Bio‐availability and Dissolution of Three Phenytoin Preparations for Children

Abstract

SUMMARY A study of bio‐availability of three drug companies' brands of phenytoin preparations (50mg capsule/tablets) was undertaken on 30 children with tonic‐clonic or complex partial seizures. Eight children were excluded because of non‐compliance and three because of abnormally high serum levels. Phenytoin capsules (Parke Davis) and tablets (Boots) produced significantly higher serum‐level profiles than phenytoin tablets (Evans). Seizure frequencies did not differ significantly with the three brands of phenytoin. Dissolution of the three preparations tested in vitro was different. As a result of this study the authors recommend that children remain on the same manufacturer's brand of phenytoin throughout their treatment. RÉSUMÉ Biodisponibilité et diffusion de trois préparations de phénytoine, chez l'enfant Une étude de la biodisponibilité de préparation de phénytoine (capsules et comprimés de 50mg), de trois sociétés pharmaceutiques, àété entreprise chez 30 enfants présentant des crises tonico‐cloniques ou partielles complexes. Huit enfants ont été exclus pour cause d'intolérance et trois en raison de taux sérique anormalement élevés. Les capsules de phenytoine de Park Davis et les comprimés de Boots procuraient des profiles de taux sériques significativement plus élevés que les comprimés de Evans. La fréquence des crises ne différaient pas significativement avec les trois formes de phénytoine. La diffusion des trois préparations explorées in vitro etait différente. En conclusion de notre étude, nous recommandons que les enfants soient traités par une phénytoine venant toujours de la même société pharmaceutique. ZUSAMMENFASSUNG Bioverfügbarkeit und Löslichkeit von drei Phenytoin Präparationen bei Kindern Bei 30 Kindern mit tonisch‐klonischen Anfällen oder komplexen Fokalanfällen wurde die Bioverfügbarkeit von Phenytoin Präparationen von drei pharmazeutischen Firmen (50mg Kapseln/Tabletten) untersucht. Acht Kinder wurden ausgeschlossen wegen unzuverlässiger Einnahme und drei wegen abnorm hoher Serumspiegel. Phenytoin Kapseln (Parke Davis) und Tabletten (Boots) erzeugten signifikant höhere Serumspiegel als Phenytoin Tabletten (Evans). Die Anfallhäufigkeit unterschied sich bei den drei Präparationen nicht signifikant. Die in vitro getestete Löslichkeit der drei Präparationen war unterschiedlich. Als Ergebnis unserer Untersuchungen empfehlen wir, daß die Behandlung der Kinder mit dem Phenytoin einer Firma durchgeführt werden sollte. RESUMEN Bioficacia y solubilidad de tres prerarados de fenitona en niños Se Ilevóà cabo un estudio sobre la bioeficacia de tres marcas diferentes de fenitoine (cápsulas/tabletas de 50 mg), en 30 niños con crisis tónico‐clónicas o parciales complejas. Ocho niños fueron excluídos por falta de complianca y tres por presentar unos niveles séricos anormalmente altos. Las cápsulas de fenitoina (Parke Davis) y las tabletas (Boots) dieron unos perfiles de niveles sericos significativamente más altos que las tabletas de fenitoina (Evans). La frecuencia de los ataques no difirió significativamen...

Seizure Outcomes Following the Use of Generic versus Brand-Name Antiepileptic Drugs

“…Two patients in each of the three generic groups had recurrent seizures, as compared to five patients in the Dilantin group, which was not statistically significant (p>0.05). Hodges et al enrolled newly diagnosed pediatric patients with epilepsy to a rotating schedule of three four-week blocks of Dilantin and two generic versions available in the United Kingdom (UK) 33. Forty-three seizures were recorded among children in the Dilantin group, 30 in one generic group, and 60 in the other (not statistically significant).…”

Brand-to-generic levetiracetam switch in patients with epilepsy in a routine clinical setting

“…The physicochemical characteristics of a particular drug and whether or not it has a narrow therapeutic index would be expected to impact on bioequivalence and indeed there have been numerous such studies involving the older first generation AEDsphenytoin, carbamazepine and valproic acid [27][28][29][30][31][32][33]. In these studies, brand and generic carbamazepine [30][31][32][33] and valproic acid [34] were determined to be bioequivalent whilst that of phenytoin, which has a narrow therapeutic index, was not [27][28][29]. For carbamazepine, there was no significant difference in seizure frequency, nor in cognitive profile [35], although Hartley et al observed more adverse events during the generic ingestion [33].…”

Recommendations of the Italian League Against Epilepsy Working Group on Generic Products of Antiepileptic Drugs

“…In contrast to the lack of controlled studies, there are several published reports of loss or worsening of seizure control (Koch and Allen, 1978;Pedersen and Dam, 1985;McDonald, 1987;Wyllie et al, 1987;Sachdeo and Belendiuk, 1987;Hartley et al, 1990;Welty et al, 1992;Jain, 1993;Meyer and Straughn, 1993;Guberman and Corman, 2000;Burkhardt et al, 2004;Wilner, 2004;Haskins et al, 2005) or appearance of adverse events (Finestone and Williams, 1985;Gilman et al, 1993;Brown et al, 1998;Guberman and Corman, 2000;Wilner, 2004;Haskins et al, 2005) following substitution of a brand AED with a generic. Many of these reports date back several years, when regulatory requirements for the approval of generics were not as stringent as those currently in force in major industrialized countries (Richens, 1997;American Medical Association, 2006) and therefore some products of inadequate quality found their way into the market (Bochner et al, 1972;Sansom et al, 1975;Manson et al, 1975;Stewart et al, 1975;Tammisto et al, 1976;Hodges et al,1986;Mikati et al, 1992;Soryal and Richens, 1992;Meyer et al, 1992;Rosenbaum et al, 1994). In 1988, the U.S. Food and Drug Administration (FDA) set up a special committee to investigate these issues.…”

“…Many of these reports date back several years, when regulatory requirements for the approval of generics were not as stringent as those currently in force in major industrialized countries (Richens, 1997;American Medical Association, 2006) and therefore some products of inadequate quality found their way into the market (Bochner et al, 1972;Sansom et al, 1975;Manson et al, 1975;Stewart et al, 1975;Tammisto et al, 1976;Hodges et al,1986;Mikati et al, 1992;Soryal and Richens, 1992;Meyer et al, 1992;Rosenbaum et al, 1994). In 1988, the U.S. Food and Drug Administration (FDA) set up a special committee to investigate these issues.…”