Pharmacy & Therapeutics - January 2009 - (Page 27) Pharmaceutical Approval Update Uniqueness of Product: The precise mechanism by which rufinamide exerts its antiepileptic effect is unknown. In vitro studies suggest that the principal mechanism of action is by modulation of the activity of sodium channels and, in particular, by prolongation of the inactive state of the channel. Rufinamide (≥1 μM) significantly slowed sodium channel recovery from inactivation after a prolonged pre-pulse in cultured cortical neurons and limited sustained repetitive firing of sodiumdependent action potentials. Warnings: Suicidal behavior and ideation. Antiepileptic drugs increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients using any antiepileptic drug for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, or any unusual changes in mood or behavior. In pooled analyses of 199 placebo-controlled trials (median duration, 12 weeks), patients randomly assigned to receive an antiepileptic drug had approximately twice the risk of suicidal thinking or behavior compared with patients receiving placebo. In these trials, the estimated incidence of suicidal behavior or ideation among 27,863 treated patients was 0.43%, compared with 0.24% among 16,029 placebo patients (an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated). There were four suicides among the treated patients and none in placebo patients, but the number of events was too small to draw a conclusion about the drug’s effect on suicide. This increased risk was observed as early as one week after treatment started and persisted for at least 24 weeks. Because most trials included in the analysis did not extend beyond 24 weeks, the risk beyond 24 weeks could not be assessed. This risk was consistent among drugs in the data analyzed. The finding of increased risk with antiepileptic drugs of varying mechanisms of action and for a range of indications suggests that the risk applies to all antiepileptic drugs used for any indication. Risk did not vary substantially by age. The relative risk of suicidal thoughts or behavior was higher in trials of epilepsy than in trials of psychiatric disorders or other conditions. Epilepsy and many other illnesses for which antiepileptics are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior arise during treatment, prescribers should consider whether the emergence of these symptoms in a patient might be related to the illness being treated. Patients, their caregivers, and families should be informed that antiepileptic drugs might increase the risk of suicidal thoughts and behavior. Central nervous system reactions. The use of rufinamide has been associated with central nervous system–related adverse reactions. The most significant of these can be classified into the categories of (1) somnolence or fatigue and (2) coordination abnormalities, dizziness, gait disturbances, and ataxia. Precautions: In electrocardiographic studies, shortening of the QT interval (up to 20 msec) occurred with rufinamide. In one study, a higher percentage of rufinamide-treated subjects (46% receiving 2,400 mg, 46% receiving 3,200 mg, and 65% receiving 4,800 mg) experienced a QT shortening of more than 20 msec at the time to maximum concentration, compared with placebo (5%–10%). Reductions of the QT interval below 300 msec were not observed in the QT studies with doses up to 7,200 mg/day. Moreover, there was no signal for druginduced sudden death or ventricular arrhythmias. The degree of QT shortening induced by rufinamide is not linked to 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. Nonclinical data also indicate that QT shortening is associated with ventricular fibrillation. Patients with familial short QT syndrome should not use rufinamide. Caution should be used when rufinamide is given with other drugs that shorten the QT interval. Multiorgan hypersensitivity reactions. A serious condition sometimes induced by antiepileptic drugs, multiorgan hypersensitivity syndrome has occurred in association with rufinamide. One patient experienced rash, urticaria, facial edema, fever, elevated eosinophils, a stuporous state, and severe hepatitis beginning on day 29 of therapy and extending over a course of 30 days of continued therapy; symptoms resolved 11 days after therapy was discontinued. Rash, fever, elevated liver enzymes, hematuria, and lymphadenopathy were also noted. These cases occurred in children younger than 12 years of age within four weeks of starting treatment and resolved or improved upon discontinuation of therapy. This syndrome has been reported with other anticonvulsants. Patients sometimes present with fever and rash associated with other organ system involvement. Because this disorder is variable in expression, other organ system signs and symptoms may occur. If this reaction is suspected, rufinamide should be discontinued and a different treatment should be started. If a rash develops, the patient must be closely supervised. Withdrawal of antiepileptic drugs. As with all antiepileptic drugs, rufinamide should be withdrawn gradually to minimize the risk of precipitating or exacerbating seizures or status epilepticus. If the drug must be stopped abruptly, the transition to another drug should be closely supervised. In clinical trials, discontinuation was achieved by reducing the dose by approximately 25% every two days. Status epilepticus. It is difficult to estimate the incidence of treatment-emergent status epilepticus among the rufinamide patients because standard definitions were not employed. In a controlled trial involving patients with Lennox–Gastaut syndrome, three of 74 rufinamide-treated patients (4.1%) had status epilepticus–like episodes compared with none of the 64 placebo patients. In all controlled trials that included patients with different types of epilepsy, 11 of 1,240 rufinamide-treated patients (0.9%) had episodes that could be described as status epilepticus, compared with none of 635 placebo patients. Dosage and Administration: The tablets are scored on both sides. They can be taken whole, as half-tablets, or crushed. Rufinamide should be taken with food. Children four years of age and older with Lennox– Gastaut syndrome: Initial treatment should be a daily dose of approximately 10 mg/kg per day, given in two equally Vol. 34 No. 1 • January 2009 • P&T® 27
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