Brand Name: Banzel
Generic Name: rufinamide
Manufacturer3: Eisai Co.
Drug Class1,2: Anticonvulsant, Triazole Derivative1,2
Labeled Uses1,2,3,4,5: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years and older and adults.
Unlabeled Uses1: Adjunctive treatment of refractory partial seizures.
Mechanism of Action:1,2,3,4,5
The exact mechanism of rufinamide is unknown. However, studies suggest that it exhibits activity on sodium channels extending their inactive state. This slows sodium channel recovery thereby limiting repeated firing of sodium-dependent action potentials.
Pharmacokinetics1,2,3,4,5:
Absorption:
Tmax |
4-6 hours |
Vd |
50L |
t ½ |
6-10 hours |
Clearance |
Not reported |
Protein binding |
34% (27% albumin) |
Bioavailability |
85% |
Metabolism: Rufinamide is extensively metabolized in the liver primarily by carboxylesterases. Neither CYP 450 enzymes nor glutathione are involved in its metabolism. Rufinamide is a weak inhibitor of CYP 2E1 and a weak inducer of CYP 3A4.
Elimination: Rufinamide is primarily excreted through the kidneys into urine (85%). Of the metabolites, 66% of the dose was excreted as the acid metabolite CGP 47292 and only 2% was excreted unchanged as rufinamide.
Efficacy:
Glauser T, Kluger G, Sachdeo R, Krauss G, Perdomo C, Arroyo S. Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome. Neurology. 2008;70:1950-8.
Study Design: Multicenter, double-blind, placebo-controlled, parallel-group design study
Description of Study:
Methods: One-hundred-thirty-eight patients meeting the diagnostic criteria for Lenox-Gastaut syndrome were randomized to receive either placebo or rufinamide in addition to their current antiepileptic drug regimen. The study consisted of a 28-day baseline period to develop a basis for seizure control and events without the study drug or placebo. This was followed by a 14-day titration period and 70-day maintenance period for a total 84 day treatment period. Patient doses were titrated according to the recommended schedule with the goal of achieving the maximum dose of 45 mg/kg/day in the 14-day titration period. Efficacy and safety were evaluated using daily diaries of seizure frequency and adverse events as well as physical and neurological evaluations and drug concentration and clinical laboratory assessments. At the end of the study, parental/guardian evaluations of seizure severity and the condition of the patient were evaluated using a Likert scale. Analysis was based on the intent-to-treat population consisting of all patient randomized into the study.
Outcome Results: The median percentage change in total seizure frequency per 28 days showed decreases of 32.7% and 11.7% (p=0.0015) in the rufinamide and placebo groups respectively. A median decrease in tonic-atonic seizure frequency per 28 days of 42.5% was observed for rufinamide while the placebo group frequency experienced a 1.4% increase (p<0.0001). Seizure severity as reported by parents and guardians showed more improvement in the rufinamide treatment group (0.88 with rufinamide vs 0.27 with placebo; p=0.0041). Patients in the rufinamide group were more likely to observe at least a 50% decrease in tonic-atonic seizure frequency per 28 days (42.5% vs 15.7%; OR 3.81; p=0.002) and total seizure frequency per 28 days (31.1% vs 10.9%; p=0.0045) when compared to the placebo group. Rufinamide treatment showed a decrease in frequency per 28 days relative to baseline for absence and atypical absence seizures (50.6% vs 29.8%; p=0.0222) and atonic seizures (44.8% vs 21.0%; p=0.0125). No significant differences were observed between the mean composite scores of the parent/guardian evaluation of patient condition.
Limitations: This study was sponsored by Eisai Pharmaceutical, the manufacturer of rufinamide. Also, two authors were employees of the company, introducing a potential conflict of interest. Parents or guardians were responsible for identifying the type and recording the number of seizures the patient had. Parents and guardians were trained for 6 to 24 hours on seizure identification, but the accuracy of their reports was never reported. This could potentially affect the results for seizure subtypes. The median age and weight of patients in the trail were 13.0 years old 35.9kg. This makes the results difficult to extrapolate to adults or patients with higher weights and raises the question of effective doses in adults or heavier patients.
Conclusion: The study showed that rufinamide as adjunct therapy in patients with Lennox-Gastaut syndrome significantly lowered the total frequency of seizures per 28 days from baseline when compared to placebo (32.7% vs 11.7%; p=0.0015). This supports the effectiveness of using rufinamide as adjunct therapy in Lennox-Gastaut syndrome. However, more studies need to be conducted to assess what specific antiepileptic drug combination with rufinamide is most effective. Also, more studies are needed to determine which subtype of seizures rufinamide is most effective at treating.
Palhagen S, Canger R, Henriksen O, van Parys JA, Riviere ME, Karolchyk MA. Epilepsy Research. 2001;43:115-24.
Study Design: Multicenter, double-blind, randomized, placebo-controlled, parallel group study
Description of Study:
Methods: Fifty patients diagnosed with either partial or primary generalized tonic-clonic seizures were randomized to receive either rufinamide or placebo as adjunct therapy to current antiepileptic treatment. All patients received one 800mg dose of rufinamide with breakfast on Day 1 followed by a 7 day washout period to assess pharmacokinetics over a 96 hour period after the dose. On Day 8, patients started a 28 day double-blinded trial period on either placebo or the study drug. Patients receiving rufinamide started on 400mg/day twice daily followed by weekly increases of 400mg/day up to 1600mg/day by the end of the study. All patients completing the trial received an additional 800mg dose of rufinamide with breakfast on Day 35. Pharmacokinetic data was obtained over the 96 hours following the dose. Efficacy was evaluated using patient estimates of seizure frequency 28 days before starting the trial compared to patient diaries kept during the trial. Pharmacokinetic data was obtained in the treatment group throughout the 28 day study period. Adverse events were monitored for all participants throughout the study period.
Outcome Results: Evaluable patients treated with rufinamide (n=23) showed a median decrease in seizure frequency per 28 days of 41% when compared to baseline as opposed to the placebo group (n=21) who saw a 52% increase in frequency (p=0.0397). Of the evaluable patients, 52% treated with rufinamide achieved a reduction in seizure frequency ≥25% as compared to 16% of placebo treated patients (p=0.020). The difference between treatment and placebo groups in evaluable patients was not significant when evaluating those who had a decrease in seizure frequency ≥50% (39% rufinamide, 16% placebo; p=0.105). More patients taking rufinamide than placebo in the evaluable group were categorized as having low seizure frequency (61% rufinamide, 21% placebo; p=0.042).
Limitations: The differences between the groups at baseline were recorded but the significance of these were not expressed (i.e. no p-values). This may have biased the data if one group had more of one type of seizure or were more likely to be on a specific antiepileptic drug. Power was never reported; therefore it is impossible to determine the minimum number of patients for each group. The difference between placebo and treatment groups with ≥50% reduction in seizures may have been significantly different if there had been more patients in the study. Baseline seizure activity was only assessed through anecdotal evidence supplied by the patients before entering the study. Patients may have overestimated the number of seizures they had experienced in the past 28 days which could have resulted in false reductions in seizure frequencies. Patients were also responsible for categorizing and recoding the number of seizures they experienced affecting the validity of the number of seizures recorded in the trial.
Conclusion: The results of the study showed that rufinamide when used as adjunct therapy to a patient’s current regimen, does reduce the frequency of seizures in patients with epilepsy. Safety and adverse events cannot be fully assessed due to the absence of p-values and expressed power. Pharmacokinetic studies also revealed that phenytion and carbamazepine can significantly lower the AUC and t1/2 of rufinamide versus valproate alone. Further studies are needed to assess change in seizure frequency from baseline without relying on patient reports. Also, more safety studies need to be evaluated to determine the safety of rufinamide.
Aldenkamp AP, Alpherts WCJ. The effect of the new antiepileptic drug rufinamide on cognitive functions. Epilepsia. 46(7);2006:1153-59.
Study Design: Multicenter, multinational, double blind, randomized, placebo-controlled parallel study
Description of Study:
Methods: In the study, 213 patients were randomized to receive either placebo or four different doses of rufinamide (200 mg/day, 400 mg/day, 800 mg/day and 1,600 mg/day) as adjunct therapy for 3 months. Cognitive assessments were completed at baseline and the end of the trial period. Cognitive tests included auditory reaction time and visual reaction time for attentional function, Binary Choice Reaction Test and Computerized Visual Searching Task for mental information-processing speed, dominant and nondominant hand Finger Tapping Task for psychomotor speed and motor fluency and recognition of words and figures for working memory. Results of baseline and post-treatment assessments were compared to determine how rufinamide affects cognitive function.
Outcome Results: No significant changes in cognitive function were observed when comparing placebo and treatment groups or changes at the end of the study from baseline within the treatment group. Patients in the treatment group showed improvement when compared to baseline in all cognitive tests though none reached statistical significance.
Limitations: The average age of the patients studied was 37.5 years making it difficult to assess how this drug affects cognitive function in children. Cognitive function effects over extended durations of therapy are not addressed in this study. Neither of the authors address possible conflicts of interest making it impossible to assess how conflicts could have influence the results of the study. Cognitive effects were only assessed at the end of the study. Patients may have exhibited cognitive effects upon initiation of the study drug but may have adapted to the effects by the time the tests were completed.
Conclusion: Despite its finding that rufinamide does not exhibit significantly serious cognitive effects; it cannot be guaranteed that these effects will not be seen in patients. This is especially true for patients being initiated on rufinamide therapy in addition to their other antiepileptic drugs. The study only evaluated the effects on patients 3 months after initiation. At this time, patients may have adapted to the side effects of the drug. Additionally, long-term effects of rufinamide on function were not assessed. More studies need to be completed on short-term and long-term effects of rufinamide on cognitive function.
Contraindications1,2,3,4,5:
Familial Short QT syndrome: Rufinamide is contraindicated in patients with Familial Short QT syndrome due to the increased risk of sudden death and ventricular arrhythmias.
Precautions1,2,3,4,5:
Multi-organ Hypersensitivity Reactions: Antiepileptic drugs sometimes cause this condition. Rufinamide should be discontinued immediately if this reaction is suspected. Patients who develop a rash while on rufinamide therapy should be closely observed. Patients should be instructed to report any rash with an associated fever.
Withdrawal of AEDs: Gradual withdrawal from the medication should be implemented to prevent precipitating seizures, seizure exacerbation or status epilepticus. Patients needing sudden discontinuation should be monitored closely while being transitioned to a new AED.
Status Epilepticus: Status epilepticus has been reported.
Suicidal Ideation: Patients, caregivers and families should be informed about the risks of antiepileptic drugs causing suicidal thoughts and behaviors. Any emergence or worsening of the signs and symptoms of depression, unusual mood or behavioral changes, emergence of suicidal thoughts, behavior or thoughts about self-harm should be reported to the healthcare provider immediately.
CNS Effects: Patients should be warned of the potential for rufinamide to cause dizziness and tiredness. Patients should also be warned not to consume alcohol while on rufinamide because of the additive CNS effects.
Contraceptive Failure: Women of childbearing age should be warned that use rufinamide may decrease the effectiveness of hormonal contraceptives and other forms of contraception should be used while on this medication.
Pregnancy: Rufinamide is a pregnancy category C and produced developmental toxicity when given to animals. Women who become pregnant or intend to become pregnant should notify their physician.
Lactation: Rufinamide is likely excreted in breast milk. Patients should notify their physician if they are or intend to nurse while on the medication. Breast-feeding should be discontinued due to the potential adverse effects on the infant.
Pediatrics Use: Safe and effective use for children under 4 has not been established.
Geriatric Use: Insufficient data is available to assess differences in response. It is advisable that elderly patients start at the lower end of the dose range and be titrated carefully.
Hepatic Disease: Patients with mild to moderate hepatic disease should be titrated carefully because of rufinamide’s extensive hepatic metabolism.
Dialysis: Hemodialysis has been shown to decrease patient exposure by 30%. Doses should be adjusted to account for drug loss from dialysis.
Adverse Effects:
Occurring in >10% of patients
Cardiovascular:
Shortened QT Interval (46% to 65%)
Gastrointestinal
Nausea (7% to 12%)
Vomiting (5% to 17%)
Neurologic
Dizziness (2.7% to 19%)
Headache (16% to 27%)
Somnolence (11% to 24.3%)
Other
Fatigue (9% to 16%)
Occurring in >1% to <10% of patients
Central Nervous System
Ataxia (4% to 5%)
Seizure (children 5%)
Status epilepticus (up to 4%)
Aggression (children 3%)
Anxiety (adults 3%)
Attention disturbance (children 3%)
Hyperactivity (children 3%)
Vertigo (adults 3%)
Dermatologic
Rash (children 4%)
Pruritus (children 3%)
Gastrointestinal
Appetite decrease (≥1% to 5%)
Abdominal pain (3%)
Constipation (adults 3%)
Dyspepsia (adults 3%)
Appetite increase (>1%)
Hematologic
Leukopenia (≤4%)
Anemia (≥1%)
Neuromuscular & Skeletal
Tremor (adults 6%)
Back pain (adults 3%)
Gait disturbance (1% to 3%)
Ocular
Diplopia (4% to 9%)
Blurred vision (adults 6%)
Nystagmus (adults 6%)
Otic
Otitis media (children 3%)
Renal
Pollakiuria (≥1%)
Respiratory
Nasopharyngitis (≥5%)
Bronchitis (children 3%)
Sinusitis (children 3%)
Miscellaneous
Influenza (children 5%)
Uncommon (<1%) but serious
Atrioventricular block (first degree)
Bundle branch block (right)
Neutropenia
Leukopenia
Thrombocytopenia
Multiorgan hypersensitivity
Drug Interactions1,2,3,4,5:
Co-administration with drugs that cause shortening of the QT interval
Ranolazine, digoxin, mexiletine, magnesium salts, lamotragine
Carboxylesterase inducers
Rufinamide is highly metabolized by carboxylesterases. Inducers of carboxylesterases may result in decreased levels of rufinamide.
Carbamazepine and phenobarbital
Carboxylesterase inhibitors
Rufinamide is highly metabolized by carboxylesterases. Inhibitors of carboxylesterases may result in increased levels of rufinamide.
Phenytoin/Fosphenytoin
Population studies have shown that concurrent administration causes increases in phyentoin levels and decreases in rufinamide levels.
Primidone
Population studies have shown that primidone decreases rufinamide levels.
Valproic acid
Population studies have shown that valproic acid increases rufinamide levels.
Induction of CYP 3A4
Rufinamide is a weak inducer of CYP 3A4 and as a result may cause decreased levels of drugs metabolized by this enzyme
Ethinyl estradiol, northindrone, amiodarone, alprazolam, astemizole, bepridil, bortezomib, buprenorphine, busulfan, cevimeline, cilostazol, cisapride, cyclosporine, dapsone, docetaxel, donepezil, dutasteride, ergot alkaloids, ethosuximide, etoposide, galantamine, gefitinib, imatinib, levobupivacaine, loratadine, midazolam, nefazadone, pacliltaxel, paricalcitol, pimozide, quinidine, reboxetine, sibutramine, sirolimus, tacrolimus, tamoxifen, telithromycin, terfenadine, triazolam, trimetrexate, vinca alkaloids, zolpidem, and zonisamide.
Induction of CYP 2E1
Rufinamide is a weak inducer of CYP 3A4 and as a result may cause decreased levels of drugs metabolized by this enzyme.
Chlorzoxazone
Quinine
Quinine is metabolized by CYP 3A4 and to a lesser extent by CYP 2E1. Therefore it is possible that coadministration of quinine with rufinamide may cause increased levels of quinine.
Ethanol
The consumption of ethanol with rufinamide may compound CNS depression effects
Dosing/Administration1,2,3,4,5:
Adult Dosing
Initial dose: 400-800 mg/day administered in two equally divided doses
Dosage titration: Increase by 400-800 mg/day every two days until a maximum dose of 3,200 mg/day, administered in two equally divided doses is reached.
Maintenance dose: 3,200mg
Pediatrics (≥4 years of age)
Initial dose: Approximately 10 mg/kg/day administered in two equally divided doses.
Dosage titration: Increase by approximately 10 mg/kg increments every other day to a target dose of 45mg/kg/day or 3,200 mg/day, whichever is less, administered in two equally divided doses
Maintenance dose: 45 mg/kg/day or 3,200 mg/day (whichever is less)
Elderly
Dose selection should be cautious. Start at the low end of the dosing range.
Renal impairment
Renally impaired patients do not require dose adjustments.
Hemodialysis may cause reduced exposure to rufinamide. Dose adjustments should be made during the dialysis process.
Hepatic impairment
Due to lack of study, use of rufinamide should be avoided in patients with severe hepatic impairment. Use caution when administering rufinamide to patients with mild to moderate hepatic impairment.
Use in special circumstances:
Overdosage: 3 There is no specific antidote to rufinamide. If indicated, induction of emesis or gastric lavage should be used to remove any unabsorbed drug from the stomach. Airway should be maintained and supportive care and monitoring should be initiated. Hemodialysis may result in limited clearance of rufinamide.
Conclusion:
Rufinamide is an effective adjunct therapy for patients with Lennox-Gastaut syndrome and shows possible efficacy in patients with other types of seizure disorders. More studies need to be conducted to evaluate the most effective antiepileptic combination to treat Lennox-Gastaut syndrome. Rufinamide is safe to use with other antiepileptic agents with minimal risk of drug interactions. Studies determining rufinamide’s place in the treatment of generalized seizure disorders also need to be completed. The side effects and adverse events of the drug appear to be minimal. However, it is difficult to assess to what degree rufinamide initiation may affect cognitive function at the start of therapy. With its tolerability, minimal drug interactions, effectiveness in Lennox-Gastaut syndrome and probable use in generalized seizures, rufinamide appears to be another clinically useful antiepileptic agent.
Recommended References:
Prepared by: Michael A. Biddle, Jr., Doctor of Pharmacy Candidate