Carbamazepine in Difficult to Control Epileptic Out-Patients

Kutt, Henn; Solomon, Gail E.; Wasterlain, Claude G.; Peterson, Hart de C.; Louis, Sydney; Carruthers, R. I.

doi:10.1111/j.1600-0404.1975.tb01384.x

Cited by 22 publications

(6 citation statements)

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“…Thus, Kutt et al (1975) observed blurred vision, nystagmus and disturbances in coordination when blood concentrations approached values greater than 17 ~mol/L in patients given also phenytoin, phenobarbitone or primidone in high, near toxic, doses. Tomson (1984) noted dizziness in a patient on antiepileptic poly therapy as plasma concentrations exceeded 1 7 ~mol/L.…”

Section: Total Plasma Concentration and Clinical Effectsmentioning

confidence: 92%

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Bertilsson

Tomson

1986

Clinical Pharmacokinetics

261

120

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Carbamazepine is a first-line drug in the treatment of most forms of epilepsy and also the drug of first choice in trigeminal neuralgia. Furthermore, it is now frequently used in bipolar depression. Most oral formulations of carbamazepine are well absorbed with high bioavailability. The drug is 75% bound to plasma proteins. The degree of protein binding shows little variation between different subjects, and there is no need to monitor free rather than total plasma concentrations. Carbamazepine is metabolised in the liver by oxidation before excretion in the urine. A major metabolite is carbamazepine-10,11-epoxide which is further metabolised by hydration before excretion. This epoxide-diol pathway is induced during long term treatment with carbamazepine. Co-medication with phenytoin or phenobarbitone further induces this metabolic pathway. Some but not all studies indicate an increased metabolism of carbamazepine during pregnancy. The drug crosses the placenta, and the newborns who are exposed to the drug during fetal life eliminate the drug readily after birth. There seems to be no problem to nurse children during treatment with carbamazepine. Metabolism of carbamazepine is comparable in children and adults. Several studies have tried to establish a relationship between plasma carbamazepine and clinical effect in epilepsy, but very few of these are controlled. The best anticonvulsant effect seems to be obtained at plasma concentrations of 15 to 40 mumol/L and a similar optimal plasma concentration range was found in a controlled study in trigeminal neuralgia. Side effects are more frequent at higher plasma concentrations but are also seen within that range. In some patients, with pronounced fluctuation of plasma concentrations during the dosage interval, side effects may be avoided by more frequent dosing. Carbamazepine-10,11-epoxide is a potent anticonvulsant in animal models. During treatment with carbamazepine the plasma concentrations of this metabolite are usually 10 to 50% of those of the parent drug. It has not been possible to establish the relative contribution of the two compounds to the pharmacological effects. The epoxide has therefore been given to humans with the aim of determining the relative potency of the parent drug and its metabolite. After single oral doses of carbamazepine-10,11-epoxide to healthy subjects, the compound was rapidly absorbed. As a mean of 90% of the given dose was recovered in urine as trans-10,11-dihydroxy-10,11-dihydro-carbamazepine, a complete absorption of unchanged epoxide was shown.(ABSTRACT TRUNCATED AT 400 WORDS)

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Section: Total Plasma Concentration and Clinical Effectsmentioning

confidence: 92%

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Bertilsson

Tomson

1986

Clinical Pharmacokinetics

261

120

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“…Schmidt (1982), in a more recent study, showed that a reduction of >75% in seizure frequency occurred in only 4 patients (13%) when a second drug was added to therapy in patients who failed to respond to optimal treatment with monotherapy, and in this study no patient became seizure free. A better outcome was obtained by Kutt et al (1977), who stated that when carbamazepine was added to 20 patients with intractable epilepsy, 12 (60%) had a >50% reduction in seizure frequency. Shorvon and Reynolds (1977) carried out a retrospective study in 50 patients with chronic epilepsy on two antiepileptic drugs and found that a reduction of 50% or more in seizure frequency occurred in 36% of their patients.…”

Section: Additive Treatmentmentioning

confidence: 99%

Adjunctive Therapy in Resistant Epilepsy

Callaghan

Goggin

1988

Epilepsia

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It is now established that the overall prognosis for epilepsy is good and that remission will occur in at least 75% of patients following adequate treatment with monotherapy. Patients who fail to respond to monotherapy, who are not suitable for surgery, and who continue to have frequent seizures may have to be considered for an alternative drug regimen. A review of the literature indicates that complete seizure control with adjunctive treatment is rare, but improved seizure control can be obtained in up to 40% of patients. In a study of clobazam as adjunctive treatment, 60% (N = 20) of our patients responded to treatment initially and 33% maintained an improvement over an 18-month period. In 31 patients who failed to respond to carbamazepine as monotherapy, primidone (N = 16) or valproate (N = 15) were prescribed as adjunctive treatment. One patient obtained complete freedom from seizures and 14 (45%) had a greater than 50% reduction in seizure frequency. Suggested indications for the use of additive treatment in epilepsy are discussed.

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“…The incidence of AE during the rapid switchover was not higher than that expected in patients started on CBZ with slow-dose increments (16)(17)(18)(19)(20), despite the fact that they reached a mean CBZ C,, of >9 mg/l, which often has been associated with AE occurrence (16,21). In addition, discontinuation of CBZ because of AE was no different among our patients (7%) than in a CBZ monotherapy trial of newly diagnosed patients (11%) who were started slowly on this drug with target serum concentrations in the midtherapeutic range (22).…”

Section: Discussionmentioning

confidence: 77%

Rapid Switchover to Carbamazepine Using Pharmacokinetic Parameters

et al. 1998

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Summary:Purpose: The standard practice of switching patients to carbamazepine (CBZ) involves initiating a low dose and raising it by small increments until the desired dose is reached, to avoid intolerable adverse effects (AE). In a pilot study, a protocol using single-dose kinetic studies was developed to switch patients to CBZ through rapid-dose increments and to manage concurrent rapid taper of the previous antiepileptic drugs (AEDs) without causing AE. The purpose of this prospective study was (a) to reassess whether a rapid switchover to CBZ could be done with minimal or no AE and without causing an increase in seizures; (b) to determine whether the maintenance dose of CBZ predicted at the time of the singledose kinetic study can yield the desired concentration at steady state (C,,); and (c) to determine the degree to which the calculated maintenance dose of CBZ will need to be adjusted after the previous AED has been discontinued for a four-week period.Methods: Twenty-five patients taking phenytoin (PHT) and/ or phenobarbital (PB) andor primidone (PRM) underwent a rapid switchover to CBZ following a 10 mg/kg single-dose kinetic study (day 1) which allowed calculation of a maintenance dose necessary to yield a mean C,, of 10.2 (&2.2) mgA. On day 2, patients received a CBZ dose equivalent to 10 mgkg + 200 mg; thereafter, they underwent daily dose increments of 200 mg until the calculated maintenance dose was reached. Dose increments were modified in the case of AE. Concurrent tapering of the previous AED was started as of day 1: PHT by 100 mg/day, while PB and PRM were stopped on day 1; PB was restarted before patients were to be discharged from the hospital if a PB serum concentration above 10 mgA was identified at that time. Pharmacokinetic data and occurrence of AE were compared between the two groups at the time of the single-dose kinetic study, at the completion of the switchover to CBZ, and 4 weeks after discontinuation of the previous AED.Results: All patients completed the switchover to CBZ within a mean time period of 6 days (22), reaching a mean maintenance dose of 1,639 mg/day (rt370) which yielded a mean C,, of 11.3 (k3.2) mg/l. The maintenance dose had to be lowered by 20.4% (28.3) in 59% of patients within the four-week period following discontinuation of at least one of the previous AEDs. None of the patients experienced an increase in seizure frequency relative to baseline. Fifteen (60%) patients had no AE; five (20%) experienced AE of mild severity. AE rated as moderately severe (n = 4) or severe (n = 1) occurred in patients with a static encephalopathy (p = 0.02, Fisher's exact test) and among patients 2-55 years (p = 0.017, Fisher's exact test).Conclusions: A rapid switch-over to CBZ from PHT, PB, or PRM can be carried out safely with no, or minimal, AE in young adults, unless they suffer from static encephalopathy.

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Carbamazepine in Difficult to Control Epileptic Out-Patients

Cited by 22 publications

References 1 publication

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Clinical Pharmacokinetics and Pharmacological Effects of Carbamazepine and Carbamazepine-10,11-Epoxide

Adjunctive Therapy in Resistant Epilepsy

Rapid Switchover to Carbamazepine Using Pharmacokinetic Parameters

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