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Rufinamide

Pronunciation

(roo FIN a mide)

Index Terms

  • CGP 33101
  • E 2080
  • RUF 331
  • Xilep

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Suspension, Oral:

Banzel: 40 mg/mL (460 mL) [contains methylparaben, propylene glycol, propylparaben; orange flavor]

Tablet, Oral:

Banzel: 200 mg, 400 mg [scored]

Brand Names: U.S.

  • Banzel

Pharmacologic Category

  • Anticonvulsant, Triazole Derivative

Pharmacology

A triazole-derivative antiepileptic whose exact mechanism is unknown. In vitro, it prolongs the inactive state of the sodium channels, thereby limiting repetitive firing of sodium-dependent action potentials mediating anticonvulsant effects.

Absorption

Slow; extensive ≥85%; increased with food

Distribution

Vd: ~50 L

Metabolism

Extensively via carboxylesterase-mediated hydrolysis of the carboxylamide group to CGP 47292 (inactive metabolite); weak inhibitor of CYP2E1 and weak inducer of CYP3A4

Excretion

Urine (85%, ~66% as CGP 47292, 2% as unchanged drug)

Time to Peak

4 to 6 hours

Half-Life Elimination

~6 to 10 hours

Protein Binding

34%, primarily to albumin (27%)

Special Populations: Renal Function Impairment

Patients undergoing dialysis 3 hours postdosing displayed a decrease in AUC and Cmax of 29% and 16%, respectively. Consider adjusting dose for drug loss during dialysis.

Special Populations: Gender

Population pharmacokinetic analyses of women show a 6% to 14% lower apparent Cl of rufinamide compared with men.

Use: Labeled Indications

Lennox-Gastaut syndrome: Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in adults and children 1 year and older

Contraindications

Patients with familial short QT syndrome

Canadian labeling: Additional contraindications (not in U.S. labeling): Family history of short QT syndrome; presence or history of short QT interval; hypersensitivity to rufinamide, triazole derivatives, or any component of the formulation

Dosing: Adult

Lennox-Gastaut syndrome (adjunctive): Oral:

US labeling: Initial: 400 to 800 mg daily in 2 equally divided doses; increase dose by 400 to 800 mg daily every other day to a maximum dose of 3,200 mg daily in 2 equally divided doses

Canadian labeling:

<30 kg: Initial: 200 mg daily in 2 equally divided doses; increase dose by 5 mg/kg/day every 2 weeks until satisfactory control (maximum dose: 1,300 mg daily)

≥30 kg: Initial: 400 mg daily in 2 equally divided doses; increase dose by 5 mg/kg/day every 2 weeks until satisfactory control (maximum dose: 30 to 50 kg: 1,800 mg daily; 50.1 to 70 kg: 2,400 mg daily; ≥70.1 kg: 3,200 mg daily). Note: Dose was increased as frequently as every other day in clinical trials.

Note: Discontinue therapy gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Reducing dose by approximately 25% every 2 days was effective in trials.

Dosage adjustment for concomitant medications: Valproate:

US labeling: Initial rufinamide dose should be <400 mg daily

Canadian labeling: Initial rufinamide dose should be less than the initial daily recommended dosage; however, a specific dosage recommendation is not included in the manufacturer's labeling.

Dosing: Geriatric

Refer to adult dosing. Initiate at the low end of the dosing range; use with caution.

Dosing: Pediatric

Lennox-Gastaut syndrome (adjunctive): Oral:

US labeling:

Children and Adolescents <17 years: Initial: 10 mg/kg/day in 2 equally divided doses; increase dose by ~10 mg/kg every other day to a maximum dose of 45 mg/kg/day, not to exceed 3,200 mg daily in 2 equally divided doses

Adolescents ≥17 years: Refer to adult dosing.

Canadian labeling: Children ≥4 years and Adolescents:

<30 kg: Initial: 200 mg daily in 2 equally divided doses; increase dose by 5 mg/kg/day every 2 weeks until satisfactory control (maximum dose: 1,300 mg daily)

≥30 kg: Initial: 400 mg daily in 2 equally divided doses; increase dose by 5 mg/kg/day every 2 weeks until satisfactory control (maximum dose: 30 to 50 kg: 1,800 mg daily; 50.1 to 70 kg: 2,400 mg daily; ≥70.1 kg: 3,200 mg daily). Note: Dose was increased as frequently as every other day in clinical trials.

Note: Discontinue therapy gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Reducing dose by approximately 25% every 2 days was effective in trials.

Dosage adjustment for concomitant medications: Valproate:

US labeling: Initial rufinamide dose should be <10 mg/kg/day

Canadian labeling: Initial rufinamide dose should be less than the initial daily recommended dosage; however, a specific dosage recommendation is not included in the manufacturer's labeling.

Dosing: Renal Impairment

CrCl <30 mL/minute: No dosage adjustment necessary.

Hemodialysis: There are no dosage adjustments provided in the manufacturer’s labeling. However, consider dosage adjustment for loss of drug.

Dosing: Hepatic Impairment

Mild to moderate impairment (Child-Pugh score 5 to 9): Use with caution.

Severe impairment (Child-Pugh score 10 to 15): There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use is not recommended.

Extemporaneously Prepared

A 40 mg/mL oral suspension may be made using tablets. Crush twelve 400 mg tablets (or twenty-four 200 mg tablets) and reduce to a fine powder. Add 60 mL of Ora-Plus® in incremental proportions until a smooth suspension is obtained; then mix well while adding 60 mL of Ora-Sweet® or Ora-Sweet® SF; transfer to a calibrated bottle. Label "shake well". Stable 90 days at room temperature.

Hutchinson DJ, Liou Y, Best R, et al, "Stability of Extemporaneously Prepared Rufinamide Oral Suspensions," Ann Pharmacother, 2010, 44(3):462-5.20150505

Administration

Administer with food. Tablets may be swallowed whole, split in half, or crushed. Oral suspension should be administered using the provided adapter and calibrated oral syringe; shake well before each dose.

Dietary Considerations

Take with food.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect tablets from moisture. Discard oral suspension within 90 days after opening; cap of bottle fits over the adapter.

Drug Interactions

Alcohol (Ethyl): May enhance the adverse/toxic effect of Rufinamide. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

ARIPiprazole: CYP3A4 Inducers may decrease the serum concentration of ARIPiprazole. Management: Double the oral aripiprazole dose and closely monitor response. Reduce oral aripiprazole dose to 10-15 mg/day (for adults) if the inducer is discontinued. Avoid use of CYP3A4 inducers for more than 14 days with extended-release injectable aripiprazole. Consider therapy modification

CarBAMazepine: Rufinamide may decrease the serum concentration of CarBAMazepine. CarBAMazepine may decrease the serum concentration of Rufinamide. Monitor therapy

CNS Depressants: Rufinamide may enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Ethinyl Estradiol: Rufinamide may decrease the serum concentration of Ethinyl Estradiol. Consider therapy modification

Fosphenytoin: May decrease the serum concentration of Rufinamide. Rufinamide may increase the serum concentration of Fosphenytoin. Monitor therapy

HYDROcodone: CYP3A4 Inducers (Weak) may decrease the serum concentration of HYDROcodone. Monitor therapy

NiMODipine: CYP3A4 Inducers (Weak) may decrease the serum concentration of NiMODipine. Monitor therapy

Norethindrone: Rufinamide may decrease the serum concentration of Norethindrone. Consider therapy modification

PHENobarbital: Rufinamide may increase the serum concentration of PHENobarbital. PHENobarbital may decrease the serum concentration of Rufinamide. Monitor therapy

Phenytoin: Rufinamide may increase the serum concentration of Phenytoin. Phenytoin may decrease the serum concentration of Rufinamide. Monitor therapy

Primidone: May decrease the serum concentration of Rufinamide. Monitor therapy

SAXagliptin: CYP3A4 Inducers may decrease the serum concentration of SAXagliptin. Monitor therapy

Valproate Products: May increase the serum concentration of Rufinamide. Management: Initiate rufinamide at a dose less than 10 mg/kg/day (children) or 400 mg/day (adults) in patients receiving valproic acid. In patients receiving rufinamide, initiate valproic acid at a low dose and titrate based on clinical response. Consider therapy modification

Adverse Reactions

>10%:

Cardiovascular: Shortened QT interval (46% to 65%; dose related)

Central nervous system: Headache (adults 27%, children 16%), drowsiness (11% to 24%), dizziness (3% to 19%), fatigue (9% to 16%)

Gastrointestinal: Vomiting (children 17%, adults 5%), nausea (7% to 12%)

1% to 10%:

Central nervous system: Ataxia (4% to 5%), status epilepticus (≤4%), aggressive behavior (children 3%), anxiety (adults 3%), disturbance in attention (children 3%), hyperactivity (children 3%), vertigo (adults 3%), abnormal gait (1% to 3%), convulsions (children 2%)

Dermatologic: Skin rash (children 4%), pruritus (children 3%)

Gastrointestinal: Decreased appetite (children 5%), constipation (adults 3%), dyspepsia (adults 3%), upper abdominal pain (3%), increased appetite (≥1%)

Hematologic & oncologic: Leukopenia (4%), anemia (1%)

Infection: Influenza (children 5%)

Neuromuscular & skeletal: Tremor (adults 6%), back pain (adults 3%)

Ophthalmic: Diplopia (4% to 9%), blurred vision (adults 6%), nystagmus (adults 6%)

Otic: Otic infection (children 3%), pollakiuria (1%)

Respiratory: Nasopharyngitis (children 5%), bronchitis (children 3%), sinusitis (children 3%)

<1% (Limited to important or life-threatening): Atrioventricular block (first degree), bundle branch block (right), dysuria, hematuria, hypersensitivity (multiorgan), iron-deficiency anemia, lymphadenopathy, nephrolithiasis, neutropenia, nocturia, polyuria, Stevens-Johnson syndrome, suicidal ideation, thrombocytopenia, urinary incontinence

Warnings/Precautions

Concerns related to adverse effects:

• Altered cardiac conduction: Has been associated with shortening of the QT interval. Use caution in patients receiving concurrent medications that shorten the QT interval. Contraindicated in patients with familial short-QT syndrome. Canadian labeling also contraindicates use in patients with a family history of short QT syndrome or presence or history of short QT interval.

• CNS effects: Use has been associated with CNS-related adverse events, most significant of these were cognitive symptoms (including somnolence or fatigue) and coordination abnormalities (including ataxia, dizziness, and gait disturbances). Caution patients about performing tasks which require mental alertness (eg, operating machinery or driving).

• Multiorgan hypersensitivity reactions: Potentially serious, sometimes fatal, multiorgan hypersensitivity reactions (also known as drug reaction with eosinophilia and systemic symptoms [DRESS]) have been reported. Monitor for signs and symptoms (eg, fever, rash, lymphadenopathy, eosinophilia) in association with other organ system involvement (eg, hepatitis, nephritis, hematological abnormalities, myocarditis, myositis). Evaluate immediately if signs or symptoms are present. Discontinuation and conversion to alternate therapy may be required.

• Dermatologic reactions: Potentially serious, sometimes fatal, dermatologic reactions including Stevens-Johnson syndrome (SJS) have been reported; monitor for signs and symptoms of skin reactions; discontinuation and conversion to alternate therapy may be required.

• Leukopenia: Decreased white blood cell count has been reported during treatment.

• Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials ≤24 weeks). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify healthcare provider immediately if symptoms occur.

Disease-related concerns:

• Hepatic impairment: Use with caution in patients with mild-to-moderate impairment; use in not recommended in patients with severe impairment.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Dosage form specific issues:

• Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Zar, 2007).

Other warnings/precautions:

• Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal. Reducing dose by ~25% every two days was effective in trials.

Monitoring Parameters

Seizure (frequency and duration); serum levels of concurrent anticonvulsants; suicidality (eg, suicidal thoughts, depression, behavioral changes); rash (may indicate multi-organ hypersensitivity reactions)

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse effects were seen in animal reproduction studies. Hormonal contraceptives may be less effective with concurrent rufinamide use; additional forms of nonhormonal contraceptives should be used.

Patients exposed to rufinamide during pregnancy are encouraged to enroll themselves into the AED Pregnancy Registry by calling 1-888-233-2334. Additional information is available at www.aedpregnancyregistry.org.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, headache, vomiting, or nausea. Have patient report immediately to prescriber signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of depression (suicidal ideation, anxiety, emotional instability, or illogical thinking), shortness of breath, excessive weight gain, swelling of arms or legs, chills, pharyngitis, enlarged lymph nodes, severe loss of strength and energy, bruising, bleeding, severe muscle pain, severe muscle weakness, severe joint pain, severe joint edema, arrhythmia, lack of appetite, increased hunger, change in balance, abnormal gait, severe dizziness, passing out, tremors, vision changes, seizures, agitation, irritability, panic attacks, mood changes, or signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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