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Banzel

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Banzel

Side Effects
Interactions

SIDE EFFECTS

Controlled Trials

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Placebo-controlled double-blind studies were performed in adults and in pediatric patients, down to age of 4, in other forms of epilepsy, in addition to the trial in Lennox-Gastaut syndrome. Data on CNS Reactions [see WARNINGS AND PRECAUTIONS] from the Lennox-Gastaut study are presented first. Because there is no reason to suspect that adverse reactions would substantially differ between these patient populations, safety data from all of these controlled studies are then presented. Most of these adverse reactions were mild to moderate and transient in nature.

Common central nervous system reactions in the controlled trial of patients 4 years or older with Lennox-Gastaut syndrome treated with BANZEL (rufinamide tablets) as adjunctive therapy [see WARNINGS AND PRECAUTIONS]

Somnolence was reported in 24.3% of BANZEL (rufinamide tablets) -treated patients compared to 12.5% of placebo patients and led to study discontinuation in 2.7% of treated patients compared to 0% of placebo patients. Fatigue was reported in 9.5% of BANZEL (rufinamide tablets) -treated patients compared to 7.8% of placebo patients. It led to study discontinuation in 1.4% of treated patients and 0% of placebo patients.

Dizziness was reported in 2.7% of BANZEL (rufinamide tablets) -treated patients compared to 0% of placebo patients, and did not lead to study discontinuation.

Ataxia and gait disturbance were reported in 5.4% and 1.4% of BANZEL (rufinamide tablets) -treated patients, respectively, and in no placebo patients. Balance disorder and abnormal coordination were each reported in 0% of BANZEL (rufinamide tablets) -treated patients and 1.6% of placebo patients. None of these reactions led to study discontinuation.

All Adverse Reactions for All Treated Patients with Epilepsy, Double-blind Adjunctive Therapy Studies: The most commonly observed ( ≥ 10%) adverse reactions in BANZEL (rufinamide tablets) -treated patients, when used as adjunctive therapy at all doses studied (200 to 3200 mg/day) with a higher frequency than in placebo were: headache, dizziness, fatigue, somnolence, and nausea.

Table 2 lists treatment-emergent adverse reactions that occurred in at least 3% of pediatric patients with epilepsy treated with BANZEL (rufinamide tablets) in controlled adjunctive studies and were numerically more common in patients treated with BANZEL (rufinamide tablets) than placebo.

At the target dose of 45 mg/kg/day for adjunctive therapy in children, the most commonly observed ( ≥ 3%) adverse reactions with an incidence greater than in placebo, for BANZEL (rufinamide tablets) were somnolence, vomiting and headache.

Table 2: Incidence (%) of Treatment-Emergent Adverse Reactions in all Pediatric Double-Blind Adjunctive Trials by Preferred Term at the Recommended Dose of 45 mg/kg/day (Adverse Reactions occurred in at least 3% of BANZEL (rufinamide tablets) -treated patients and occurred more frequently than in Placebo Patients)

Preferred Term BANZEL (rufinamide tablets)
(N=187)
%
Placebo
(N=182)
%
Somnolence 17 9
Vomiting 17 7
Headache 16 8
Fatigue 9 8
Dizziness 8 6
Nausea 7 3
Influenza 5 4
Nasopharyngitis 5 3
Decreased Appetite 5 2
Rash 4 2
Ataxia 4 1
Diplopia 4 1
Bronchitis 3 2
Sinusitis 3 2
Psychomotor Hyperactivity 3 1
Abdominal Pain Upper 3 2
Aggression 3 2
Ear Infection 3 1
Disturbance in Attention 3 1
Pruritis 3 0

Table 3 lists treatment-emergent adverse reactions that occurred in at least 3% of adult patients with epilepsy treated with BANZEL (rufinamide tablets) (up to 3200mg/day) in adjunctive controlled studies and were numerically more common in patients treated with BANZEL (rufinamide tablets) than placebo. In these studies, either BANZEL (rufinamide tablets) or placebo was added to current AED therapy.

At all doses studied of up to 3200 mg/day given as adjunctive therapy in adults, the most commonly observed ( ≥ 3%) adverse reactions, and with the greatest increase in incidence compared to placebo, for BANZEL (rufinamide tablets) were dizziness, fatigue, nausea, diplopia, vision blurred, and ataxia.

Table 3: Incidence (%) of Treatment-Emergent Adverse Reactions in all Adult Double-Blind Adjunctive Trials (up to 3200mg/day) by Preferred Term (Adverse Reactions occurred in at least 3% of BANZEL (rufinamide tablets) -treated patients and occurred more frequently than in Placebo Patients)

Preferred Term BANZEL (rufinamide tablets)
(N=823)
%
Placebo
(N=376)
%
Headache 27 26
Dizziness 19 12
Fatigue 16 10
Nausea 12 9
Somnolence 11 9
Diplopia 9 3
Tremor 6 5
Nystagmus 6 5
Vision Blurred 6 2
Vomiting 5 4
Ataxia 4 0
Abdominal Pain Upper 3 2
Anxiety 3 2
Constipation 3 2
Dyspepsia 3 2
Back Pain 3 1
Gait Disturbance 3 1
Vertigo 3 1

Discontinuation in Controlled Clinical Studies

In controlled double-blind adjunctive clinical studies, 9.0% of patients receiving BANZEL (rufinamide tablets) as adjunctive therapy and 4.4% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (rufinamide tablets) ( > 1%) used as adjunctive therapy were generally similar in adults and children.

In pediatric double-blind adjunctive clinical studies, 8.0% of patients receiving BANZEL (rufinamide tablets) as adjunctive therapy and 2.2% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (rufinamide tablets) ( > 1%) used as adjunctive therapy are presented in Table 4.

Table 4: Adverse Reactions Most Commonly Leading to Discontinuation in Double-Blind Adjunctive Trials (At The Recommended Dose of 45mg/kg/day) in Pediatric Patients

Preferred Term BANZEL (rufinamide tablets)
(N=187)
%
Placebo
(N=182)
%
Convulsion 2 1
Rash 2 1
Fatigue 2 0
Vomiting 1 0

In adult double-blind adjunctive clinical studies (up to 3200 mg/day), 9.5% of patients receiving BANZEL (rufinamide tablets) as adjunctive therapy and 5.9% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions most commonly leading to discontinuation of BANZEL (rufinamide tablets) ( > 1%) used as adjunctive therapy are presented in Table 5.

Table 5: Adverse Reactions Most Commonly Leading to Discontinuation in Double-Blind Adjunctive Trials (up to 3200 mg/day) in Adult Patients

Preferred Term BANZEL (rufinamide tablets)
(N=823)
%
Placebo
(N=376)
%
Dizziness 3 1
Fatigue 2 1
Headache 2 1
Nausea 1 0
Ataxia 1 0

Other Adverse Events Observed During Clinical Trials

BANZEL (rufinamide tablets) has been administered to 1978 individuals during all epilepsy clinical trials (placebo­controlled and open-label). Adverse events occurring during these studies were recorded by the investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of patients having adverse events, these events were grouped into standardized categories using the MedDRA dictionary. Adverse events occurring at least three times and considered possibly related to treatment are included in the System Organ Class listings below. Terms not included in the listings are those already included in the tables above, those too general to be informative, those related to procedures and terms describing events common in the population. Some events occurring fewer than 3 times are also included based on their medical significance. Because the reports include events observed in open-label, uncontrolled observations, the role of BANZEL (rufinamide tablets) in their causation cannot be reliably determined.

Events are classified by body system and listed in order of decreasing frequency as follows: frequent adverse events- those occurring in at least 1/100 patients; infrequent adverse events-those occurring in 1/100 to 1/1000 patients; rare- those occurring in fewer than 1/1000 patients. Blood and Lymphatic System Disorders: Frequent: anemia. Infrequent: lymphadenopathy, leukopenia, neutropenia, iron deficiency anemia, thrombocytopenia. Cardiac Disorders: Infrequent: bundle branch block right, atrioventricular block first degree. Metabolic and Nutritional Disorders: Frequent: decreased appetite, increased appetite. Renal and Urinary Disorders: Frequent: pollakiuria. Infrequent: urinary incontinence, dysuria, hematuria, nephrolithiasis, polyuria, enuresis, nocturia, incontinence.

Read the Banzel (rufinamide tablets) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Based on in vitro studies, rufinamide shows little or no inhibition of most cytochrome P450 enzymes at clinically relevant concentrations, with weak inhibition of CYP 2E1. Drugs that are substrates of CYP 2E1 (e.g. chlorzoxazone) may have increased plasma levels in the presence of rufinamide, but this has not been studied.

Based on in vivo drug interaction studies with triazolam and oral contraceptives, rufinamide is a weak inducer of the CYP 3A4 enzyme and can decrease exposure of drugs that are substrates of CYP 3A4.

Rufinamide is metabolized by carboxylesterases. Drugs that may induce the activity of carboxylesterases may increase the clearance of rufinamide. Broad-spectrum inducers such as carbamazepine and phenobarbital may have minor effects on rufinamide metabolism via this mechanism. Drugs that are inhibitors of carboxylesterases may decrease metabolism of rufinamide.

Effects of BANZEL (rufinamide tablets) on other AEDs

Population pharmacokinetic analysis of average concentration at steady state of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate showed that typical rufinamide Cavss levels had little effect on the pharmacokinetics of other AEDs. Any effects, when they occur, have been more marked in the pediatric population.

Table 6 summarizes the drug-drug interactions of BANZEL (rufinamide tablets) with other AEDs.

Table 6: Summary of drug-drug interactions of BANZEL (rufinamide tablets) with other antiepileptic drugs

AED Co-administered Influence of Rufinamide on AED concentrationa) Influence of AED on Rufinamide concentration
Carbamazepine Decrease by 7 to 13%b) Decrease by 19 to 26% Dependent on dose of carbamazepine
Lamotrigine Decrease by 7 to 13%b) No Effect
Phenobarbital Increase by 8 to 13% b) Decrease by 25 to 46%c) d) Independent of dose or concentration of phenobarbital
Phenytoin Increase by 7 to 21% b) Decrease by 25 to 46%c) d) Independent of dose or concentration of phenytoin
Topiramate No Effect No Effect
Valproate No Effect Increase by <16 to 70%c)Dependent on concentration of valproate
Primidone Not Investigated Decrease by 25 to 46%c) d) Independent of dose or concentration of primidone
Benzodiazepines e) Not Investigated No Effect
a) Predictions are based on BANZEL (rufinamide tablets) concentrations at the maximum recommended dose of BANZEL (rufinamide tablets) .
b) Maximum changes predicted to be in children and in patients who achieve significantly higher levels of BANZEL, as the effect of rufinamide on these AEDs is concentration-dependent.
c) Larger effects in children at high doses/concentrations of AEDs.
d) Phenobarbital, primidone and phenytoin were treated as a single covariate (phenobarbital-type inducers) to examine the effect of these agents on BANZEL (rufinamide tablets) clearance.
e) All compounds of the benzodiazepine class were pooled to examine for 'class effect' on BANZEL (rufinamide tablets) clearance.

Phenytoin: The decrease in clearance of phenytoin estimated at typical levels of rufinamide (Cavss 15 μg/mL) is predicted to increase plasma levels of phenytoin by 7 to 21%. As phenytoin is known to have non-linear pharmacokinetics (clearance becomes saturated at higher doses), it is possible that exposure will be greater than the model prediction.

Effects of Other AEDs on BANZEL (rufinamide tablets)

Potent cytochrome P450 enzyme inducers, such as carbamazepine, phenytoin, primidone, and phenobarbital appear to increase the clearance of BANZEL (rufinamide tablets) (see Table 6). Given that the majority of clearance of BANZEL (rufinamide tablets) is via a non-CYP-dependent route, the observed decreases in blood levels seen with carbamazepine, phenytoin, phenobarbital, and primidone are unlikely to be entirely attributable to induction of a P450 enzyme. Other factors explaining this interaction are not understood. Any effects, where they occurred were likely to be more marked in the pediatric population.

Valproate: Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. In children, valproate administration may lead to elevated levels of rufinamide by up to 70%. Patients stabilized on BANZEL (rufinamide tablets) before being prescribed valproate should begin valproate therapy at a low dose, and titrate to a clinically effective dose. Similarly, patients on valproate should begin at a BANZEL (rufinamide tablets) dose lower than 10 mg/kg/day (children) or 400 mg/day (adults) [see DOSAGE AND ADMINISTRATION].

Effects of BANZEL (rufinamide tablets) on other Medications

Hormonal contraceptives: Co-administration of BANZEL (rufinamide tablets) (800 mg BID for 14 days) and Ortho-Novum 1/35® resulted in a mean decrease in the ethinyl estradiol AUC0-24 of 22% and Cmax by 31% and norethindrone AUC0-24 by 14% and Cmax by 18%, respectively. The clinical significance of this decrease is unknown. Female patients of childbearing age should be warned that the concurrent use of BANZEL (rufinamide tablets) with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using BANZEL [see PATIENT INFORMATION].

Triazolam: Co-administration and pre-treatment with BANZEL (rufinamide tablets) (400 mg bid) resulted in a 37% decrease in AUC and a 23% decrease in Cmax of triazolam, a CYP 3A4 substrate.

Olanzapine: Co-administration and pre-treatment with BANZEL (rufinamide tablets) (400mg bid) resulted in no change in AUC and Cmax of olanzapine, a CYP 1A2 substrate.

Drug Abuse And Dependence

The abuse and dependence potential of BANZEL (rufinamide tablets) has not been evaluated in human studies.

Read the Banzel Drug Interactions Center for a complete guide to possible interactions

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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