with their treatment regimens. Less than half — 44 percent — reported satisfactory compliance and 34 per cent reported poor compliance.
Involving teenage patients in the decision to start treatment and discussing drug options can help them to take responsibility for their condition and fully comply with their treatment.
The Panel (below) lists ways in which pharmacists can play a key role in improving compliance. All these strategies should be considered as soon as a diagnosis has been made and AEDs are initiated.
Encouraging children and their parents or carers to be involved in administering medicines as early on as in hospital is thought to prepare them for discharge and coping at home where healthcare professionals and advice may not be as easy to seek.
Transition from paediatric to adult care should be well planned and adolescents should be fully involved in all decision-making with the relevant healthcare professionals.
Panel: Improving compliance
Pharmacists can play a key role in improving compliance by:
- Emphasising the importance at initiation stage;
- Enquiring into missed doses at subsequent dispensing
- Advising on keeping regimens as simple as possible, particularly with regard to measuring doses and administration times;
- Advising on suitable formulations that are age appropriate and fit into the patient’s lifestyle;
- Providing information on potential adverse effects and how to manage them.
Pharmacists’ awareness of the use of ketogenic diets to treat refractory epilepsy is important because many medicines contain carbohydrates.
Patients on a ketogenic diet should avoid products containing lactose and sorbitol as well as sucrose, glucose and fructose. Pharmacists are ideally placed to make recommendations on ketogenic-friendly formulations, both for long-term and any one-off medicines.
If a medicine contains less than 1g of carbohydrate per dose, it is considered to be ketogenic diet-friendly and is not taken into account when calculating the diet. Most liquid preparations (eg, antibiotic elixirs) contain sugar or sugar substitutes. Tablets can be a good substitute because the lactose content is usually not significant enough to affect the diet or seizure control. However, crushing a tablet to aid administration can destroy its pharmacokinetic properties so tablets are not always the most appropriate alternative.
It is considered good practice to avoid sugar-containing medicines in long-term conditions to avoid dental caries but if unavoidable pharmacists should work closely with dietitians to reach a compromise. Dietitians can adjust the ratios of the diet to allow for small amounts of carbohydrate in regular medicines if no suitable low carbohydrate formulation can be found.
A frequent query from parents of children on a ketogenic diet involves the use of one-off or short-course medicines. Although parents are usually aware of the need to make the pharmacist aware of the diet when requesting medicines over the counter, this is often an area worth investigating if antiepileptics come up when asking about other medication.
Care must also be taken when children on a ketogenic diet undergo surgical procedures and are nil by mouth. For example, it is essential that intravenous fluids containing glucose are avoided. It is also important to monitor serum pH and bicarbonate levels due to the risk of metabolic acidosis. For patients who are gastrostomy fed ketogenic-friendly feeds are available that have been shown to be safe and effective.