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The availability of generic products of antiepileptic drugs (AEDs) has been increasing in recent years. In view of the importance of the issue, the Italian League against Epilepsy (LICE) set up an ad hoc working group whose task was to assess available evidence on the efficacy and safety of generic AEDs in the treatment of epilepsy and to produce recommendations on their use. A careful review of the literature revealed no adequately powered randomized controlled trials that assessed the risk/benefit ratio of generic substitution. Although there have been reports of loss or worsened seizure control, or appearance of adverse events, following the switch from brand products to generics, a critical assessment of the evidence generally does not allow us to establish a cause-effect relationship between the switch and a change in clinical status. Overall, the working group concluded that generic AEDs meeting current regulatory criteria for bioequivalence represent a valuable choice in the management of epilepsy by allowing a substantial reduction of treatment costs, particularly in patients initiating monotherapy or adjunctive treatment and in those with persistent seizures. The working group considered that in patients who achieved seizure freedom a modest change in plasma drug levels, which may occasionally occur even after substitution of products that meet bioequivalence criteria, could in rare cases lead to seizure breakthrough. Therefore, generic substitution is not recommended in patients who achieved seizure remission. Switches between a particular generic and another generic should also be preferably avoided. Finally, sustained-release AED formulations should not be used interchangeably with immediate-release brand or generic products. Patients need to be informed about the stringent criteria that currently govern the approval of generic products and about the implications of the use of generic AEDs, and their opinion should be taken into consideration at the time of prescribing.

Summary: Free and total carnitine and acylcarnitine in plasma and urine samples was measured in 22 epileptic patients before and after 15 and 45 days of valproate (VPA) therapy and in 16 healthy volunteers on a single occasion. Carnitine plasma concentration and renal excretion observed in epileptic patients before VPA therapy did not differ from control values. After VPA was started, free and total plasma concentration decreased significantly (p < 0.05) from 49 ± 17 to 35 ± 16 at 15 days and to 35 ± 13 nmol/ml at 45 days of therapy (free carnitine) and from 60 ± 18 to 50 ± 18 at 15 days and to 55 ± 14 nmol/ml at 45 days of therapy (total carnitine), whereas acylcarnitine increased significantly (p < 0.05) from 10 ± 8 to 14 ± 8 at 15 days and to 18 ± 16 nmol/ml at 45 days of therapy. Free carnitine urinary excretion decreased significantly (p < 0.05) from 200 ± 135 to 115 ± 76 and 118 ± 75 μmol/24 h, whereas acylcarnitine urinary excretion increased significantly (p < 0.05) from 78 ± 56 to 154 ± 98 and 155 ± 89 μmol/24 h after VPA therapy was started. As a consequence, acylcarnitine renal clearance increased significantly (+ 30%, p < 0.05) whereas free carnitine renal clearance did not change during VPA therapy. No difference was detected between 15 and 45 days of therapy. No patients experienced symptoms of VPA toxicity. Our results suggest that VPA in patients increases both formation and renal clearance of acylcarnitine. ReSUMe Les taux plasmatiques et urinaires de carnitine libre, totale et d'acylcarnitine ont ete mesures chey 22 patients epileptiques avant et 15 et 45 jours apres traitement par valproate (VPA), ainsi qu'une seule fois chez 16 volontaires sains. La concentration plasmatique de carnitine et l'excretion renale observees chez les patients epleptiques avant traitement par VPA ne differaient pas des valeurs controles. Apres mise en route d'un traitement par VPA, la concentration libre et totale a diminue significativement (p < 0.05) de 49 ± 17 B 35 ± 16 a 15 jours et B 35 ± 13 nmol/ml a 45 jours de traitement (pour la carnitine libre) et de 60 ± 18 B 50 ± 18 B 15 jours et B 55 ± 14 nmol/ml B 45 jours de traitement (carnitine totale), alors que l'acylcarnitine augmentait significativement (p < 0.05) de 10 ± 8 B 14 ± 8 15 jours et 18 ± 16 nmol/ml B 45 jours de traitement. L'excrCtion urinaire de carnitine libre a diminut significativement (p < 0.05) de 200 ± 135 a 115 ± 76 et 118 ± 75 pmo1124H00, alors que l'excrCtion urinaire d'acylcarnitine augmentait significativement (p < 0.05) de 78 ± 56 B 154 ± 98 et 155 ± 89 p, mo1/24H00 apres mise en route du traitement par VPA. La clearance rCnale de l'acylcarnitine a donc augmente significativement (+30% p < 0.05), alors que la clearance rtnale de la carnitine libre n'a pas ete modifiee sous traitement par VPA. Il n'y a pas eu de differences entre le 15 eme et le 45 meme jour de traitement. Aucun patient n'a presente de symptbmes de toxicit/ au VPA. Ces resultats suggerent que le VPA augmente la formation et la clearance rCnale d'acylcarnitine chez les patients epileptiques. RESUMEN Se han determinado los niveles plasmaticos y de orina de acilcarnitina libre y total en 22 pacientes antes de 15 y 45 dias de tratamiento con valproato (VPA) y en 16 voluntarios normales en una sola ocasion. Las concentraciones plasmeticas de carnitina y la excreccion renal observadas en los enfermos epilepticos antes de la terapia con VPA no se diferenciaron de los valores control. Despues de iniciar el VPA las concentraciones libre y total plasmaticas se redujeron significativamente (p < 0.05) de 49 ± 17 a 35 ± 16 a los 15 dias y de 35 ± 13 nmol/ml a los 45 dias de tratamiento (carnitina libre), de 60 ± 18 a 50 ± 18 a los 15 dias y a 55 ± 14 nmol/ml a los 45 dias de tratamiento (carnitina total) mientras que la acilcarnitina se incremento significativamente (p < 0.05) de 10 ± 8 a1 14 ± 8 y a los 15 y a 18 ± 16 nmol/ml a los 45 dias del tratamiento. La excreccion urinaria de carnitina libre se redujo significativamente (p < 0.05) de 200 ± 135 a 115 ± 76 y 118 ± 75 μmo1/24 h mientras que la excreccion urinaria de acilcarnitina se incremento significativamente (p < 0.05) de 78 ± 56 a 154 ± 98 y de 155 ± 89 μmo1/24 h despues de iniciar la terapia con VPA. Como consecuencia el aclaramiento renal de acilcarnitina se incremento significativamente (+30%; p < 0.05) mientras que el aclaramiento renal de carnitina libre no cambio durante el tratamiento con VPA. No se observaron diferencias entre 15 y 45 dias de tratamiento. Ningun paciente experimento sintomas de toxicidad a1 VPA. Los resultados sugieren que el VPA en pacientes incrementa tanto la formacion como el aclaramiento renal de acilcarnitina. ZUSAMMENFASSUNG Bei 22 epileptischen Patienten wurden das freie, das gesamte und das Acylcarnitin in Plasma und Urin vor und nach 15 und 45 Tagen unter Valproat-Therapie gemessen, sowie bei 16 gesunden Freiwilligen in einer einmaligen Probe. Die Carnitin Plasmakonzentration und renale Ausscheidung bei epileptischen Patienten vor der Valproat-Therapie unterschieden sich nicht von den Kontrollwerten. Unter Valproat sank die gesamte und freie Plasmakonzentration signifikant (p < 0.05) von 49 ± 17 auf 35 ± 16 (Tag 15) und auf 35 ± 13 nmol/ml (Tag 45) ab (freies Carnitin) und von 60 ± 18 auf 50 ± 18 (Tag 15), bzw. auf 55 ± 14 nmol/ml (Tag 45) (Gesamtcarnitin), wahrend Acylcarnitin signifikant (p < 0.05) von 10 ± 8 auf 14 ± 8 (Tag 15) bzw. 18 ± 16 nmol/ml (Tag 45) anstieg. Die freie Carnitinurinaus scheidung fie1 signifikant (p < 0.05) von 200 ± 135 auf 115 ± 76, bzw 118 ± 75 pmo1/24 Std., wahrend die Acylcarnitinurinausscheidung signifikant (p < 0.05) von 78 ± 56 auf 154 ± 98 bzw. 155 ± 89 pmo1/24 Std. nach Beginn der Valproat-Therapie anstieg. Die renale Acylcarnitin Clearance stieg signifikant (+30%; p < 0.05) an, wahrend die renale freie Carnitin Clearance sich unter der Therapie nicht anderte. Zwischen Tag 15 und Tag 45 wurden keine Unterschiede gefunden. Kein Patient zeigte Symptome einer Valproat-Toxizitat. Diese Ergebnisse zeigen, daβ Valproat sowohl die Bil-dung als auch die renale Clearance von Acylcarnitin erhoht.

Felbamate (FBM) is a novel antiepileptic drug (AED) currently undergoing clinical evaluation in the United States. During a controlled clinical trial conducted at the National Institutes of Health Clinical Center, FBM was added to constant carbamazepine (CBZ) monotherapy. CBZ total concentrations were reduced during active FBM treatment (mean reduction 25%, range 10-42%, p less than 0.001). The effect was evident after the first week of treatment and reached a plateau in 2-4 weeks. To clarify the interaction mechanism, free and total concentrations of CBZ and its plasma metabolites were determined by high-performance liquid chromatography (HPLC) and ultrafiltration in four patients. In these patients, FBM treatment reduced CBZ concentrations and increased CBZ-epoxide (CBZ-E) concentrations (p less than 0.01). Free fractions of all compounds were unmodified. FBM appears to be capable of inducing CBZ metabolism. CBZ-FBM interaction may be clinically relevant.

We report a clinically relevant interaction between a new macrolide antibiotic, clarithromycin, and carbamazepine (CBZ). In a patient receiving CBZ monotherapy, 10-day antibiotic treatment increased CBZ concentration despite concomitant CBZ dose reduction and doubled the CBZ concentration/dose ratio. Concentration of the CBZ epoxide (CBZ-E) metabolite was reduced, suggesting that the interaction occurs at a metabolic level.

The relationship between diurnal fluctuations in free (unbound) and total plasma carbamazepine levels and the appearance of intermittent side effects was investigated in nine epileptic patients receiving chronic therapy with carbamazepine, alone or in combination with phenobarbital. On a three-times-daily or four-times-daily dosing schedule, both total and free carbamazepine levels fluctuated considerably (on an average, 41 and 45%, respectively, around the mean). Side effects (particularly diplopia and nystagmus) were observed in five patients and showed an intermittent pattern in four. Side effects were never found at total carbamazepine levels less than 34 mumol/L but invariably appeared at levels greater than 38 mumol/L. At levels between 34 and 38 mumol/L adverse effects were inconsistently observed. The correlation between plasma carbamazepine levels and manifestations of toxicity was slightly stronger when free rather than total levels were considered. Side effects were always apparent at free levels greater than 7.2 mumol/L. These data underline the limitations of relying on a single drug level determination during the monitoring of carbamazepine therapy and emphasize the necessity of carefully adjusting the dosing schedule, to minimize the appearance of intermittent adverse effects.

Summary: Total and free serum concentrations of carbamazepine (CBZ) and carbamazepine-10,11-epoxide (CBZ-E) at steady state were determined in 10 infants (ages 4–13 months), 10 preschool children (ages 3–5 years), and 11 school children (ages 7–11 years) receiving equivalent doses of CBZ alone. Free and total CBZ levels tended to increase with increasing age, while CBZ-E levels did not show any significant age dependency. As a result, CBZ-E/CBZ ratios were higher in infants and preschool children than in the older age group. The degree of plasma protein binding of CBZ and CBZ-E did not show any important differences among the various groups. These data provide evidence that, within a pediatric population, CBZ shows age-related dispositional changes which may be clinically important. RESUME Les concentrations totales et les concentrations libres seriques de la Carbamazepine (CBZ) du carbamazepine-10,11-epoxide (CBZ-E) a l'etat d'equilibre ont eteetudiees chez 10 nourrissons (de 4 a 13 mois), 10 enfants d'âge pre-scolaire (de 3 a 5 ans) et 11 enfants d'âge scolaire (de 7 a 11 ans), recevant des doses equivalentes de CBZ en monotherapie. Les taux libres et totaux de CBZ tendent a augmenter avec l'âge, alors que celui de CBZ-E n'est pas dependant de l'âge. Il en resulte que le rapport CBZ-E/CBZ est plus eleve chez les nourrissons et les enfants d'âge pre-scolaire que chez les enfants plus âges. Le degre de liaison proteique du CBZ et du CBZ-E ne differe pas d'une maniere importante suivant les groupes. Ces resultats montrent qu'a l'interieur d'une population pediatrique il existe des modifications du metabolisme du CBZ, en relation avec l'âge, qui peuvent avoir une importance clinique. RESUMEN En diez ninos lactantes (edades entre 4 y 13 meses), 10 preescolares (edades entre 3 y 5 anos) y en 11 escolares (edades entre 7 y 11 anos) que recibian dosis equivalentes de carbamazepina (CBZ) se han determinado las concentraciones sericas de CBZ total y libre y las de carbamazepina-diez, once-epoxido (CBZ-E) en estado constante. Los niveles de CBZ libre y total tendieron a incrementarse con el aumento de edad mientras que los niveles de CBZ-E no mostraron ninguna dependiencia con la edad, de tipo significativo. Como resultado, la relacion CBZ-E/CBZ fue mayor en los lactantes y en los preescolares que en los grupos de edad mas avanzada. El grado de acoplamiento a proteinas plasmaticas del CBZ y de la CBZ-E no mostro diferencias importantes entre los varios grupos. Esta informacion indica que, en una poblacion pediatrica, la CBZ muestra cambios en su disponibilidad que estan relacionados con la edad y este dato puede tener importancia clinica. ZUSAMMENFASSUNG Totale und freie Serumkonzentration von Carbamazepin sowie Carbamazepin 10, 11-Epoxyd (CBZ-E) wurden im steady state bei 10 Sauglingen (4–13 Monate alt), 10 Vorschulkindern (3–5 Jahre alt) und 11 Schulkindern (7–11 Jahre alt) untersucht, die aquivalente Dosen von Carbamazepin allein erhielten. Freie und totale Carbamazepin-Spiegel zeigen einen Trend zu hoheren Werten mit zunehmendem Alter, wahrend CBZ-E keine signifikante Altersabhangigkeit zeigte. CBZ-E/CBZ-Fraktionen waren bei Sauglingen und Vorschulkindern hoher als in der alteren Gruppe. Die Plasma-Eiweis-Bindung von Carbamazepin und CBZ-E zeigte keine wesentlichen Unterschiede in den verschiedenen Gruppen. Die Daten zeigen altersabhangige dispositionelle Anderungen von CBZ bei Kindern, was von klinischer Wichtigkeit sein kann.

We report a case of interaction between anticonvulsant and antineoplastic drugs in one male patient with seizures from brain tumour. The patient was treated with phenytoin (PHT), phenobarbital (PB), and an antineoplastic protocol based on a combination regimen with carmustine (BCNU), vinblastin (VLB), methotrexate (MTX), and radiotherapy. Plasma concentrations of PHT fell from 9.4 to 5.6 micrograms/ml 24 h after VLB administration, and remained low for at least 10 days. During this period, partial seizures occurred. Plasma concentrations of PB were unchanged during the period of observation. It is suggested that impaired absorption of PHT, caused by VLB or MTX or both, is responsible for this interaction.