Abstract
What is already known about this subject
Recently the European Medicines Agency recommended further research in all newly marketed antiepileptic drugs (AEDs).
There is no information in the literature about how AEDs are used in children in primary care.
What this study adds
There is a rapid increase in newer AED prescribing to children and adolescents in UK primary care, while prescribing of conventional AEDs is in decline.
The uptake of lamotrigine, topiramate and levetiracetam is rapid, and their prescribing is favoured over the conventional AEDs, particularly in adolescents.
Following concerns about visual field defects with vigabatrin, long-term safety surveillance of all the newer AEDs is strongly recommended.
Aims
To investigate the prescribing epidemiology, in UK primary care, of newer antiepileptic drugs (AEDs) compared with conventional AEDs and to identify AEDs for further research in response to the European Medicines Agency report on epilepsy.
Methods
Subjects aged 0–18 years, from the UK General Practice Research Database, who were prescribed an AED between 1993 and 2005. Prescribing prevalence and incidence, stratified by age and AED, were calculated.
Results
A total of 7721 subjects were included and 70% were prescribed one drug. Overall prescribing prevalence for all AEDs had increased by 19%. The prevalence (95% confidence interval) of newer AED prescribing had increased fivefold from 0.67 (0.58, 0.76) to 3.20 (3.03, 3.37) per 1000 person-years. Conversely, the prevalence of conventional AEDs had declined by 17% from 6.63 (6.34, 6.92) per 1000 person-years to 5.51 (5.28, 5.73). Lamotrigine had 65% of newer AED prescriptions and was the most prescribed newer drug for both the 2–11 years and 12–18 years age groups with prevalences of 1.47 and 2.55 per 1000 person-years, respectively.
Conclusions
There is a rapid increase in newer AED prescribing to children and adolescents in UK primary care, while prescribing of conventional AEDs is declining. Since 1997, the prevalence of vigabatrin has fallen, coinciding with the UK safety warnings on visual field defects. The uptake of lamotrigine, topiramate and levetiracetam is rapid and as the safety of these drugs has not been established, they should be prioritized for further research. Following concerns with vigabatrin, long-term safety surveillance of all newer AEDs is strongly recommended.
Keywords: anticonvulsants/antiepileptic drugs, child/adolescent/infant, drug utilization, epilepsy, pharmacoepidemiology
Introduction
The US regulator (Food and Drug Administration) and the National Institutes of Health have been taking the lead in reforming the regulations and research structure to improve medicines for children in the last 10 years [1, 2]. Following in the footsteps of the US initiatives, the European Union has proposed the ‘Better Medicines for Children’ regulation and also devised a research strategy to improve paediatric medicines research in the hope of increasing the availability of licensed medicines for children [3, 4]. Recently the European Medicines Agency (EMEA) published reports assessing the paediatric medication needs in the therapeutic areas of cardiology, chemotherapy, epilepsy, immunology, pain and rheumatology [5]. The report on epilepsy recommended research on 21 drugs used for treating epilepsy [6]. Unfortunately, the list of antiepileptic drugs (AEDs) identified is not in any order of priority and the recommendations cover a vast area, implying that it is challenging for the scientific community in Europe to make decisions on the specific research that should be initiated. The European Commission has established a network of excellence [Task-force of European Drug Development for the Young (TEDDY)] to improve medicines research in children [7]. TEDDY has recognized the necessity for research prioritization. Against this background, pharmacoepidemiological studies are being conducted to ascertain the medicines of priority. In order to obtain a representative paediatric cohort, a large clinical database is required; the General Practice Research Database (GPRD) was selected by TEDDY as one of the main data sources for paediatric pharmacoepidemiological studies.
In the last 15 years the treatment of epilepsy has advanced with the development of newer AEDs. In March 2004, the UK National Institute for Clinical Excellence (NICE) published guidelines for the prescribing of the newer drugs for epilepsy in children. NICE defined the newer AEDs: vigabatrin (VGB), lamotrigine (LTG), gabapentin (GBP), topiramate (TPM), oxcarbazepine (OXC), levetiracetam (LVT) and tiagabine [8]. These newer drugs are recommended for the management of childhood epilepsy, within their licensed indications, if the child has not benefited from treatment with the conventional drugs such as phenytoin, carbamazepine or sodium valproate, or if the conventional drugs are unsuitable because of contraindications, interactions or poor tolerability.
The licensing for use of these drugs in the UK (Table 1) varies for different seizure types, age of patient and whether they are used as monotherapy or in combination with other AEDs. VGB (first marketed in 1989) is licensed only for monotherapy in the management of infantile spasms. LTG (1991), TPM (1995), LVT (2000) and OXC (2000) are licensed for use as monotherapy in partial seizures with or without secondary generalization. GBP (1993) and tiagabine (2002) are licensed only for use in combination with other agents. Two further drugs have recently been released onto the UK market, pregabalin (2004) and zonisamide (2005), but they are not licensed for use in children aged < 18 years.
Table 1.
Licensing of the newer antiepileptic drugs in children and adolescents in the UK, listed in order of date of marketing*
| Age in which use is licensed | |||
|---|---|---|---|
| Drug | Details of licensing | Monotherapy | Adjunctive treatment |
| Vigabatrin | Monotherapy in treatment of infantile spasms. Combination treatment for resistant partial epilepsy with or without secondary generalization | No age limit specified | No age limit specified |
| Lamotrigine | Indicated for simple partial seizures, complex partial seizures, primary and secondarily generalized tonic-clonic seizures. Seizures associated with Lennox–Gaustaut syndrome | >12 years | >2 years |
| Gabapentin | Indicated as adjunctive therapy for partial seizures with or without secondary generalization | Unlicensed | ≥6 years |
| Topiramate | Indicated for partial seizures with or without secondarily generalized seizures, primary generalized tonic-clonic seizures. Seizures associated with Lennox–Gaustaut syndrome | ≥6 years | >2 years |
| Oxcarbazepine | Monotherapy or adjunctive therapy for partial seizures with or without secondarily generalized tonic-clonic seizures | ≥6 years | ≥6 years |
| Levetiracetam | Monotherapy in newly diagnosed epilepsy. Indicated as adjunctive therapy in the treatment of partial-onset seizures with or without secondary generalization | ≥16 years | ≥4 years |
| Tiagabine | Indicated as adjunctive therapy for partial seizures with or without secondary generalization | Unlicensed | ≥12 years |
| Pregabalin | Indicated as adjunctive therapy for partial seizures with or without secondary generalization | Unlicensed | ≥18 years |
| Zonisamide | Indicated as adjunctive therapy for partial seizures with or without secondary generalization | Unlicensed | ≥18 years |
Information from the Summary of Product Characteristics for each drug [37]. Please refer to the British National Formulary and Summary of Product Characteristics for current information on these drugs.
To our knowledge, the use of newer AEDs in children has never been assessed in large pharmacoepidemiological studies. An epidemiological study in the Netherlands has shown that the uptake of lamotrigine was slow compared with the use of conventional drugs; unfortunately, the study did not report paediatric data [9].
The objectives of this study were (i) to investigate the prescribing patterns of the newer AEDs in children and adolescents, in UK primary care, and compare them with those of conventional AEDs, and (ii) to recommend the AEDs which should be prioritized for further research in response to the EMEA report on ‘paediatric medication needs in epilepsy’.
Methods
Data source
The GPRD is a longitudinal clinical database maintained by the UK Medicines and Healthcare products Regulatory Agency. In early 2006, the GPRD contained anonymized primary care records for 3 million patients, approximately 5% of the UK population, from almost 400 practices, providing a total of 35 million person-years [10]. The demographic distribution of the population covered is similar to that of the UK population. Participating general practitioners enter demographic details, clinical information and diagnoses, detailed prescription data, immunizations, hospital referrals and the results of clinical investigations and tests in a standardized manner into their clinical computing systems [11]. Validation studies show quality and completeness of the data are high [12]. Data quality is assessed both on a patient and on a practice level [13].
A paediatric cohort of the GPRD (online Full Feature version) was made available for the study and data were extracted in March 2006 using the online data extraction tools provided by the GPRD [10].
Ethical approval was granted from the GPRD Scientific and Ethical Advisory Group.
The study covered the period between 1 January 1993 and 31 December 2005. The study population comprised all children and adolescents with at least 12 months' research standard data (unless the subject was < 1 year old where the subject was included regardless of the amount of data available) who received at least one antiepileptic prescription in the study period. Subjects with a temporary registration status were excluded.
Age classification was modified from the International Conference of Harmonization as newborns and infants ( < 2 years), children (2–11 years) and adolescents (12–18 years) [14].
Prescribing epidemiology
All AED prescriptions issued during the study period while the subjects were < 19 years old were identified. AEDs were then grouped as newer and conventional. For this study VGB, LTG, TPM, GBP, OXC, LVT, tiagabine, pregabalin and zonisamide were classified as ‘newer AEDs’, although some of these have been licensed in the UK for over 10 years. ‘Conventional AEDs’ included phenytoin, phenobarbitone, sodium valproate and carbamazepine. Other ‘conventional AEDs’, such as ethosuximide, were prescribed too infrequently in primary care to warrant analysis. Subjects prescribed drugs from both AED groups were counted towards both of the groups.
The first 12 months' data for each subject were used as a screening period. Subjects who did not receive an AED during this screening period but did thereafter were classified as incident (new starters). Subjects < 1 year old were automatically classified as incident.
The age-specific and gender-specific annual incidence and prevalence of each AED prescribed were calculated. Incidence was defined as the number of subjects classified as incident divided by the person-years at risk in the GPRD paediatric population (age 0–18 years) in a particular year. Person-years was used as it is a preferred measure of population, in a given time period, than the number of patients and is widely used.
 |
Prevalence was defined as the number of subjects receiving a prescription for an AED divided by the person-years at risk in the GPRD paediatric population in a particular year.
 |
Because the GPRD does not directly link prescriptions to medical diagnoses, the clinical records of all subjects in the study cohort were screened in order to ascertain the percentage of subjects with diagnoses of epilepsy.
Statistical analyses were conducted using STATA/SE version 9.1 (Stata Corp., College Station, TX, USA).
Results
A total of 7721 subjects were prescribed at least one AED. Of these subjects, 70% were prescribed one drug (range 1–9). Table 2 shows the number of prescriptions and the characteristics of the subjects by conventional and newer AED groups. Only four and 19 prescriptions were issued for zonisamide and pregabalin, respectively, so these drugs were excluded from further analysis. Just over 41% of all prescriptions were for liquid or powder formulations. The clinical diagnoses of the study cohort were screened and 75% of subjects had a diagnosis of epilepsy associated with their AED prescriptions.
Table 2.
Study population characteristics by antiepileptic drug (AED) group
| Newer AEDs | Conventional AEDs | Any AED | |
|---|---|---|---|
| Prescriptions (%) | 79 192 (30.7) | 178 471 (69.3) | 257 663 (100.0) |
| Median number of prescriptions (IQR) | 20 (7–48) | 14 (5–33) | 17 (5–41) |
| Most commonly prescribed drug | Lamotrigine | Valproate | – |
| Prescriptions (%) | 51 204 (19.9) | 93 558 (36.3) | – |
| Subjects* (%) | 2 202 (28.5) | 7 112 (92.1) | 7 721 (100.0) |
| Male/female | 1 023/1179 | 3 971/3141 | 4 201/3520 |
| New starters† | 1 705 | 4 407 | 4 839 |
| Age groups: | – | – | – |
| < 2 years | 176 | 692 | 765 |
| 2–11 years | 717 | 2 076 | 2 163 |
| 12–18 years | 812 | 1 639 | 1 911 |
Subjects were counted more than once if prescribed AEDs from both groups.
Subjects could be new starter for new and old AED.
Figure 1 shows that the prevalence of newer AED prescribing, specifically LTG, TPM and LVT, has significantly (P < 0.001) risen fivefold from 0.67 [95% confidence interval (CI) 0.58, 0.76] to 3.20 (95% CI 3.03, 3.37) per 1000 person-years in 1993 and 2005, respectively. Conversely, the prevalence of the conventional AEDs has significantly (P < 0.001) decreased by 17% from 6.63 (95% CI 6.34, 6.92) per 1000 person-years in 1993 to 5.51 (95% CI 5.28, 5.73) in 2005. Prescribing prevalence for all AEDs has increased by 19% over the 13-year study period.
Figure 1.
Prevalence of antiepileptic drugs (AEDs) in children aged 0–18 years (with 95% CI). Conventional AEDs (
), new AEDs 
), all AEDs (
)
Figure 2 shows that the incidence of newer AEDs, particularly LTG, TPM and LVT, has increased significantly (P < 0.001) over the last 13 years from 0.12 (95% CI 0.08, 0.16) to 0.33 (95% CI 0.27, 0.38) per 1000 person-years between 1993 and 2005. The incidence of the conventional AEDs declined significantly (P < 0.001) from 0.88 (95% CI 0.78, 0.99) to 0.57 (95% CI 0.50, 0.64) per 1000 person-years in 1993 and 2005, respectively.
Figure 2.
Incidence of antiepileptic drugs (AEDs) in children aged 0–18 years (with 95% CI). All AEDs (), conventional AEDs (), new AEDs (
)
Figure 3 illustrates prescribing trends for LTG, TPM and LVT have linearly increased in prevalence over time. LTG was the most prescribed drug, with 65% of all newer AED prescriptions. VGB prescribing prevalence increased until 1997. The prevalence decreased rapidly for 4 years, and then levelled. GBP prevalence has been level for the last 10 years. OXC and tiagabine prevalence was very low, so their prescribing trends were difficult to establish.
Figure 3.
Prevalence of newer antiepileptic drugs in children aged 0–18 years. Levetiracetam (
), gabapentin (
), lamotrigine (), oxcarbazepine (
), tiagabine (
), topiramate (
), vigabatrin (
)
Figure 4 shows the prescribing patterns for children of different age bands in 2005. VGB was the most prevalent drug in the < 2 years age group (0.73 subjects per 1000 person-years), followed by TPM (0.31 subjects per 1000 person-years). GBP, OXC and tiagabine were not prescribed at all in the < 2 years age group. LTG was the most commonly prescribed drug for both the 2–11 years and 12–18 years age groups, with a prevalence of 1.47 and 2.55 per 1000 person-years, respectively. TPM prevalence was very similar for the 2–11 years and 12–18 years age groups, with a prevalence of 0.61 and 0.66 per 1000 person-years, respectively.
Figure 4.
Prevalence by age bands of newer antiepileptic drugs in 2005. < 2 years (
), 2–11 years (▪), 12–18 years (□)
Discussion
To our knowledge, this is the first large paediatric cohort study to compare newer and conventional AED prescribing in the UK.
Seventy percent of subjects were prescribed just one AED, which implies that these subjects were receiving monotherapy. This is consistent with the adult literature, which suggests that 60–70% of patients with epilepsy will have their condition controlled by one AED [15] and that about 70% of children will become seizure free with AED treatment [16]. It also implies that NICE guidance is being implemented, as it recommends that children should be treated with monotherapy wherever possible and if initial treatment with a single AED is unsuccessful, then the child should be treated with another single AED [8].
The GPRD does not directly link prescriptions to medical diagnoses and this is a recognized limitation of databases including the GPRD [11]. The clinical records of all subjects in the study cohort were screened and 75% of subjects had a diagnosis of epilepsy recorded within the time-frame studied. The remaining patients could have a diagnosis of epilepsy that was recorded outside the study period, or it could be unrecorded due to management in secondary care. However, other indications for AED use include stabilization of mood disorders, neuropathic pain and migraine.
The increase in prescribing incidence and prevalence of the newer AEDs was to be expected with the growing number of drugs on the market. However, the huge increase in LTG prescribing indicates that this newer drug is favoured over the more conventional AEDs; this is reflected in the decline in incidence and prevalence of the conventional AEDs. Fewer licensing restrictions for the newer AEDs, as more clinical data are obtained from randomized controlled trials, might result in a continued increase in prevalence. Conversely, as new safety data emerge, restrictions in prescribing may be implemented. The reduction in VGB prevalence from 1997 onwards corresponds to the Committee on Safety of Medicines (CSM) warning that VGB can cause visual field defects, which was first reported in 1997 [17]. In November 1999, prescribing restrictions stated VGB should be used only when all other therapies have failed and must be used only as monotherapy in infantile spasms [18].
The main advantage of the newer over the conventional AEDs is that they are considered to have more acceptable adverse-effect profiles [19–21]. Most of the newer AEDs have a lower potential for interacting with other drugs, whereas the conventional AEDs interact with numerous drugs through hepatic enzyme induction, e.g. phenobarbitone, phenytoin and carbamazepine, or hepatic enzyme inhibition, e.g. sodium valproate [22].
LTG is the most prevalent of the newer AEDs. Apart from VGB, it has been on the market the longest of the newer AEDs and from 1995 it was licensed for use as monotherapy in children >12 years old. LTG has a similar antiepileptic spectrum to sodium valproate and a broader spectrum of action than carbamazepine, but has a more favourable side-effect profile [19, 23].
Although LTG was initially reported not to affect the blood concentrations of oral contraceptives [24], a recent study of 20 healthy female volunteers demonstrated that LTG, at a dosage of 300 mg day−1, decreases by about 20% the AUC of levonorgestrel [25]. It should also be noted that the oral contraceptive can decrease LTG blood levels [26, 27]. Conventional AEDs, particularly carbamazepine and sodium valproate, are known to be teratogenic; LTG is believed to be a safer choice in females of child-bearing age, although data are still being collected [28]. Unlike LTG, for which the monotherapy licence is restricted to patients ≥12 years old, TPM is licensed for use as monotherapy in children >5 years old; the high prevalence of TPM in the age group 2–11 years reflects this licensing. The overall prevalence of TPM is steadily increasing and it is the second most popular newer AED. Both LTG and TPM are available in child-friendly formulations, such as dispersible tablets for LTG and sprinkle capsules for TPM, which render them particularly suitable for the paediatric population.
The uptake of LVT is also increasing, similar to LTG and TPM, and the prescribing in children aged 12–18 years was the third highest in 2005. It is only licensed as monotherapy in patients ≥16 years old with newly diagnosed epilepsy, but is licensed for adjunctive therapy in children who are ≥4 years old. It is also available as an oral solution, which facilitates its use in children.
VGB has the highest prevalence of all the newer AEDs in the under 2-year age group. This is because it is used for the treatment of children with infantile spasms, which usually start around 4–8 months of age [29].
The prescribing prevalence for GBP has been constant for the last 10 years, possibly because it is perceived as having limited efficacy in children and because there are several other options available for the treatment of partial seizures [30]. In addition, GBP is available only in a solid oral dosage form, limiting its use for younger children. It has not been used in children aged under 2 years in this cohort.
Priorities for future research
Hypersensitivity reactions to LTG, including Stevens–Johnston syndrome, toxic epidermal necrolysis, multiorgan failure, hepatic failure, renal failure and leucopenia, have been reported [31]. Skin rash is the major adverse drug reaction that leads to discontinuation of the drug and a risk factor for developing rash has been identified as age < 13 years [32]. In addition to LTG causing skin reactions, blood disorders have also been reported and the CSM has issued a warning for both of these adverse events [33, 34]. However, the full extent of all these safety issues is unknown, specifically in children. Due to the high volume of prescribing in children and these safety concerns, we propose LTG should be prioritized for research; furthermore, generic LTG has recently become available, which will imply a reduction in cost and therefore a continued rise in prescribing. The EMEA recommended further research and development in safety, monotherapy in 2–12-year-olds and availability of age-appropriate formulation for LTG [6].
TPM was the second most commonly prescribed newer AED in this population in the past 5 years and the data suggest an upward trend. The safety of TPM has not been assessed on a large scale in children. However, in adult studies TPM has been found to cause a loss in body weight [31]. It is unknown what long-term affects this could have, especially on growth in children. In addition to this, the CSM has issued a report stating that acute myopia and raised intraocular pressure may occur early in treatment [35]. We propose that TPM should be a priority for further research. The EMEA has recommended that further research for TPM should be targeted on children < 2 years old, long-term safety and age-appropriate formulation [6].
The next priority should be LVT, as it is rapidly overtaking other newer AEDs in popularity, and the rate of increase is parallel with the rates of LTG and TPM. In addition, the safety of LVT has not been assessed on a large scale in children. The EMEA has recommended further studies in pharmacokinetics, efficacy and safety in children < 16 years [6].
We recognize that visual field defects in children using VGB are a major safety concern; this issue is currently under active surveillance and, because of this, it is no longer a priority for new studies. There has been a recent single case report in an adult, stating that GBP may cause reversible visual field constriction [36]. Although single case reports need to be interpreted with caution, this underlines the importance of long-term safety surveillance of all the newer AEDs.
Conclusions
There is a rapid increase in newer AED prescribing to children and adolescents in UK primary care, while prescribing of conventional AEDs is in decline. Seventy percent of children and adolescents are being treated with monotherapy. Since 1997, the prevalence of VGB has been falling, coinciding with the UK safety warning on visual field defects. The uptake of LTG, TPM and LVT is rapid and, as the safety of these drugs has not been established, these newer AEDs should be prioritized for further research. Following concerns about visual field defects with VGB, long-term safety surveillance of all the newer AEDs is strongly recommended.
Acknowledgments
The authors thank the general practitioners who contributed data to the GPRD.
Conflict of interest
I.C.K.W.'s post is funded by a Department of Health Public Health Career Scientist Award to investigate safety of psychotropic medications in children. The views expressed are those of the authors and are not of the Department of Health. I.C.K.W. received funding from various pharmaceutical companies, including GlaxoSmithKline, Janssen-Cilag and Pfizer (manufacturers of lamotrigine, topiramate and gabapentin). F.M.C.B. has been sponsored to attend conferences and has received research and equipment grants from various pharmaceutical companies. He is the former editor-in-chief of a journal sponsored by GlaxoSmithKline. This study has received research funding from the Network of Excellence TEDDY (Task-Force in Europe for the Drug Development in the Young) supported by the European Community-Sixth Framework Programme (Contract no. 0005216 LSHB-CT-2005–005126). R.A. and M.L.M. have no competing interests.
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