Perampanel

WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS 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 perampanel ( 5.1). These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression ( 5.1). 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 perampanel or after discontinuing perampanel ( 5.1). Closely monitor patients particularly during the titration period and at higher doses ( 5.1). Perampanel should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening ( 5.1). WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS See full prescribing information for complete boxed warning. 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 perampanel ( 5.1) Monitor patients for these reactions as well as for changes in mood, behavior, or personality that are not typical for the patient, particularly during the titration period and at higher doses ( 5.1) Perampanel should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening ( 5.1)

5 WARNINGS AND PRECAUTIONS Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior ( 5.2 ) Neurologic Effects: Monitor for dizziness, gait disturbance, somnolence, and fatigue ( 5.3 ) Patients should use caution when driving or operating machinery ( 5.3 ) Falls: Monitor for falls and injuries ( 5.4 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.5 ) Withdrawal of Antiepileptic Drugs: In patients with epilepsy, there may be an increase in seizure frequency ( 5.6 ) 5.1 Serious Psychiatric and Behavioral Reactions In the controlled partial-onset seizure clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive perampanel 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. Perampanel-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 perampanel 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 occurred with perampanel 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 0.1% of 4,368 perampanel-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 perampanel. 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 perampanel significantly worsened mood and increased anger. Patients taking perampanel should avoid the use of alcohol [see Drug Interactions (7.3) ]. Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic seizure clinical trial. In healthy volunteers taking perampanel, 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. In the postmarketing setting, there have been reports of psychosis (acute psychosis, hallucinations, delusions, paranoia) and delirium (delirium, confusional state, disorientation, memory impairment) in patients treated with perampanel [see Adverse Reactions (6.2) ] . Patients, their caregivers, and families should be informed that perampanel may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least 1 month after the last dose of perampanel, 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 perampanel should be reduced if these symptoms occur. Permanently discontinue perampanel for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including perampanel, 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 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 to 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 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 perampanel 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. 5.3 Neurologic Effects Dizziness and Gait Disturbance Perampanel caused dose-related increases in events related to dizziness and disturbance in gait or coordination [see Adverse Reactions (6.1) ]. In the controlled partial-onset seizure clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive perampanel 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 perampanel 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 perampanel-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 Perampanel 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 perampanel 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 perampanel at doses of 8 mg and 12 mg per 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 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 perampanel is known. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when perampanel is used with other drugs with sedative properties because of potential additive effects. 5.4 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 perampanel (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 perampanel 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 perampanel-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and pediatric patients. 5.5 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 perampanel. 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. Perampanel should be discontinued if an alternative etiology for the signs or symptoms cannot be established. 5.6 Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. Perampanel has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In epilepsy clinical trials perampanel 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.

<table width="80%"><caption>Table 1. Risk by indication for antiepileptic drugs in the pooled analysis</caption><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><col width="20%" align="left" valign="middle"/><thead><tr><th styleCode="Lrule Rrule">Indication</th><th styleCode="Rrule">Placebo Patients with Events per 1000 Patients</th><th styleCode="Rrule">Drug Patients with Events per 1000 patients</th><th styleCode="Rrule">Relative Risk: Incidence of Events in drug Patients/Incidence in Placebo Patients </th><th styleCode="Rrule">Risk Difference: Additional Drug Patients with Events per 1000 Patients </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Epilepsy</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">3.4</td><td styleCode="Rrule">3.5</td><td styleCode="Rrule">2.4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Psychiatric</td><td styleCode="Rrule">5.7</td><td styleCode="Rrule">8.5</td><td styleCode="Rrule">1.5</td><td styleCode="Rrule">2.9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Other</td><td styleCode="Rrule">1.0</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.9</td><td styleCode="Rrule">0.9</td></tr><tr><td styleCode="Lrule Rrule">Total</td><td styleCode="Rrule">2.4</td><td styleCode="Rrule">4.3</td><td styleCode="Rrule">1.8</td><td styleCode="Rrule">1.9</td></tr></tbody></table>

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Serious Psychiatric and Behavioral Reactions [see Warnings and Precautions (5.1) ] Suicidal Behavior and Ideation [see Warnings and Precautions (5.2) ] Neurologic Effects [see Warnings and Precautions (5.3) ] Falls [see Warnings and Precautions (5.4) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.5) ] Most common adverse reactions (≥5% and ≥1% higher than placebo) include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 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 of age and older) A total of 1,038 patients receiving perampanel (2 mg, 4 mg, 8 mg, 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 perampanel at the recommended doses of 4 mg, 8 mg, and 12 mg per day, respectively, and 5% in patients randomized to receive placebo [see Clinical Studies (14) ]. The adverse reactions most commonly leading to discontinuation (≥1% in the 8 mg or 12 mg perampanel group and greater than placebo) were dizziness, somnolence, vertigo, aggression, anger, ataxia, blurred vision, irritability, and dysarthria [see Warnings and Precautions (5.1 , 5.3) ]. 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 perampanel 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 perampanel 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 Perampanel Dose (12 mg) Group and More Frequent than Placebo) Placebo n=442 % Perampanel Tablets 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 Confusional state <1 1 1 2 Hyponatremia <1 0 0 2 Limb injury <1 1 1 2 Mood altered <1 1 <1 2 Arthralgia 1 0 3 2 Asthenia 1 1 2 2 Contusion 1 0 2 2 Memory impairment 1 0 1 2 Musculoskeletal pain 1 1 1 2 Oropharyngeal pain 1 2 2 2 Paraesthesia 1 0 1 2 Peripheral edema 1 1 1 2 Skin laceration 1 0 2 2 Pediatric Patients (4 to <12 years of age) In two studies in pediatric patients 4 to <12 years of age with epilepsy, a total of 225 patients received perampanel, with 110 patients exposed for at least 6 months, and 21 patients for at least 1 year. Adverse reactions in pediatric patients 4 to <12 years of age were similar to those seen in patients 12 years of age and older. Primary Generalized Tonic-Clonic Seizures A total of 81 patients receiving perampanel 8 mg once daily constituted the safety population in the placebo-controlled trial in patients with primary generalized tonic-clonic seizures (Study 4). Approximately 57% of patients were female, and the mean age was 27 years. In the controlled primary generalized tonic-clonic seizure clinical trial (Study 4), the adverse reaction profile was similar to that noted for the controlled partial-onset seizure clinical trials (Studies 1, 2, and 3). Table 3 gives the incidence of adverse reactions in patients receiving perampanel 8 mg (≥4% and higher than in the placebo group) in Study 4. The most common adverse reactions in patients receiving perampanel (≥10% and greater than placebo) were dizziness (32%), fatigue (15%), headache (12%), somnolence (11%), and irritability (11%). The adverse reactions most commonly leading to discontinuation in patients receiving perampanel 8 mg (≥2% and greater than placebo) were vomiting (2%) and dizziness (2%). Table 3. Adverse Reactions in a Placebo-Controlled Trial in Patients with Primary Generalized Tonic-Clonic Seizures (Study 4) (Reactions ≥4% of Patients in Perampanel Group and More Frequent than Placebo) Placebo n=82 % Perampanel 8 mg n=81 % Dizziness 6 32 Fatigue 6 15 Headache 10 12 Somnolence 4 11 Irritability 2 11 Vertigo 2 9 Vomiting 2 9 Weight gain 4 7 Contusion 4 6 Nausea 5 6 Abdominal pain 1 5 Anxiety 4 5 Urinary tract infection 1 4 Ligament sprain 0 4 Balance disorder 1 4 Rash 1 4 Weight Gain Weight gain has occurred with perampanel. In controlled partial-onset seizure clinical trials, perampanel-treated adults gained an average of 1.1 kg (2.5 lbs) compared to an average of 0.3 kg (0.7 lbs) in placebo-treated adults with a median exposure of 19 weeks. The percentages of adults who gained at least 7% and 15% of their baseline body weight in perampanel-treated patients were 9.1% and 0.9%, respectively, as compared to 4.5% and 0.2% of placebo-treated patients, respectively. Clinical monitoring of weight is recommended. Similar increases in weight were also observed in adult and adolescent patients treated with perampanel in the primary generalized tonic-clonic seizure clinical trial. Elevated triglycerides Increases in triglycerides have occurred with perampanel use. Comparison of Sex and Race No significant sex differences were noted in the incidence of adverse reactions. Although there were few non-Caucasian patients, no differences in the incidence of adverse reactions compared to Caucasian patients were observed. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of perampanel. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Dermatologic : Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) [see Warnings and Precautions (5.5) ] Psychiatric : Acute psychosis, hallucinations, delusions, paranoia, delirium, confusional state, disorientation, memory impairment [see Warnings and Precautions (5.1) ] .

<table width="90%"><caption>Table 2. Adverse Reactions in Pooled Placebo-Controlled Trials in Adult and Adolescent Patients with Partial-Onset Seizures (Studies 1, 2, and 3) (Reactions &#x2265; 2% of Patients in Highest Perampanel Dose (12 mg) Group and More Frequent than Placebo)</caption><col width="35%" align="left" valign="top"/><col width="17%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><col width="16%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th rowspan="2" styleCode="Rrule" valign="bottom">Placebo n=442 % </th><th colspan="3" styleCode="Rrule Botrule">Perampanel Tablets</th></tr><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">4 mg n=172 % </th><th styleCode="Rrule">8 mg n=431 % </th><th styleCode="Rrule">12 mg n=255 % </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">9</td><td styleCode="Rrule">16</td><td styleCode="Rrule">32</td><td styleCode="Rrule">43</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Somnolence</td><td styleCode="Rrule">7</td><td styleCode="Rrule">9</td><td styleCode="Rrule">16</td><td styleCode="Rrule">18</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">11</td><td styleCode="Rrule">11</td><td styleCode="Rrule">11</td><td styleCode="Rrule">13</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Irritability</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td><td styleCode="Rrule">7</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">5</td><td styleCode="Rrule">8</td><td styleCode="Rrule">8</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Falls</td><td styleCode="Rrule">3</td><td styleCode="Rrule">2</td><td styleCode="Rrule">5</td><td styleCode="Rrule">10</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Ataxia</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">5</td><td styleCode="Rrule">3</td><td styleCode="Rrule">6</td><td styleCode="Rrule">8</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vertigo</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">3</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Back pain</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dysarthria</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anxiety</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Blurred vision</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Gait disturbance</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight gain</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Cough</td><td styleCode="Rrule">3</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Upper respiratory tract infection</td><td styleCode="Rrule">3</td><td styleCode="Rrule">3</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">3</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypersomnia</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anger</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Aggression</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Balance disorder</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">5</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Diplopia</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Head injury</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hypoaesthesia</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Pain in extremity</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Constipation</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Myalgia</td><td styleCode="Rrule">2</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">3</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Coordination abnormal</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Euphoric mood</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Confusional state</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Hyponatremia</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Limb injury</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Mood altered</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">&lt;1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Arthralgia</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">3</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Asthenia</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Contusion</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Memory impairment</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Musculoskeletal pain</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Oropharyngeal pain</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Paraesthesia</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Peripheral edema</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">1</td><td styleCode="Rrule">2</td></tr><tr><td styleCode="Lrule Rrule">Skin laceration</td><td styleCode="Rrule">1</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2</td><td styleCode="Rrule">2</td></tr></tbody></table>

<table width="80%"><caption>Table 3. Adverse Reactions in a Placebo-Controlled Trial in Patients with Primary Generalized Tonic-Clonic Seizures (Study 4) (Reactions &#x2265;4% of Patients in Perampanel Group and More Frequent than Placebo)</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Lrule Rrule"/><th styleCode="Rrule">Placebo n=82 % </th><th styleCode="Rrule">Perampanel 8 mg n=81 % </th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Dizziness</td><td styleCode="Rrule">6</td><td styleCode="Rrule">32</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Fatigue</td><td styleCode="Rrule">6</td><td styleCode="Rrule">15</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Headache</td><td styleCode="Rrule">10</td><td styleCode="Rrule">12</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Somnolence</td><td styleCode="Rrule">4</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Irritability</td><td styleCode="Rrule">2</td><td styleCode="Rrule">11</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vertigo</td><td styleCode="Rrule">2</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Vomiting</td><td styleCode="Rrule">2</td><td styleCode="Rrule">9</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Weight gain</td><td styleCode="Rrule">4</td><td styleCode="Rrule">7</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Contusion</td><td styleCode="Rrule">4</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Nausea</td><td styleCode="Rrule">5</td><td styleCode="Rrule">6</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Abdominal pain</td><td styleCode="Rrule">1</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Anxiety</td><td styleCode="Rrule">4</td><td styleCode="Rrule">5</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Urinary tract infection</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Ligament sprain</td><td styleCode="Rrule">0</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule">Balance disorder</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule"/><td styleCode="Rrule"/><td styleCode="Rrule"/></tr><tr><td styleCode="Lrule Rrule">Rash</td><td styleCode="Rrule">1</td><td styleCode="Rrule">4</td></tr></tbody></table>