<P>Ad Page INDICATIONS AND USAGE FYCOMPA (perampanel) is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy aged 12 years and older. DOSAGE AND ADMINISTRATION Dosing Information In the Absence of Enzyme-Inducing AEDs The recommended starting dosage of FYCOMPA is 2 mg once daily taken orally at bedtime. Increase dosage by 2 mg per day increments no more frequently than every week to a dose of 4 mg to 8 mg once daily taken at bedtime. In elderly patients, dosage increases during titration are recommended no more frequently than every two weeks. The recommended dose range is 8 mg to 12 mg once daily. A dose of 12 mg once daily resulted in somewhat greater reductions in seizure rates than the dose of 8 mg once daily, but with a substantial increase in adverse reactions. Individual dosing should be adjusted based on clinical response and tolerability see Clinical Studies (14). In the Presence of Enzyme-Inducing AEDs The recommended starting dosage of FYCOMPA in the presence of enzyme-inducing AEDs, including phenytoin, carbamazepine, and oxcarbazepine, is 4 mg and patients should be monitored closely for response. Clinical trials revealed a substantially reduced effect on seizure rates in these patients. The reduction in seizure frequency was somewhat greater at 12 mg than at 8 mg see Clinical Studies (14). When these enzyme-inducing AEDs are introduced or withdrawn from a patients treatment regimen, patient should be closely monitored for clinical response and tolerability. Dose adjustment of FYCOMPA may be necessary. Dosage Adjustments in Patients with Hepatic Impairment Based on higher exposure and the longer half-life of perampanel in patients with mild and moderate hepatic impairment, dosage adjustment is recommended. Starting dose should be 2 mg per day with weekly increments of 2 mg per day every two weeks until target dose is achieved. The maximum recommended daily dose is 6 mg for patients with mild hepatic impairment and 4 mg for patients with moderate hepatic impairment. Dose increases in patients with mild and moderate hepatic impairment, as with all patients, should be based on clinical response and tolerability. Use in patients with severe hepatic impairment is not recommended see Use in Specific Populations (8.6), Clinical Pharmacology (12.3). Patients with Renal Impairment FYCOMPA can be used in patients with moderate renal impairment with close monitoring. A slower titration may be considered based on clinical response and tolerability. Use in patients with severe renal impairment or patients undergoing hemodialysis is not recommended see Use in Specific Populations (8.7), Clinical Pharmacology (12.3). CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Serious Psychiatric and Behavioral Reactions In the controlled Phase 3 epilepsy clinical trials, hostility- and aggression-related adverse reactions occurred in 12 and 20 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 6 of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. FYCOMPA-treated patients experienced more hostility- and aggression- related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. In general, in placebo-controlled Phase 3 epilepsy trials, neuropsychiatric events were reported more frequently in patients being treated with FYCOMPA than in patients taking placebo. These events included irritability, aggression, anger, and anxiety which occurred in 2 or greater of perampanel treated patients and twice as frequently as in placebo-treated patients. Other symptoms that were observed with perampanel treatment and more commonly than with placebo, included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1 of 4,368 perampanel treated patients in controlled and open label studies, including non-epilepsy studies. In the Phase 3 epilepsy trials these events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression. Some patients experienced worsening of their pre-existing psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger see Drug Interactions (7.3). Patients taking FYCOMPA should avoid the use of alcohol. In healthy volunteers taking FYCOMPA, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state. In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated subjects more often than placebo-treated subjects included disorientation, delusion, and paranoia. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of FYCOMPA should be reduced if these symptoms occur. Permanently discontinue FYCOMPA for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including FYCOMPA, 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 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. Risk by indication for antiepileptic drugs in the pooled analysis IndicationPlacebo Patients with Events Per 1000 Patients Drug Patientswith Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy1.03.43.52.4 Psychiatric5.78.51.52.9 Other1.01.81.90.9 Total2.44.31.81.9 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 FYCOMPA 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. Neurologic Effects Dizziness and Gait Disturbance FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination see Adverse Reactions (6.1). In the controlled Phase 3 epilepsy clinical trials, dizziness and vertigo were reported in 35 and 47 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 10 of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and coordination abnormal) were reported in 12 and 16 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 2 of placebo-treated patients. These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3 of perampanel-treated subjects compared to 1 of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. Somnolence and Fatigue FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the controlled Phase 3 epilepsy clinical trials, 16 and 18 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported somnolence compared to 7 of placebo patients. In the controlled Phase 3 epilepsy clinical trials, 12 and 15 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, reported fatigue-related events compared to 5 of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2 of perampanel-treated patients and 0.5 of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. Risk Amelioration Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known. In the controlled Phase 3 epilepsy clinical trials these adverse reactions occurred mostly during the titration phase. Falls An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures). In the controlled Phase 3 epilepsy clinical trials, falls were reported in 5 and 10 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg/day, respectively, compared to 3 of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and adolescents. Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. FYCOMPA has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In antiepileptic clinical trials FYCOMPA was withdrawn without down-titration. Although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens. A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered. ADVERSE REACTIONS The following adverse reactions are discussed in more detail in other sections of the prescribing information: • Serious Psychiatric and Behavioral Reactions see Warnings and Precautions (5.1) • Suicidal Behavior and Ideation see Warnings and Precautions (5.2) • Dizziness and Gait Disturbance see Warnings and Precautions (5.3) • Somnolence and Fatigue see Warnings and Precautions (5.3) • Falls see Warnings and Precautions (5.4) Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. A total of 1,038 patients on perampanel (2, 4, 8, or 12 mg once daily) constituted the safety population in the pooled analysis of Phase 3 placebo controlled studies (Studies 1, 2, and 3) in patients with partial onset seizures. Approximately 51 of patients were female and the mean age was 35 years. Adverse Reactions Leading to Discontinuation In controlled Phase 3 clinical trials (Studies 1, 2, and 3), the rate of discontinuation as a result of an adverse reaction was 3, 8 and 19 in patients randomized to receive FYCOMPA at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 5 in patients randomized to receive placebo see Clinical Studies (14). The adverse events most commonly leading to discontinuation (=1 in the 8 mg or 12 mg FYCOMPA group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria see Warnings and Precautions (5.1 and 5.3). Most Common Adverse Reactions Table 2 gives the incidence in the Phase 3 controlled trials (Studies 1, 2, and 3) of the adverse reactions that occurred in =2 of patients with partial-onset seizures in any FYCOMPA dose group. Overall, the most frequently reported dose-related adverse reactions in patients receiving FYCOMPA at doses of 8 mg or 12 mg (=4 and occurring at least 1 higher than the placebo group) included dizziness (36), somnolence (16), fatigue (10), irritability (9), falls (7), nausea (7), ataxia (5), balance disorder (4), gait disturbance (4), vertigo (4), and weight gain (4). For almost every adverse reaction, rates were higher on 12 mg and more often led to dose reduction or discontinuation. Table 2. Adverse Reactions in Pooled Double-blind Trials in Patients with Partial-Onset Seizures (Reactions </p> <UL><LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/1/1/">Front-Cover</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/2/2/">Inside-Front-Cover</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/3/3/">Page-3</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/4/4/">Page-4</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/5/5/">Page-5</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/6/6/">Page-6</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/7/7/">Page-7</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/8/8/">Page-8</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/9/9/">Page-9</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/10/10/">Page-10</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/11/11/">Page-11</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/12/12/">Page-12</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/13/13/">Page-13</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/14/14/">Page-14</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/15/15/">Page-15</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/16/16/">Page-16</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/17/17/">Page-17</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/18/18/">Page-18</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/19/19/">Page-19</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/20/20/">Page-20</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/21/21/">Page-21</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/22/22/">Page-22</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/23/23/">Page-23</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/24/24/">Page-24</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/25/25/">Page-25</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/26/26/">Page-26</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/27/27/">Page-27</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/28/28/">Page-28</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/29/29/">Page-29</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/30/30/">Page-30</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/31/31/">Page-31</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/32/32/">Page-32</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/33/33/">Page-33</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/34/34/">Page-34</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/35/35/">Page-35</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/36/36/">Page-36</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/37/37/">Page-37</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/38/38/">Page-38</a></LI> <LI><a href="http://www.mzines.net/publication/704/lhbdvotqg/39/39/">Back-Cover</a></LI> <LI><a href="http://www.mzines.net/publications/704/x/sitemap.xml" target="_blank">site map</a></LI> </UL>

 

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