Chain Drug Review, July 27, 2020
FYCOMPA perampanel tablets for oral use CIII FYCOMPA perampanel oral suspension CIII Initial U S Approval 2012 Brief Summary of Full Prescribing Information dated May 2019 WARNING SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS Serious or life threatening psychiatric and behavioral adverse reactions including aggression hostility irritability anger and homicidal ideation and threats have been reported in patients taking FYCOMPA These reactions occurred in patients with and without prior psychiatric history prior aggressive behavior or concomitant use of medications associated with hostility and aggression Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood behavior or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA Closely monitor patients particularly during the titration period and at higher doses FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening WARNINGS AND PRECAUTIONS Serious Psychiatric and Behavioral Reactions In the controlled partial onset seizure clinical trials hostilityand aggression related adverse reactions occurred in 12 and 20 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per 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 partial onset seizure clinical 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 FYCOMPA treated patients and twice as frequently as in placebo treated patients Other symptoms that occurred with FYCOMPA and were more common 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 01 of 4368 FYCOMPA treated patients in controlled and open label trials including non epilepsy trials Homicidal ideation and or threat have also been reported postmarketing in patients treated with FYCOMPA In the partial onset seizure clinical 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 FYCOMPA significantly worsened mood and increased anger Patients taking FYCOMPA should avoid the use of alcohol Similar serious psychiatric and behavioral events were observed in the primary generalized tonic clonic seizure clinical trial 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 patients more often than placebo treated patients 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 1 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 18 95 CI 12 27 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 27863 AED treated patients was 043 compared to 024 among 16029 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 1 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 Indication Placebo Patients with Events per 1000 Patients Drug Patients with 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 Epilepsy 10 34 35 24 Psychiatric 57 85 15 29 Other 10 18 19 09 Total 24 43 18 19 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 Neurologic Effects Dizziness and Gait Disturbance FYCOMPA caused dose related increases in events related to dizziness and disturbance in gait or coordination In the controlled partial onset seizure 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 per day respectively compared to 10 of placebo treated patients The gait disturbance related events including ataxia gait disturbance balance disorder and abnormal coordination were reported in 12 and 16 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day respectively compared to 2 of placebo treated patients Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3 of FYCOMPA treated patients compared to 1 of placebo treated patients These adverse reactions were also observed in the primary generalized tonic clonic seizure clinical trial Somnolence and Fatigue FYCOMPA caused dose dependent increases in somnolence and fatigue related events including fatigue asthenia and lethargy In the controlled partial onset seizure clinical trials 16 and 18 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day respectively reported somnolence compared to 7 of placebo patients In the controlled partial onset seizure clinical trials 12 and 15 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day respectively reported fatigue related events compared to 5 of placebo patients Somnolence or fatiguerelated events led to discontinuation in 2 of FYCOMPA treated patients and 05 of placebo treated patients Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients In the controlled partial onset seizure clinical trials these adverse reactions occurred mostly during the titration phase These adverse reactions were also observed in the primary generalized tonic clonic seizure clinical trial 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 Patients should be carefully observed for signs of central nervous system CNS depression such as somnolence and sedation when FYCOMPA is used with other drugs with sedative properties because of potential additive effects 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 partial onset seizure clinical trials falls were reported in 5 and 10 of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per 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 pediatric patients Drug Reaction with Eosinophilia and Systemic Symptoms DRESS Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms DRESS also known as Multiorgan hypersensitivity has been reported in patients taking antiepileptic drugs including FYCOMPA DRESS may be fatal or life threatening DRESS typically although not exclusively presents with fever rash lymphadenopathy and or facial swelling in association with other organ system involvement such as hepatitis nephritis hematological abnormalities myocarditis or myositis sometimes resembling an acute viral infection Eosinophilia is often present Because this disorder is variable in its expression other organ systems not noted here may be involved It is important to note that early manifestations of hypersensitivity such as fever or lymphadenopathy may be present even though rash is not evident If such signs or symptoms are present the patient should be evaluated immediately FYCOMPA should be discontinued if an alternative etiology for the signs or symptoms cannot be established 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 epilepsy 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 Clinical Trials 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 Partial Onset Seizures Adult and Adolescent Patients 12 years A total of 1038 patients receiving FYCOMPA 2 4 8 or 12 mg once daily constituted the safety population in the pooled analysis of the placebo controlled trials 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 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 per day respectively and 5 in patients randomized to receive placebo The adverse reactions 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 Most Common Adverse Reactions Table 2 gives the incidence in the controlled clinical trials Studies 1 2 and 3 of the adverse reactions that occurred in 2 of patients with partial onset seizures in the FYCOMPA 12 mg dose group and more frequent than placebo in order of decreasing frequency for the 12 mg dose group The most common 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 Placebo Controlled Trials in Adult and Adolescent Patients with Partial Onset Seizures Studies 1 2 and 3 Reactions 2 of Patients in Highest FYCOMPA Dose 12 mg Group and More Frequent than Placebo Placebo n 442 FYCOMPA 4 mg n 172 8 mg n 431 12 mg n 255 Dizziness 9 16 32 43 Somnolence 7 9 16 18 Headache 11 11 11 13 Irritability 3 4 7 12 Fatigue 5 8 8 12 Falls 3 2 5 10 Ataxia 0 1 3 8 Nausea 5 3 6 8 Vertigo 1 4 3 5 Back pain 2 2 2 5 Dysarthria 0 1 3 4 Anxiety 1 2 3 4 Blurred vision 1 1 3 4 Gait disturbance 1 1 4 4 Weight gain 1 4 4 4 Cough 3 1 1 4 Upper respiratory tract infection 3 3 3 4 Vomiting 3 2 3 4 Hypersomnia 0 1 2 3 Anger 1 0 1 3 Aggression 1 1 2 3 Balance disorder 1 0 5 3 Diplopia 1 1 1 3 Head injury 1 1 1 3 Hypoaesthesia 1 0 0 3 Pain in extremity 1 0 2 3 Constipation 2 2 2 3 Myalgia 2 1 1 3 Coordination abnormal 0 1 1 2 Euphoric mood 0 0 1 2
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