Monotherapy with conventional and controlled‐release carbamazepine: a double‐blind, double‐dummy comparison in epileptic patients.

Abstract

1 Twenty-one epileptic patients completed a double-blind, double-dummy, random order, crossover comparison of conventional carbamazepine (CBZ, Tegretol, CibaGeigy) with a new controlled-release formulation (CBZ-CR, Tegretol Retard). All participants were stabilised on maximally tolerated doses of CBZ as monotherapy (one twice daily, twelve three times daily, eight four times daily). Each preparation was taken with a matched placebo of the other for 4 weeks. 2 Peak serum CBZ concentrations (mean ± s.e. mean) were lower (CBZ 11.4 ± 0.4 mg 1-1; CBZ-CR 10.4 ± 0.5 mg 1-1; P < 0.01) and times to peak longer (CBZ 3.6 ± 0.5 h, CBZ-CR 5.2 ± 0.7 h, P < 0.01) during CBZ-CR treatment. Mean CBZ concentrations, however, were also slightly reduced with the new formulation (CBZ 9.9 ± 0.3 mg I-1; CBZ-CR 9.1 ± 0.5 mg 1-1, P < 0.05) and this was associated with greater seizure frequency (CBZ 2.8 ± 1.2, CBZ-CR 3.8 ± 0.9; P < 0.05) during the CBZ-CR treatment phase.3 Diurnal fluctuations (CBZ 41 ± 3%, CBZ-CR 28 ± 2%, P < 0.01) and variations (CBZ 53 ± 5%, CBZ-CR 33 ± 3%; P < 0.01) in serum CBZ concentration were substantially less with CBZ-CR and were similar to those calculated during a 6 or 8 hourly dosage interval with conventional CBZ (fluctuation 33 ± 3%, variation 42 + 5%). 4 Trough serum concentrations of the active metabolite CBZ 10,11 epoxide (CBZ-E)were lower on CBZ-CR (P < 0.05) than with conventional CBZ but no differences in peak or mean CBZ-E concentrations nor times to peak were found. Similar variations and fluctuations in CBZ-E concentrations were obtained with both formulations.5 Reaction times were longer (P < 0.05) and subjective side-effect scores higher (P < 0.05) shortly after dosing with conventional CBZ. 6 Blind patient preference significantly favoured CBZ-CR (fifteen CBZ-CR, two CBZ, four neither; P < 0.01). 7 CBZ-CR is a pharmacokinetically attractive method of administering CBZ and produces fewer subjective side-effects. However, the new formulation resulted in lower mean CBZ concentrations when given in the same total daily dose as the conventional preparation and may be less effective unless the dose is modified.

What do the suffixes - XR, ER, Chrono, Chronosphere - really mean as it pertains to modified-release antiepileptic drugs?

“…A MR dosage formulation is one that has been pharmaceutically engineered to be delayedrelease (a tablet coating that prevents drug release initially, then some time later releasing all drug immediately), or extended-release (ER), or manufactured to exhibit some combination of active drug ingredient release rates over time in the gastrointestinal tract. Each MR AED [CBZ (18)(19)(20)(21)(22)(23)(24)(25); PHT (26); divalproex ⁄ VPA (27)(28)(29)(30)(31)(32)(33)(34)(35)(36); LTG (15,(37)(38)(39)(40); LEV (41,42)] is formulated with the intent of achieving improved seizure control in patients with epilepsy (1,(43)(44)(45)(46)(47)(48)(49), via minimization of peak-trough plasma AED concentration fluctuation, thus reducing peak AED-concentration-related adverse events, increasing convenience for the patient by permitting a reduction in the dosing frequency or interval and hopefully augmenting adherence.…”

Pharmacokinetic Evaluation of Sustained Release Formulations of Antiepileptic Drugs

“…Another recent study also described the lower diurnal fluctuation obtained with Tegretol Retard' in 21 patients with epilepsy This study concludes that 'Tegretol Retard' is a pharmacokinetically attractive method of administering carbamazepine and produces fewer sUbjective side effects. However, 'Tegretol Retard' resulted in lower mean carbamazepine concentrations when given in the same total daily dose as the conventional preparation ('Tegretol') and may be less effective unless the dose is modified (McKee et al 1990(McKee et al , 1991. During a 3-month double-blind crossover study (Persson et al 1990), a slow release formulation of carbamazepine ('Neurotol Slow') was found to produce fewer side effects than a conventional preparation ('Neurotol'), while an earlier study showed that there appeared to be a correlation between the frequency of side effects associated with carbamazepine treatment and the daily variations in peak serum concentrations (Tomson 1984).…”

Double dummy comparison between once and twice daily dosing with modified‐release carbamazepine in epileptic patients.

“…This reduced the fluctuation in concentration during a dosage interval by around 50% in healthy volunteers [3]. In epileptic patients, less diurnal fluctuation in serum drug concentrations and minor improvements in psychomotor function were found with twice daily CBZ-MR compared with three and four daily dosing with conventional CBZ [4].…”

“…The patient may realise these kinetic benefits in fewer side-effects, improved compliance and better seizure control [2,22]. Open [18,23,24], singleblind [19,25] and double-blind studies in healthy volunteers and in epileptic patients [3,4,17,20,21,26] have shown that twice daily administration of CBZ-MR has a pharmacokinetic profile and efficacy similar to three and four times daily dosing with conventional CBZ. Formal psychomotor testing using adequate placebo controls also favoured CBZ-MR [4,25].…”