AHFS Class:

• Ion Channel Inhibition Agents 28:12.24

Generic Name(s):

• Rufinamide

Rufinamide is a triazole-derivative anticonvulsant.1,6,7,9,10,11,12,13,14,15,17,18

Seizures Associated with Lennox-Gastaut Syndrome

Rufinamide is used as adjunctive therapy (i.e., in combination with other anticonvulsant agents) in the management of seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients 1 year of age or older.1,5,6,8,9,10,11,28,35 Rufinamide has been designated an orphan drug by the FDA for use in this condition.5,8,10

Efficacy of rufinamide as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in adults and pediatric patients 4 years of age or older was established in a multicenter, randomized, double-blind, placebo-controlled study.1,9 In this study, 138 patients (age range: 4-30 years) with inadequately controlled seizures of multiple types associated with Lennox-Gastaut syndrome (including both atypical absence seizures and tonic-atonic seizures [drop attacks]) who experienced at least 90 seizures in the month prior to study entry and who were receiving 1-3 anticonvulsants at stable dosages during a 4-week baseline period were randomized to receive either rufinamide or placebo during the 12-week, double-blind phase.1,9 The double-blind phase consisted of a 2-week titration period followed by a 10-week maintenance period.1,9 During the titration period, patients receiving rufinamide were titrated up to a target dosage of approximately 45 mg/kg daily (3.2 g in adults weighing 70 kg or more) given in 2 divided doses.1,9

Efficacy of rufinamide in this study was mainly evaluated in terms of the change in seizure frequency (i.e., median percent change in total seizure frequency and median percent change in drop attack frequency over 28 days) and improvement in seizure severity rating from the global evaluation.1,9 Patients receiving rufinamide experienced a median decrease in total seizure frequency of 32.7%, while those receiving placebo experienced a median decrease of 11.7%.1,9 Patients receiving rufinamide also experienced a 42.5% median decrease in tonic-atonic (drop attack) seizure frequency, while those receiving placebo experienced a median increase of 1.4%.1,9 In addition, improvement in seizure severity was reported in 53.4% of the rufinamide-treated patients compared with 30.6% of those receiving placebo.1,9 The beneficial effects of rufinamide in reducing seizure frequency were maintained in an open-label, long-term (up to 3 years) extension of this study.12,22,26,28

Efficacy of rufinamide as adjunctive therapy for seizures associated with Lennox-Gastaut syndrome in pediatric patients 1 to less than 4 years of age is based on data from a pharmacokinetic bridging study.1,35 In this multicenter, randomized, active-controlled study that was conducted in 37 children (1 to less than 4 years of age) with inadequately controlled seizures, the pharmacokinetic and safety profiles of rufinamide were comparable to those observed in patients 4 years of age or older.1,35

Partial Seizures

Although rufinamide has only been approved in the US for use in combination with other anticonvulsant agents in the management of seizures associated with Lennox-Gastaut syndrome, the drug has been studied with some success in the adjunctive management of refractory or inadequately controlled partial seizures† in adolescents and adults.6,7,10,11,12,13,16,17,18,19,21,22,24,25,29,30 However, further study is needed to establish the role of rufinamide in the treatment of partial seizures.11,19

Administration

Rufinamide is administered orally (as tablets or suspension) twice daily in equally divided doses with food.1 Scored tablets of rufinamide may be administered whole, as half tablets, or crushed.1,21

Rufinamide oral suspension should be shaken well prior to administration of each dose.1 The appropriate dose should be administered using the bottle adapter and calibrated oral dosing syringe supplied by the manufacturer.1 The adapter should be inserted firmly into the neck of the bottle before first use and should remain in place as long as the bottle is in use (up to 90 days).1

The commercially available 200- and 400-mg scored tablets of rufinamide may not provide the exact mg/kg dosage that has been calculated for use in children; the manufacturer's recommended dosages in children are therefore designated as approximate.1,21

Rufinamide therapy should be withdrawn gradually to minimize the risk of precipitating or exacerbating seizures and status epilepticus.1 (See Discontinuance of Therapy under Cautions: Warnings/Precautions.) If abrupt discontinuance is medically necessary, the transition to another anticonvulsant should be made under close medical supervision.1 In clinical trials, rufinamide discontinuance was achieved by reducing the dosage by approximately 25% every 2 days.1

Patients currently receiving or beginning therapy with rufinamide and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.1,2,4,20 (See Suicidality Risk under Cautions: Warnings/Precautions.)

Dosage

For the adjunctive management of seizures associated with Lennox-Gastaut syndrome in children and adolescents 1 to less than 17 years of age, rufinamide therapy should be initiated at a dosage of approximately 10 mg/kg daily administered in 2 equally divided doses.1 Dosage should be increased in increments of approximately 10 mg/kg every other day up to a maximum dosage of 45 mg/kg (not to exceed 3.2 g) daily, administered in 2 equally divided doses.1 The manufacturer states that the efficacy of dosages lower than the target dosage has not been established.1

For the adjunctive management of seizures associated with Lennox-Gastaut syndrome in adults 17 years of age and older, rufinamide therapy should be initiated at a dosage of 400-800 mg daily administered in 2 equally divided doses.1 Dosage should be increased in increments of 400-800 mg every other day until a maximum daily dosage of 3.2 g, administered in 2 equally divided doses, is reached.1 The manufacturer states that the efficacy of dosages lower than 3.2 g daily has not been established.1,23

The target dosage was achieved in 88% of rufinamide-treated patients with Lennox-Gastaut syndrome in the principal efficacy study; the majority of these patients reached the target dosage within 7 days, with the remaining patients achieving the target dosage within 14 days.1,9

Valproic acid may increase plasma concentrations of rufinamide by up to 70% during concurrent use.1,21,24 Patients who are stabilized on rufinamide therapy should initiate valproic acid therapy at a low dosa dosage of valproic acid should then be titrated to a clinically effective dosage.1 Patients already receiving valproic acid therapy should begin rufinamide therapy at a dosage lower than 10 mg/kg daily (in children) or a dosage lower than 400 mg daily (in adults).1,11

Special Populations

Rufinamide has not been studied in patients with hepatic impairment.1,21 (See Hepatic Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

Because hemodialysis within 3 hours after a dose of rufinamide may reduce drug exposure to a limited extent (by about 30%), dosage adjustment in patients undergoing dialysis should be considered.1,11,21

Although there are no significant age-related differences in the pharmacokinetics of rufinamide in geriatric individuals compared with younger individuals, the manufacturer states that dosage selection in geriatric patients should be cautious, generally starting at the lower end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy in such patients.1,10

Contraindications

Patients with familial short QT syndrome.1,21 (See Shortening of QT Interval under Cautions: Warnings/Precautions.)

Warnings/Precautions

Sensitivity Reactions

Multi-organ Hypersensitivity

Multi-organ hypersensitivity (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]), a potentially fatal or life-threatening reaction, has been reported in patients receiving rufinamide.1,32 The clinical presentation is variable, but typically includes eosinophilia, fever, rash, and/or lymphadenopathy associated with other organ system involvement such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis.1 However, signs and symptoms associated with other organ systems also may occur.1 In clinical studies evaluating rufinamide, multi-organ hypersensitivity was reported in children younger than 12 years of age, developed within 4 weeks of treatment initiation, and resolved and/or improved upon drug discontinuance.1 Multi-organ hypersensitivity also has been reported in adults and pediatric patients during postmarketing experience with the drug.1

If signs and symptoms associated with multi-organ hypersensitivity occur during rufinamide therapy, the patient should be immediately evaluated.1 Rufinamide should be discontinued and alternative treatment initiated.1

Serious Dermatologic Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome and other serious rashes, have been reported during postmarketing experience in patients receiving rufinamide.1

Suicidality Risk

An increased risk of suicidality (suicidal behavior or ideation) was observed in an analysis of studies using various anticonvulsants compared with placebo.1,2,4,20 The analysis of suicidality reports from 199 placebo-controlled studies involving 11 anticonvulsants (carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, and zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%).1,2,4 This increased risk of suicidality was observed as early as 1 week after beginning therapy and continued through 24 weeks.1,2,4 Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased risk of suicidality compared with those receiving placebo, the relative risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.1,2,4

Clinicians should inform patients, their families, and caregivers of the potential for an increased risk of suicidality with anticonvulsant therapy; all patients currently receiving or beginning therapy with any anticonvulsant be closely monitored for the emergence or worsening of suicidal thoughts or behavior or depression.1,2,4,20

Clinicians who prescribe rufinamide or any other anticonvulsant should balance the risk of suicidality with the clinical need for the drug and the risk associated with untreated illness.1,2 Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.1,20 If suicidal thoughts or behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.1,20 (See Advice to Patients.)

CNS Effects

Adverse CNS effects reported during rufinamide treatment are classified into 2 general categories: 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia.1

In studies in patients with epilepsy, somnolence and fatigue occurred in 24 and 10%, respectively, of patients receiving rufinamide, compared with 13 and 8%, respectively, of those receiving placebo.1 Dizziness, ataxia, and gait disturbances were reported in 2.7, 5.4, and 1.4%, respectively, of patients receiving rufinamide compared with 0% of those receiving placebo.1

Patients should be cautioned about the possibility of adverse neurologic effects with rufinamide therapy.1 (See Advice to Patients.)

Shortening of QT Interval

Formal ECG studies have demonstrated shortening of the QT interval (by a mean of 20 msec) with rufinamide therapy (dosage of 2.4 g or more twice daily).1 In a placebo-controlled clinical trial of the drug's effects on the QT interval, a higher percentage of rufinamide-treated individuals (46% at 2.4 g, 46% at 3.2 g, and 65% at 4.8 g) had QT shortening of greater than 20 msec at the time of peak plasma concentrations compared with those receiving placebo (5-10%).1,11 Reductions in QT interval below 300 msec were not observed in the formal QT-interval studies with dosages up to 7.2 g daily; there also was no signal for drug-induced sudden death or ventricular arrhythmias.1

The manufacturer states that the degree of QT-interval shortening induced by rufinamide is without any known clinical risk.1,11 However, familial short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation; such events are thought to occur primarily when the corrected QT (QT_c) interval falls below 300 msec.1 Nonclinical data also indicate that QT-interval shortening is associated with ventricular fibrillation.1

The manufacturer and some clinicians state that patients with familial short QT syndrome should not be treated with rufinamide and that caution is recommended when administering rufinamide with other drugs that shorten the QT interval.1,11,21,28 Some clinicians also recommend using rufinamide with caution in patients with a history of an abnormal ECG demonstrating QT-interval shortening or a family history of unexplained cardiac arrhythmia or sudden death.28 (See Cautions: Contraindications and also see Drug Interactions: Drugs that Shorten QT Interval.)

Discontinuance of Therapy

To minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus, anticonvulsants, including rufinamide, should be withdrawn gradually.1 If abrupt discontinuance of rufinamide is medically necessary, the transition to another anticonvulsant should be made under close supervision.1 (See Dosage and Administration: Administration.)

Status Epilepticus

The manufacturer states that it is difficult to estimate the incidence of treatment-emergent status epilepticus in rufinamide-treated patients because standard definitions were not employed.1,9 In a controlled study of patients with Lennox-Gastaut syndrome, the incidence of episodes that could be described as status epilepticus was 4.1% in patients receiving rufinamide compared with 0% in those receiving placebo.1 In all controlled clinical trials of rufinamide therapy that included patients with different types of epilepsy, the incidence of episodes that could be described as status epilepticus was 0.9% in patients receiving rufinamide compared with 0% in those receiving placebo.1

Hematologic Effects

Leukopenia has been reported in 3.7% of patients receiving rufinamide compared with 1.2% of those receiving placebo in controlled studies.1

Specific Populations

Pregnancy

Category C.1 (See Users Guide.)

There are no adequate and well-controlled studies of rufinamide in pregnant women.1 Rufinamide produced developmental toxicity when administered orally to pregnant animals at clinically relevant dosages.1 The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.1

Women who are pregnant while receiving rufinamide should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry; patients can enroll by calling 888-233-2334.1 Information on the registry also can be found on the website [Web].1

Lactation

Rufinamide is likely to be distributed into milk.1,21 Because of the potential for serious adverse reactions to rufinamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.1,21

Pediatric Use

Safety and efficacy of rufinamide have not been established in children younger than 1 year of age.1

A population pharmacokinetic analysis of rufinamide that included 85 pediatric patients, including 24 patients 1-3 years of age, 40 patients 4-11 years of age, and 21 patients 12-17 years of age, demonstrated that the pharmacokinetics of the drug were similar across all pediatric age groups.1

Geriatric Use

The manufacturer states that clinical trials of rufinamide did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently than younger patients.1

A study evaluating the single- and multiple-dose pharmacokinetics of rufinamide in healthy geriatric individuals and younger healthy adults found no clinically important age-related differences in the pharmacokinetics of the drug.1 (See Dosage and Administration: Special Populations.)

Hepatic Impairment

Because the pharmacokinetics of rufinamide have not been specifically studied in patient with hepatic impairment, use of the drug in patients with severe hepatic impairment is not recommended.1,21 Rufinamide should be used with caution in patients with mild to moderate hepatic impairment.1,21

Renal Impairment

The pharmacokinetics of rufinamide in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) were similar to those observed in healthy individuals.1

Patients undergoing hemodialysis 3 hours after a dose of rufinamide demonstrated a 29% reduction in area under the plasma concentration-time curve (AUC) and a 16% reduction in peak plasma concentrations of the drug.1 Dosage adjustment during the dialysis process should be considered.1,11,21

Common Adverse Effects

Adverse effects occurring in 3% or more of pediatric patients and more frequently than with placebo in controlled studies in which rufinamide was administered in conjunction with other anticonvulsants include somnolence, headache, fatigue, dizziness, influenza, nasopharyngitis, nausea, vomiting, constipation, stomach pain, decreased appetite, decreased weight, cough, sinusitis, bronchitis, pneumonia, otitis media, rash, pruritus, ataxia, diplopia, aggression, hyperactivity, and disturbance in attention.1,6,9,10,11,13,14,15,21,35

Adverse effects occurring in 3% or more of adults and more frequently than with placebo in controlled studies in which rufinamide was administered in conjunction with other anticonvulsants include headache, dizziness, fatigue, somnolence, diplopia, tremor, nystagmus, blurred vision, nausea, vomiting, stomach pain, constipation, dyspepsia, ataxia, anxiety, back pain, gait disturbance, and vertigo.1,6,9,10,11,13,14,15,21

In vitro and in vivo studies have demonstrated that rufinamide is unlikely to be involved in clinically important pharmacokinetic interactions.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

At clinically relevant concentrations, rufinamide has demonstrated little or no inhibition of most cytochrome P-450 (CYP) isoenzymes.1,8 Rufinamide is a weak inhibitor of CYP2E1.1,21 Drugs that are substrates of CYP2E1 (e.g., chlorzoxazone) may exhibit increased plasma concentrations during concomitant rufinamide therapy.1,21

Rufinamide is a weak inducer of the CYP3A4 isoenzyme and may decrease exposure of drugs that are substrates of CYP3A4 (e.g., triazolam, oral contraceptives).1,11,14,21 (See Drug Interactions: Benzodiazepines and see Drug Interactions: Oral Contraceptives.)

Rufinamide is metabolized by carboxylesterases.1 Drugs that may induce the activity of carboxylesterases may increase rufinamide clearance.1 Broad-spectrum inducers of carboxylesterases such as carbamazepine and phenobarbital may have minor effects on the metabolism of rufinamide via this mechanism.1 (See Drug Interactions: Anticonvulsants.) Drugs that inhibit carboxylesterases may decrease the metabolism of rufinamide.1,8

Drugs that Shorten QT Interval

Because shortening of the QT interval has been reported in rufinamide-treated patients, the manufacturer recommends using caution during concurrent administration of rufinamide and other drugs that potentially may shorten the QT interval (e.g., digoxin, lamotrigine, magnesium, mexiletine, ranolazine).1,21,23

Anticonvulsants

Population pharmacokinetic analyses of carbamazepine, lamotrigine, phenobarbital, phenytoin, topiramate, and valproate have shown that typical average steady-state plasma concentrations of rufinamide generally have little effect on the pharmacokinetics of these other anticonvulsants.1 However, any effects, when they did occur, have been more marked in the pediatric population.1 (See Table 1.)

Although the clinical importance of drug interactions between rufinamide and potentially interacting anticonvulsants is unknown, some clinicians recommend monitoring plasma concentrations of other anticonvulsants and rufinamide following initiation or withdrawal of anticonvulsant therapy if clinically warranted.28 (See Dosage and Administration: Dosage.)

Benzodiazepines

Clinically important pharmacokinetic interactions with concurrent rufinamide and benzodiazepine therapy are unlikely; however, the possibility of additive CNS effects (such as sedation) should be considered during combined therapy.1,13,21,24

Clonazepam

Pharmacokinetic interaction is unlikely.6,13,24

Triazolam

Concurrent administration and pretreatment with rufinamide (400 mg twice daily) resulted in a 37% decrease in area under the plasma concentration-time curve (AUC) and a 23% decrease in peak plasma concentrations of triazolam, a CYP3A4 substrate.1,11,12 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Other CNS Agents or Alcohol

Use of centrally acting drugs or alcohol in combination with rufinamide may result in additive CNS effects (e.g., sedation).1,21

Oral Contraceptives

Concomitant administration of rufinamide (800 mg twice daily for 14 days) with norethindrone (1 mg) and ethinyl estradiol (35 mcg) decreased the AUCs of these hormonal contraceptives by 22 and 14%, respectively, and their peak plasma concentrations by 31 and 18%, respectively.1,8,10,11,12,14,15,18,23 Therefore, the manufacturer states that concurrent use of rufinamide and hormonal contraceptives may make this method of contraception less effective in female patients of childbearing a additional nonhormonal forms of contraception are recommended during rufinamide therapy in such patients.1,10,21

Description

Rufinamide, a triazole derivative, is an anticonvulsant agent that is structurally unrelated to other currently available anticonvulsants.1,6,7,9,10,11,12,13,14,15,16,17,18,21,28 Although the precise mechanism(s) of anticonvulsant action of rufinamide is unknown, results of in vitro studies suggest that the principal mechanism is modulation of sodium channel activity and, in particular, prolongation of the inactive state of the channel.1,6,7,9,10,11,12,13,14,15,16,17,18,21 Rufinamide does not appear to substantially interact with monoaminergic, cholinergic, histaminergic, glycine, γ-aminobutyric acid (GABA), or glutamate receptors or systems.6,7,10,13,14,17,18

Rufinamide is extensively metabolized but has no active metabolites; the primary form of biotransformation is via carboxylesterase-mediated hydrolysis of the carboxylamide group to the acid derivative CGP 47292.1,6,8,10,11,12,13,14,15,16,17,18,21 Cytochrome P-450 (CYP) isoenzymes and glutathione do not appear to be involved in the drug's metabolism.1,6,8,10,12,16,18 At clinically relevant concentrations, rufinamide demonstrates little or no inhibition of most CYP isoenzymes; however, the drug is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4.1,8,11,13,17,18 Following administration of a radiolabeled dose, less than 2% of the dose was recovered in the urine as unchanged drug.1,6,8,10,11,16,17,18 The majority of rufinamide (85% of a radiolabeled dose) is eliminated renally.1,11,12,13,15,16,17,18,21 Rufinamide exhibits a low degree of protein binding (34%), principally to albumin (27%), and has a mean elimination half-life of approximately 6-10 hours.1,6

Advice to Patients

Importance of providing copy of written patient information sheet (medication guide) when rufinamide treatment is begun and each time rufinamide is dispensed.1,20 Importance of advising patients to read the information carefully and to ask their clinician if they have any questions or concerns.1

Importance of patients, family members, and caregivers being aware that anticonvulsants, including rufinamide, may increase the risk of having suicidal thoughts or actions in a very small number of people (about 1 in 500).1,2,20 Advise patients, family members, and caregivers to pay close attention to any day-to-day changes in mood, behavior, and actions; these changes can happen very quickly.1,2 They should also be aware of common warning signs that may signal suicide risk (e.g., talking or thinking about wanting to hurt oneself or end ones life, withdrawing from friends and family, becoming depressed or experiencing worsening of existing depression, becoming preoccupied with death and dying, giving away prized possessions).1,2 Advise patients, family members, and caregivers to contact the responsible clinician immediately if these or any new and worrisome behaviors occur.1,2

Risk of multi-organ hypersensitivity.1 Importance of patients notifying their clinician if a rash either alone or accompanied by fever occurs.1

Importance of taking rufinamide only as prescribed by the clinician.1

Importance of taking rufinamide with food.1 Importance of informing patients that rufinamide tablets may be swallowed whole, broken in half on the score mark, or crushed.1

Importance of instructing patients in proper techniques for administration of the oral suspension, including use of the bottle adapter and oral dosing syringe.1

When applicable, advise patients that rufinamide oral suspension does not contain lactose or gluten and is dye-free.1 The oral suspension does not contain carbohydrates.1

Risk of sleepiness, tiredness, weakness, difficulty with coordination, and dizziness; avoid driving or operating machinery while taking rufinamide until experience is gained with the drug's effects on mental and/or motor performance.1,21

Importance of informing patients that using alcohol or taking other drugs that affect the CNS while taking rufinamide may cause additive CNS effects (e.g., sedation).1,21

Importance of informing patients not to stop taking rufinamide without talking to their clinician since stopping the drug suddenly can cause serious problems, including seizures.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1 Importance of clinicians informing women about the existence of and encouraging enrollment in pregnancy registries (see Pregnancy under Warnings/Precautions: Specific Populations, in Cautions).1 Importance of informing female patients of childbearing age that concomitant use of rufinamide with hormonal contraceptives may make this method of contraception less effective and that additional nonhormonal forms of contraception are recommended when taking rufinamide.1,10,21

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., kidney disease, depression, bipolar disorder) or family history of suicidality or bipolar disorder.1 Importance of informing clinicians of current diagnosis or history of familial short QT syndrome; patients with this condition should not be treated with rufinamide.1

Importance of advising patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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