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Banzel

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Banzel

Banzel

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including Banzel (rufinamide tablets) , increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1: Absolute and Relative Risk of Suicidal Behavior and Ideation

Indication Placebo Patients with Events Per1000 Patients Drug Patients with Events Per1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy 1.0 3.4 3.5 2.4
Psychiatric 5.7 8.5 1.5 2.9
Other 1.0 1.8 1.9 0.9
Total 2.4 4.3 1.8 1.9

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing Banzel (rufinamide tablets) or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

Central Nervous System Reactions

Use of BANZEL (rufinamide tablets) has been associated with central nervous system-related adverse reactions. The most significant of these can be classified into two general categories: 1) somnolence or fatigue, and 2) coordination abnormalities, dizziness, gait disturbances, and ataxia [see ADVERSE REACTIONS].

QT Shortening

Formal cardiac ECG studies demonstrated shortening of the QT interval (mean = 20 msec, for doses > 2400 mg twice daily) with BANZEL (rufinamide tablets) treatment. In a placebo-controlled study of the QT interval, a higher percentage of BANZEL (rufinamide tablets) -treated subjects (46% at 2400 mg, 46% at 3200 mg, and 65% at 4800 mg) had a QT shortening of greater than 20 msec at Tmax compared to placebo (5 – 10%).

Reductions of the QT interval below 300 msec were not observed in the formal QT studies with doses up to 7200 mg/day. Moreover, there was no signal for drug-induced sudden death or ventricular arrhythmias.

The degree of QT shortening induced by BANZEL (rufinamide tablets) is without any known clinical risk. Familial Short QT syndrome is associated with an increased risk of sudden death and ventricular arrhythmias, particularly ventricular fibrillation. Such events in this syndrome are believed to occur primarily when the corrected QT interval falls below 300 msec. Non-clinical data also indicate that QT shortening is associated with ventricular fibrillation.

Patients with Familial Short QT syndrome should not be treated with BANZEL (rufinamide tablets) . Caution should be used when administering BANZEL (rufinamide tablets) with other drugs that shorten the QT interval [see CONTRAINDICATIONS].

Multi-organ Hypersensitivity Reactions

Multi-organ hypersensitivity syndrome, a serious condition sometimes induced by antiepileptic drugs, has occurred in association with BANZEL (rufinamide tablets) therapy in clinical trials. One patient experienced rash, urticaria, facial edema, fever, elevated eosinophils, stuperous state, and severe hepatitis, beginning on day 29 of BANZEL (rufinamide tablets) therapy and extending over a course of 30 days of continued BANZEL (rufinamide tablets) therapy with resolution 11 days after discontinuation. Additional possible cases presented with rash and one or more of the following: fever, elevated liver function studies, hematuria, and lymphadenopathy. These cases occurred in children less than 12 years of age, within four weeks of treatment initiation, and were noted to resolve and/or improve upon BANZEL (rufinamide tablets) discontinuation. This syndrome has been reported with other anticonvulsants and typically, although not exclusively, presents with fever and rash associated with other organ system involvement. Because this disorder is variable in its expression, other organ system signs and symptoms not noted here may occur. If this reaction is suspected, BANZEL (rufinamide tablets) should be discontinued and alternative treatment started.

All patients who develop a rash while taking BANZEL (rufinamide tablets) must be closely supervised.

Withdrawal of AEDs

As with all antiepileptic drugs, BANZEL (rufinamide tablets) should be withdrawn gradually to minimize the risk of precipitating seizures, seizure exacerbation, or status epilepticus. If abrupt discontinuation of the drug is medically necessary, the transition to another AED should be made under close medical supervision. In clinical trials, BANZEL (rufinamide tablets) discontinuation was achieved by reducing the dose by approximately 25% every two days.

Status Epilepticus

Estimates of the incidence of treatment emergent status epilepticus among patients treated with BANZEL (rufinamide tablets) are difficult because standard definitions were not employed. In a controlled Lennox-Gastaut syndrome trial, 3 of 74 (4.1 %) BANZEL (rufinamide tablets) -treated patients had episodes that could be described as status epilepticus in the BANZEL (rufinamide tablets) -treated patients compared with none of the 64 patients in the placebo-treated patients. In all controlled trials that included patients with different epilepsies, 11 of 1240 (0.9%) BANZEL (rufinamide tablets) -treated patients had episodes that could be described as status epilepticus compared with none of 635 patients in the placebo-treated patients.

Laboratory Tests

Leucopenia (white cell count < 3X109 L) was more commonly observed in BANZEL (rufinamide tablets) -treated patients (43 of 1171, 3.7%) than placebo-treated patients (7 of 579, 1.2%) in all controlled trials.

Patient Counseling Information

Patients should be informed of the availability of a Medication guide and they should be instructed to read the Medication Guide prior to taking BANZEL (rufinamide tablets) .

Patients should be instructed to take BANZEL (rufinamide tablets) only as prescribed.

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be informed that antiepileptic drugs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.

As with all centrally acting medications, alcohol in combination with BANZEL (rufinamide tablets) may cause additive central nervous system effects.

Patients should be advised to notify their physician if they experience a rash associated with fever.

BANZEL (rufinamide tablets) should be taken with food.

Patients should be advised about the potential for somnolence or dizziness and advised not to drive or operate machinery until they have gained sufficient experience on BANZEL (rufinamide tablets) to gauge whether it adversely affects their mental and/or motor performance.

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 [see DRUG INTERACTIONS]. Additional non-hormonal forms of contraception are recommended when using BANZEL (rufinamide tablets) .

Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. They should also be encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant. To enroll, patients can call the toll free number 1-888-233-2334 [see Use In Specific Populations].

Patients should be advised to notify their physician if they are breast-feeding or intend to breast-feed.

Patients who are prescribed the oral suspension should be advised to shake the bottle vigorously before every administration and to use the adaptor and oral dosing syringe.

When applicable patients should be advised that Banzel (rufinamide tablets) oral suspension does not contain lactose or gluten and is dye-free. The oral suspension does contain carbohydrates.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Rufinamide was given in the diet to mice at 40, 120, and 400 mg/kg/day and to rats at 20, 60, and 200 mg/kg/day for two years. The doses in mice were associated with plasma AUCs 0.1 to 1 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Increased incidences of tumors (benign bone tumors (osteomas) and/or hepatocellular adenomas and carcinomas) were observed in mice at all doses. Increased incidences of thyroid follicular adenomas were observed in rats at all but the low dose; the low dose is < 0.1 times the MRHD on a mg/m² basis.

Mutagenesis

Rufinamide was not mutagenic in the in vitro bacterial reverse mutation (Ames) assay or the in vitro mammalian cell point mutation assay. Rufinamide was not clastogenic in the in vitro mammalian cell chromosomal aberration assay or the in vivo rat bone marrow micronucleus assay.

Impairment of Fertility

Oral administration of rufinamide (doses of 20, 60, 200, and 600 mg/kg/day) to male and female rats prior to mating and throughout mating, and continuing in females up to day 6 of gestation resulted in impairment of fertility (decreased conception rates and mating and fertility indices; decreased numbers of corpora lutea, implantations, and live embryos; increased preimplantation loss; decreased sperm count and motility) at all doses tested. Therefore, a no-effect dose was not established. The lowest dose tested was associated with a plasma AUC ≈ 0.2 times the human plasma AUC at the MRHD.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. BANZEL (rufinamide tablets) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Rufinamide produced developmental toxicity when administered orally to pregnant animals at clinically relevant doses.

Rufinamide was administered orally to rats at doses of 20, 100, and 300 mg/kg/day and to rabbits at doses of 30, 200, and 1000 mg/kg/day during the period of organogenesis (implantation to closure of the hard palate); the high doses are associated with plasma AUCs ≈2 times the human plasma AUC at the maximum recommended human dose (MRHD, 3200 mg/day). Decreased fetal weights and increased incidences of fetal skeletal abnormalities were observed in rats at doses associated with maternal toxicity. In rabbits, embryo-fetal death, decreased fetal body weights, and increased incidences of fetal visceral and skeletal abnormalities occurred at all but the low dose. The highest dose tested in rabbits was associated with abortion. The no-effect doses for adverse effects on rat and rabbit embryo-fetal development (20 and 30 mg/kg/day, respectively) were associated with plasma AUCs ≈ 0.2 times that in humans at the MRHD.

In a rat pre- and post-natal development study (dosing from implantation through weaning) conducted at oral doses of 5, 30, and 150 mg/kg/day (associated with plasma AUCs up to ≈1.5 times that in humans at the MRHD), decreased offspring growth and survival were observed at all doses tested. A no-effect dose for adverse effects on pre- and post-natal development was not established. The lowest dose tested was associated with plasma AUC < 0.1 times that in humans at the MRHD.

Pregnancy Registry

To provide information regarding the effects of in utero exposure to Banzel (rufinamide tablets) physicians are advised to recommend that pregnant patients taking BANZEL (rufinamide tablets) enroll in the North American Antiepileptic Drug Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

Labor and Delivery

The effect of BANZEL (rufinamide tablets) on labor and delivery in humans is not known.

Nursing Mothers

Rufinamide is likely to be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from BANZEL (rufinamide tablets) , a decision should be made whether to discontinue nursing or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use

The safety and effectiveness in patients with Lennox-Gastaut syndrome have not been established in children less than 4 years. The pharmacokinetics of rufinamide in the pediatric population (age 4-17 years) is similar to that in the adults [see CLINICAL PHARMACOLOGY]

Geriatric Use

Clinical studies of BANZEL (rufinamide tablets) did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Pharmacokinetics of rufinamide in the elderly are similar to that in the young subjects [see CLINICAL PHARMACOLOGY]

Renal Impairment: Rufinamide pharmacokinetics in patients with severe renal impairment (creatinine clearance < 30 mL/min) was similar to that of healthy subjects. Dose adjustment in patients undergoing dialysis should be considered [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY].

Hepatic Impairment

There have been no specific studies investigating the effect of hepatic impairment on the pharmacokinetics of rufinamide. Therefore, use in patients with severe hepatic impairment is not recommended. Caution should be exercised in treating patients with mild to moderate hepatic impairment [see DOSAGE AND ADMINISTRATION].

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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