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Banzel

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Banzel

CLINICAL PHARMACOLOGY

Mechanism of Action

The precise mechanism(s) by which rufinamide exerts its antiepileptic effect is unknown. The results of in vitro studies suggest that the principal mechanism of action of rufinamide is modulation of the activity of sodium channels and, in particular, prolongation of the inactive state of the channel. Rufinamide ( ≥ 1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged prepulse in cultured cortical neurons, and limited sustained repetitive firing of sodium-dependent action potentials (EC50 of 3.8 μM).

Pharmacokinetics

Overview

BANZEL (rufinamide tablets) oral suspension is bioequivalent on a mg per mg basis to BANZEL (rufinamide tablets) tablets. BANZEL (rufinamide tablets) is well absorbed after oral administration. However, the rate of absorption is relatively slow and the extent of absorption is decreased as dose is increased. The pharmacokinetics does not change with multiple dosing. Most elimination of rufinamide is via metabolism, with the primary metabolite resulting from enzymatic hydrolysis of the carboxamide moiety to form the carboxylic acid. This metabolic route is not cytochrome P450 dependent. There are no known active metabolites. Plasma half-life of rufinamide is approximately 6-10 hours.

Absorption and Distribution

Following oral administration of BANZEL (rufinamide tablets) , peak plasma concentrations occur between 4 and 6 hours (Tmax) both under fed and fasted conditions. BANZEL (rufinamide tablets) tablets display decreasing bioavailability with increasing dose after single and multiple dose administration. Based on urinary excretion, the extent of absorption was at least 85% following oral administration of a single dose of 600 mg rufinamide tablet under fed conditions.

Multiple dose pharmacokinetics can be predicted from single dose data for both rufinamide and its metabolite. Given the dosing frequency of every 12 hours and the half-life of 6 to 10 hours, the observed steady-state peak concentration of about two to three times the peak concentration after a single dose is expected.

Food increased the extent of absorption of rufinamide in healthy volunteers by 34% and increased peak exposure by 56% after a single dose of 400 mg tablet, although the Tmax was not elevated. Clinical trials were performed under fed conditions and dosing is recommended with food [see DOSAGE AND ADMINISTRATION].

Only a small fraction of rufinamide (34%) is bound to human serum proteins, predominantly to albumin (27%), giving little risk of displacement drug-drug interactions. Rufinamide was evenly distributed between erythrocytes and plasma. The apparent volume of distribution is dependent upon dose and varies with body surface area. The apparent volume of distribution was about 50 L at 3200 mg/day.

Metabolism

Rufinamide is extensively metabolized but has no active metabolites. Following a radiolabeled dose of rufinamide, less than 2% of the dose was recovered unchanged in urine. The primary biotransformation pathway is carboxylesterase(s) mediated hydrolysis of the carboxamide group to the acid derivative CGP 47292. A few minor additional metabolites were detected in urine, which appeared to be acyl-glucuronides of CGP 47292. There is no involvement of oxidizing cytochrome P450 enzymes or glutathione in the biotransformation process.

Rufinamide is a weak inhibitor of CYP 2E1. It did not show significant inhibition of other CYP enzymes. Rufinamide is a weak inducer of CYP 3A4 enzymes.

Rufinamide did not show any significant inhibition of P-glycoprotein in an in-vitro study.

Elimination/Excretion

Renal excretion is the predominant route of elimination for drug related material, accounting for 85% of the dose based on a radiolabeled study. Of the metabolites identified in urine, at least 66% of the rufinamide dose was excreted as the acid metabolite CGP 47292, with 2% of the dose excreted as rufinamide.

The plasma elimination half-life is approximately 6-10 hours in healthy subjects and patients with epilepsy.

Special Populations

Gender: Population pharmacokinetic analyses of females show a 6-14% lower apparent clearance of rufinamide compared to males. This effect is not clinically important.

Race: In a population pharmacokinetic analysis of clinical studies, no difference in clearance or volume of distribution of rufinamide was observed between the black and Caucasian subjects, after controlling for body size. Information on other races could not be obtained because of smaller numbers of these subjects.

Pediatrics: Based on a population analysis in 117 children (age 4-11 years) and 99 adolescents (age 12-17 years), the pharmacokinetics of rufinamide in these patients is similar to the pharmacokinetics in adults.

Elderly: The results of a study evaluating single-dose (400 mg) and multiple dose (800 mg/day for 6 days) pharmacokinetics of rufinamide in 8 healthy elderly subjects (65-80 years old) and 7 younger healthy subjects (18-45 years old) found no significant age-related differences in the pharmacokinetics of rufinamide. Renal Impairment: Rufinamide pharmacokinetics in 9 patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Patients undergoing dialysis 3 hours post rufinamide dosing showed a reduction in AUC and Cmax by 29% and 16% respectively. Adjusting rufinamide dose for the loss of drug upon dialysis should be considered.

Hepatic Impairment: There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment.

Clinical Studies

The effectiveness of BANZEL (rufinamide tablets) as adjunctive treatment for the seizures associated with Lennox-Gastaut syndrome (LGS) was established in a single multicenter, double-blind, placebo-controlled, randomized, parallel-group study (n=138). Male and female patients (between 4 and 30 years of age) were included if they had a diagnosis of inadequately controlled seizures associated with LGS (including both atypical absence seizures and drop attacks) and were being treated with 1 to 3 concomitant stable dose AEDs. Each patient must have had at least 90 seizures in the month prior to study entry. After completing a 4 week Baseline Phase on stable therapy, patients were randomized to have BANZEL (rufinamide tablets) or placebo added to their ongoing therapy during the 12 week Double-blind Phase. The Double-blind Phase consisted of 2 periods: the Titration Period (1 to 2 weeks) and the Maintenance Period (10 weeks). During the Titration Period, the dose was increased to a target dosage of approximately 45 mg/kg/day (3200 mg in adults of > 70kg), given on a b.i.d. schedule. Dosage reductions were permitted during titration if problems in tolerability were encountered. Final doses at titration were to remain stable during the maintenance period. Target dosage was achieved in 88% of the BANZEL (rufinamide tablets) -treated patients. The majority of these patients reached the target dose within 7 days, with the remaining patients achieving the target dose within 14 days.

The primary efficacy variables were:

  • The percent change in total seizure frequency per 28 days;
  • The percent change in tonic-atonic (drop attacks) seizure frequency per 28 days;
  • Seizure severity from the Parent/Guardian Global Evaluation of the patient's condition. This was a 7-point assessment performed at the end of the Double-blind Phase. A score of +3 indicated that the patient's seizure severity was very much improved, a score of 0 that the seizure severity was unchanged, and a score of -3 that the seizure severity was very much worse.

The results of the three primary endpoints are shown in Table 7 below.

Table 7: Lennox -Gastaut Syndrome Trial Seizure Frequency Primary Efficacy Variable Results

Variable Placebo Rufinamide
Median percent change in total seizure frequency per 28 days -11.7 -32.7 (p=0.0015)
Median percent change in tonic-atonic seizure frequency per 28 days 1.4 -42.5 (p < 0.0001)
Improvement in Seizure Severity Rating from Global Evaluation 30.6 53.4 (p=0.0041)

Last reviewed on RxList: 4/22/2011
This monograph has been modified to include the generic and brand name in many instances.

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