Banzel

Anticonvulsants, Miscellaneous

 
A MedGuide that provides information about the proper use and risks of rufinamide should be dispensed with each new prescription and refill. The MedGuide also discusses the risk of suicidal thoughts and behaviors associated with the use of anticonvulsant medications.

Administer all dosage forms orally with food.

Tablets may be administered whole, crushed, or halved. Give with food.

Oral Suspension:
Shake well before every use.
Administer with the provided adapter and calibrated oral dosing syringe. Insert adapter firmly into the neck of the bottle before use and keep in place for the duration of the bottle usage.
The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle.
Replace cap after each use. The cap fits properly when the adapter is in place.
Use within 90 days of first opening the bottle, then discard any remaining amount.
Give with food.

AV block / Early / 0.1-1.0
suicidal ideation / Delayed / Incidence not known
seizures / Delayed / Incidence not known
Stevens-Johnson syndrome / Delayed / Incidence not known
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

shortened QT interval / Delayed / 46.0-65.0
constipation / Delayed / 3.0-12.0
nystagmus / Delayed / 6.0-6.0
blurred vision / Early / 6.0-6.0
ataxia / Delayed / 4.0-5.4
nephrolithiasis / Delayed / 0.1-1.0
urinary incontinence / Early / 0.1-1.0
dysuria / Early / 0.1-1.0
bundle-branch block / Early / 0.1-1.0
hematuria / Delayed / Incidence not known
lymphadenopathy / Delayed / Incidence not known
infertility / Delayed / Incidence not known

headache / Early / 16.0-27.0
drowsiness / Early / 11.0-24.0
vomiting / Early / 5.0-24.0
dizziness / Early / 2.7-19.0
fatigue / Early / 9.0-16.0
nausea / Early / 7.0-12.0
cough / Delayed / 12.0-12.0
diplopia / Early / 4.0-9.0
weight loss / Delayed / 8.0-8.0
infection / Delayed / 3.0-8.0
nasal congestion / Early / 8.0-8.0
tremor / Early / 6.0-6.0
influenza / Delayed / 5.0-5.0
pharyngitis / Delayed / 5.0-5.0
vertigo / Early / 3.0-3.0
anxiety / Delayed / 3.0-3.0
dyspepsia / Early / 3.0-3.0
abdominal pain / Early / 3.0-3.0
back pain / Delayed / 3.0-3.0
sinusitis / Delayed / 3.0-3.0
polyuria / Early / 0.1-1.0
nocturia / Early / 0.1-1.0
appetite stimulation / Delayed / 1.0
anorexia / Delayed / 1.0
rash / Early / Incidence not known
pruritus / Rapid / Incidence not known

Banzel

Rx

Triazole derivative anticonvulsant
Used for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome
Approved for use in patients >= 1 year

Initially, 400—800 mg/day PO in 2 equally divided doses. Patients on valproate should begin rufinamide at a dose lower than 400 mg/day. The dosage should be increased every other day by 400—800 mg/day to a target and maximum dose of 3200 mg/day given in 2 equally divided doses. It is not known whether doses less than 3200 mg/day are effective. If drug discontinuation is necessary, rufinamide should be withdrawn gradually (e.g., 25% dose reduction every 2 days) to minimize the potential for increased seizure frequency.

Initially, 10 mg/kg/day PO given as 2 equally divided doses. Pediatric patients receiving valproate should begin rufinamide at a dose lower than 10 mg/kg/day. The dose should be increased every other day by 10 mg/kg to a target dose of 45 mg/kg/day or 3200 mg/day, whichever is less, given in 2 equally divided doses. If drug discontinuation is necessary, rufinamide should be withdrawn gradually (e.g., 25% dose reduction every 2 days) to minimize the potential for increased seizure frequency.

3200 mg/day PO given in 2 divided doses was compared to placebo in a study of approximately 3 months duration (n=313). Subjects in the rufinamide group had a 20.4% decrease in median seizure frequency compared to baseline versus a 1.6% median increase in the placebo group. In a separate study (n=647), subjects were randomized to placebo or rufinamide (200 mg, 400 mg, 800 mg, or 1600 mg/day given in 2 divided doses). Subjects receiving rufinamide experienced a statistically significant reduction in the primary efficacy variable, seizure frequency per 28 days, compared to those receiving placebo. NOTE: For the treatment of seizures associated with Lennox-Gastaut syndrome, the manufacturer recommends dosage titration over several days to the target dose.

†Indicates off-label use

Use in patients with severe hepatic impairment (Child-Pugh score 10—15) is not recommended. Exercise caution in patients with mild (Child-Pugh score 5—6) to moderate (Child-Pugh score 7—9) impairment. Rufinamide has not been studied in patients with hepatic impairment.

No dosage adjustments are needed.
 
Intermittent hemodialysis
Hemodialysis reduces exposure of rufinamide by approximately 30%. This reduction should be considered when dosing rufinamide in patients receiving dialysis.

Amiodarone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as amiodarone, may occur during concurrent use with rufinamide.
Benzhydrocodone; Acetaminophen: (Major) Concomitant use of opioid agonists with rufinamide may cause respiratory depression, hypotension, profound sedation, and death. Limit the use of opioid pain medications with rufinamide to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. If benzhydrocodone is initiated in a patient taking rufinamide, reduce initial dosage and titrate to clinical response. If rufinamide is initiated a patient taking an opioid agonist, use a lower initial dose of rufinamide and titrate to clinical response. Educate patients about the risks and symptoms of respiratory depression and sedation.
Bortezomib: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as bortezomib, may occur during concurrent use with rufinamide.
Buprenorphine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as buprenorphine, may occur during concurrent use with rufinamide.
Buprenorphine; Naloxone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as buprenorphine, may occur during concurrent use with rufinamide.
Busulfan: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as busulfan, may occur during concurrent use with rufinamide.
Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and rufinamide. CNS depressants can potentiate the effects of cannabidiol.
Carbamazepine: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by carbamazepine.
Cenobamate: (Moderate) Use caution when administering cenobamate and rufinamide due to the potential for a synergistic effect on the QT interval that would increase the QT shortening risk. Both cenobamate and rufinamide are associated with QT shortening. Nonclinical data indicate that QT shortening is associated with ventricular fibrillation.
Chlorzoxazone: (Moderate) In theory, plasma concentrations of chlorzoxazone or other CYP2E1 substrates may be increased due to the weak 2E1 inhibitory effects of rufinamide.
Cilostazol: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cilostazol, may occur during concurrent use with rufinamide.
Cisapride: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cisapride, may occur during concurrent use with rufinamide.
Cyclosporine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as cyclosporine, may occur during concurrent use with rufinamide.
Dapsone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as dapsone, may occur during concurrent use with rufinamide.
Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as rufinamide, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
Dextromethorphan; Quinidine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as quinidine, may occur during concurrent use with rufinamide.
Docetaxel: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as docetaxel, may occur during concurrent use with rufinamide.
Donepezil: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as donepezil, may occur during concurrent use with rufinamide.
Donepezil; Memantine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as donepezil, may occur during concurrent use with rufinamide.
Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
Ethosuximide: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as ethosuximide, may occur during concurrent use with rufinamide.
Fosphenytoin: (Moderate) A population pharmacokinetic analysis showed an increase of 7 to 21% in phenytoin concentrations and a decrease of 25 to 46% in rufinamide concentrations during concurrent use. A similar interaction may be expected to occur with fosphenytoin.
Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as rufinamide. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
Isavuconazonium: (Moderate) Use caution when administering rufinamide and isavuconazonium due to the potential for a synergistic effect on the QT interval that would increase the QT shortening risk. Both rufinamide and isavuconazonium are associated with QT shortening. Nonclinical data indicate that QT shortening is associated with ventricular fibrillation.
Lacosamide: (Moderate) Use lacosamide with caution in patients taking concomitant medications that affect cardiac conduction including those that prolong PR interval, such as sodium channel blocking anticonvulsants (e.g., rufinamide), because of the risk of AV block, bradycardia, or ventricular tachyarrhythmia. If use together is necessary, obtain an ECG prior to lacosamide initiation and after treatment has been titrated to steady-state. In addition, monitor patients receiving lacosamide via the intravenous route closely.
Lamotrigine: (Moderate) Shortening of the QT interval has occurred during treatment with rufinamide. Therefore, caution is advisable during co-administration with other drugs associated with QT-shortening including lamotrigine. In addition, a population pharmacokinetic analysis showed a 7% to 13% decrease in lamotrigine concentrations and no effect on rufinamide concentrations during concurrent use.
Macimorelin: (Major) Discontinue rufinamide and allow a sufficient washout period to pass before administering macimorelin. Use of these drugs together can decrease macimorelin plasma concentrations, and may result in a false positive test for growth hormone deficiency. No drug-drug interaction studies have been conducted; however, macimorelin is primarily metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
Midazolam: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as midazolam, may occur during concurrent use with rufinamide.
Molindone: (Moderate) Consistent with the pharmacology of molindone, additive effects may occur with other CNS active drugs such as anticonvulsants. In addition, seizures have been reported during the use of molindone, which is of particular significance in patients with a seizure disorder receiving anticonvulsants. Adequate dosages of anticonvulsants should be continued when molindone is added; patients should be monitored for clinical evidence of loss of seizure control or the need for dosage adjustments of either molindone or the anticonvulsant.
Nanoparticle Albumin-Bound Sirolimus: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sirolimus, may occur during concurrent use with rufinamide.
Nefazodone: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as nefazodone, may occur during concurrent use with rufinamide.
Non-oral combination contraceptives: (Major) Coadministration of hormonal contraceptives with rufinamide may reduce hormone concentrations and therefore reduce the clinical efficacy of hormonal contraceptives. If coadministration is necessary, recommend patients use additional non-hormonal forms of contraception. Hormonal contraceptives are metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
Oral Contraceptives: (Major) Coadministration of hormonal contraceptives with rufinamide may reduce hormone concentrations and therefore reduce the clinical efficacy of hormonal contraceptives. If coadministration is necessary, recommend patients use additional non-hormonal forms of contraception. Hormonal contraceptives are metabolized by CYP3A4 and rufinamide is a weak CYP3A4 inducer.
Paclitaxel: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as paclitaxel, may occur during concurrent use with rufinamide.
Paricalcitol: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as paricalcitol, may occur during concurrent use with rufinamide.
Phenobarbital: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by phenobarbital.
Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Rufinamide is metabolized by carboxylesterases. The clearance of rufinamide may be increased due to induction of carboxylesterases by phenobarbital.
Phenytoin: (Moderate) A population pharmacokinetic analysis showed an increase of 7 to 21% in phenytoin concentrations and a decrease of 25 to 46% in rufinamide concentrations during concurrent use. A similar interaction may be expected to occur with fosphenytoin.
Primidone: (Moderate) A population pharmacokinetic analysis showed a decrease in rufinamide concentrations during concurrent use of primidone.
Quinidine: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as quinidine, may occur during concurrent use with rufinamide.
Quinine: (Minor) The potential interaction between quinine and rufinamide is unpredictable. CYP isozymes 3A4 and, to a lesser extent, 2E1 are involved in quinine metabolism. In theory, plasma concentrations of CYP2E1 substrates may be increased due to the weak 2E1 inhibitory effects of rufinamide. Conversely, the weak CYP3A4 inducer effects of rufinamide may result in decreased exposure of drugs that are metabolized by this isozyme.
Sirolimus: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as sirolimus, may occur during concurrent use with rufinamide.
Stiripentol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of stiripentol and rufinamide. CNS depressants can potentiate the effects of stiripentol.
Tacrolimus: (Minor) Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as tacrolimus, may occur during concurrent use with rufinamide.
Tricyclic antidepressants: (Moderate) Tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, can increase CNS depression and may also lower the seizure threshold, leading to pharmacodynamic interactions. Monitor patients on anticonvulsants carefully when a TCA is used concurrently.
Valproic Acid, Divalproex Sodium: (Major) A population pharmacokinetic analysis showed no effect on valproate concentrations and an increase of less than 16 to 70% in rufinamide concentrations during concurrent use. Adult patients currently stabilized on valproic acid or divalproex should initiate rufinamide therapy at a dosage lower than 400 mg/day, and pediatric patients stabilized on valproate therapy should begin rufinamide at a dose lower than 10 mg/kg/day. Similarly, patients stabilized on rufinamide before being prescribed valproate should initiate valproate therapy at a low dose followed by careful titration.
Zolpidem: (Minor) Rufinamide is a weak inducer of CYP3A4. In theory, decreased exposure of drugs that are extensively metabolized by CYP3A4, such as zolpidem, may occur during concurrent use with rufinamide.

Banzel/Rufinamide Oral Susp: 1mL, 40mg
Banzel/Rufinamide Oral Tab: 200mg, 400mg

3200 mg/day PO.

3200 mg/day PO.

17 years: 3200 mg/day PO.
13—16 years: 45 mg/kg/day PO (Max: 3200 mg/day).

45 mg/kg/day PO (Max: 3200 mg/day).

Safety and efficacy have not been established.

Safety and efficacy have not been established.

Mechanism of Action: The exact mechanism by which rufinamide exerts its anticonvulsant effects is unknown. In vitro data suggest that the drug exerts its therapeutic effects through modulation of sodium channels, primarily through prolongation of the inactive state of the channel. Rufinamide slows sodium channel recovery from inactivation and limits sustained repetitive firing of sodium-dependent action potentials.

Rufinamide is administered orally. The volume of distribution is 50 liters at a dose of 3200 mg/day. Protein-binding is not considered to be clinically relevant (34%). Rufinamide is extensively metabolized in the liver, primarily to an inactive carboxylic acid metabolite produced via enzymatic hydrolysis. Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4. The elimination half-life is 6—10 hours. Less than 2% of a dose is excreted unchanged in the urine.
 
Affected cytochrome P450 isoenzymes and drug transporters: CYP2E1, CYP3A4
Rufinamide is not metabolized through hepatic CYP isozymes; however, it is a weak inhibitor of CYP2E1 and a weak inducer of CYP3A4.

The oral suspension is bioequivalent on a mg per mg basis to the tablet formulation. Following an oral dose, rufinamide tablets are well absorbed (>= 85%) under fed conditions; however, the rate of absorption is slow and the extent of absorption decreases with increasing doses. Food increases the extent of tablet absorption by 34% and peak exposure by 56%. Because clinical trials were conducted under fed conditions, administration with food is recommended. Maximum plasma concentrations occur 4—6 hours after administration under fed and fasted conditions.

There are no adequate data on the developmental risks associated with rufinamide use during human pregnancy. In animal reproduction studies, oral administration of rufinamide resulted in developmental toxicity in pregnant rats and rabbits at clinically relevant doses. Decreased fetal weight and increased incidence of fetal skeletal abnormalities occurred with oral administration of rufinamide (0, 20, 100, or 300 mg/kg/day) to pregnant rats throughout organogenesis. The maternal plasma exposure (AUC) at the no adverse effect dose (20 mg/kg/day) for developmental toxicity was less than that in humans at the maximum recommended human dose (MRHD) of 3,200 mg/day. Embryofetal death, decreased fetal body weight, and increased incidence of fetal visceral and skeletal abnormalities occurred with oral administration of rufinamide (0, 30, 200 and 1,000 mg/kg/day) to pregnant rabbits throughout organogenesis at doses of 200 and 1,000 mg/kg/day. The high dose (1,000 mg/kg/day) was associated with abortion. Plasma exposure (AUC) at the no-adverse effect dose (30 mg/kg/day) was less than that in humans at the MRHD. Decreased offspring growth and survival were observed at all rufinamide doses (0, 5, 30, or 150 mg/kg/day) given to rats throughout pregnancy and lactation. At the lowest dose (5 mg/kg/day), plasma exposure (AUC) was less than that in humans at the MRHD. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to rufinamide; information about the registry can be obtained at www.aedpregnancyregistry.org or by calling 1-888-233-2334.[34590]

There are no data on the presence of rufinamide in human milk, the effects on the breast-fed infant, or the effects on milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for rufinamide and any potential adverse effects on the breast-fed infant from rufinamide or the underlying maternal condition.[34590]