FYCOMPA

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Oral Administration
-Administer at bedtime without regard to meals.
Oral Liquid Formulations
Oral suspension
-Shake well before each use.
-Use the provided adapter and graduated oral dosing syringe to administer the dose.
-Storage: Discard any remaining suspension 90 days after bottle opening.

The safety and effectiveness of perampanel in patients 12 years and older was established in 3 placebo-controlled trials, which included 72 adolescents 12 to 16 years of age. Use of perampanel in children 4 to 11 years is supported by safety data from 225 patients; 110 of these patients were exposed to perampanel for at least 6 months and 21 patients were exposed for at least 1 year. The adverse effect profile of perampanel is similar in children 4 to 11 years compared to adolescents and adults. Specific incidence rates for pediatric populations are not available. The most common adverse effects were centrally-mediated. Neurologic adverse effects tended to be dose-related, commonly occurring during dose titration. During partial-onset seizure trials, drug discontinuation as a result of an adverse reaction was 3%, 8%, and 19% in patients 12 years and older receiving perampanel 4 mg, 8 mg, and 12 mg per day, respectively, and 5% in those receiving placebo. Adverse event profiles were similar among both seizure types.

Serious behavioral and psychiatric adverse reactions have occurred during perampanel use, specifically hostility- and aggression-related reactions. During partial-onset seizure clinical trials, 12% and 20% of patients randomized to 8 mg or 12 mg/day of perampanel experienced these behaviors, respectively, compared to 6% of placebo-treated patients. Effects were dose-related, and often began during the first 6 weeks of therapy; however, new events emerged more than 37 weeks after drug initiation in some patients. Irritability was one of the most common adverse events and occurred in 4% (4 mg/day dosage) to 12% (12 mg/day dosage); anger and aggression occurred in up to 3%. Aggression, anger, or irritability led to drug discontinuation in 1% or more of patients taking perampanel 8 mg or 12 mg daily. Serious and life threatening-events including physical assault and homicidal thoughts were noted during trials; homicidal ideation and/or threats occurred in 0.1% of 4,368 patients who received perampanel during controlled and open-label studies, including non-epilepsy studies. Anxiety (2% to 5%), confusion (1% to 2%), euphoria (0% to 2%), and other mood alterations (2% or less) were observed. Belligerence, delusion, disorientation, emotional lability, paranoia, and agitation are also associated with perampanel therapy. Patients with and without prior neuropsychiatric history or concomitant use of medications associated with aggression and hostility experienced these effects. Psychosis (acute psychosis, hallucinations, delusions, paranoia) and delirium (confusion, disorientation, memory impairment) have been reported with postmarketing use. Counsel patients, caregivers, and families about the risk of psychiatric and behavioral reactions with perampanel. Closely monitor patients during treatment, particularly during initial dosage titration, dosage increases, and treatment with higher doses; continue monitoring for a minimum of 1 month after perampanel discontinuation. If symptoms occur, reduce the dose. If persistent severe or worsening symptoms occur, perampanel should be discontinued and the patient should be referred for psychiatric evaluation.

Antiepileptic drugs (AEDs) such as perampanel increase the risk of suicidal ideation and behavior. Monitor all patients beginning treatment with AEDs or currently receiving such treatment closely for emerging or worsening suicidal thoughts/behavior or depression. Patients and caregivers should be informed of the increased risk of suicidal thoughts and behaviors and should be advised to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. A pooled analysis of 199 placebo-controlled trials including 11 different AEDs showed that patients (5 years and older) receiving AEDs had approximately twice the risk of suicidal behavior or ideation (0.43%) as patients receiving placebo (0.24%), with an adjusted relative risk of 1.8 (95% CI 1.2 to 2.7). Four completed suicides occurred in patients treated with AEDs compared to none among controls. The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions. Age was not a determining factor and risk was generally consistent among all AEDs examined. Suicidal ideation or behavior have occurred as early as 1 week after AED initiation and may occur any time during treatment.

Neurologic adverse effects are often dose-related and occur commonly during the titration phase of perampanel therapy. During clinical trials, these effects included dizziness (16% to 43%), gait disturbances (1% to 16%), vertigo (3% to 47%), ataxia (1% to 8%), balance disorder (0% to 5%), abnormal coordination (2% or less), drowsiness (9% to 18%), fatigue (8% to 15%), asthenia (1% to 2%), dysarthria (1% to 4%), and lethargy. Headache was also relatively common, observed in 11% to 13% of patients. Disorders of the senses such as paresthesias and hypoesthesia were reported in up to 2% and 3% of patients, respectively. Other reported reactions include hypersomnia (1% to 3%) and memory impairment (0% to 2%). Falls, likely as a result of neurologic effects, were noted in 2% to 10% of all perampanel treated patients during clinical trials and were more common in the elderly population than in adolescents or adults. Specific fall-related injuries reported included contusion (0% to 6%), head injuries (1% to 3%), limb injuries (1% to 2%), ligament sprain (4%), and skin lacerations (0% to 2%). Patients and caregivers should be counseled, and caution should be exercised during activities requiring coordination and mental alertness (e.g., gymnastics, riding a bicycle, operating a vehicle) until the effects of the drug are known.

Blurred vision (1% to 4%) and diplopia (1% to 3%) were associated with perampanel use during partial-onset seizure clinical trials. Blurred vision led to drug discontinuation in 1% or more of those taking 8 mg or 12 mg daily doses.

Respiratory and infectious adverse reactions have been noted during perampanel use. Cough (1% to 4%), throat irritation or pain (2%), upper respiratory tract infection (3% to 4%), and urinary tract infection (4%) were reported during controlled trials. The relationship of perampanel to these reactions has not been specified.

Various digestive and metabolic adverse effects have been associated with perampanel use. During partial-onset seizure clinical trials, nausea was a dose-related effect occurring in 3%, 6%, and 8% of patients treated with perampanel 4 mg, 8 mg, and 12 mg once daily. Abdominal pain (5%), vomiting (2% to 9%), and constipation (2% to 3%) were also reported. Weight gain was reported in 4% to 7% of patients; an average gain of 1.1 kg in perampanel-treated adults, compared to 0.3 kg with placebo, was observed after a median treatment timeframe of 19 weeks. A total of 9.1% and 0.9% of adults gained at least 7% and 15% of their baseline body weight, respectively. Similar increases in weight were observed in adolescent patients. Monitor patient weight during treatment, regardless of age. Hypertriglyceridemia has occurred with perampanel use. Hyponatremia, which was observed in 2% of patients taking perampanel 12 mg daily, was another metabolic effect noted during pre-marketing clinical trials.

Musculoskeletal adverse events reported during clinical trials with perampanel and include arthralgia (0% to 3%), back pain (2% to 5%), musculoskeletal pain (1% to 2%), myalgia (1% to 3%), and extremity pain (0% to 3%). Peripheral edema was noted in 1% to 2% of patients.

Rash (unspecified) was reported in 4% of patients receiving perampanel during clinical trials. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported with postmarketing use. DRESS may be fatal or life-threatening. Evaluate patients with signs or symptoms of DRESS immediately, and discontinue perampanel if an alternative etiology for symptoms cannot be identified. DRESS typically presents with fever, rash, lymphadenopathy, and/or facial swelling with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis. Eosinophilia is often present. DRESS is variable in expression, and early manifestations of hypersensitivity (e.g., fever or lymphadenopathy) may be present without rash. The first reported case of DRESS attributed to perampanel occurred in a 13-year-old female with drug-resistant epilepsy previously stabilized on lamotrigine and valproic acid over a 2 year period. Perampanel was added for breakthrough negative myoclonic seizures and titrated up to 4 mg once daily after 4 weeks. One week after the dosage increase, the patient developed a fever, cough, and lower extremity erythematous rash. Within 1 week, the patient further presented with symptoms including worsening skin lesions, lethargy, facial swelling, hypotension, leukocytosis, acute renal failure, elevated hepatic enzymes, and acute respiratory distress syndrome. Prominent lesions around the nose and lips showed no skin sloughing or bullae, with a negative Nikolsky sign (ruling out toxic epidermal necrolysis and pemphigus vulgaris). A skin punch biopsy revealed superficial perivascular and interstitial infiltrates, leading to the diagnosis of DRESS, most likely precipitated by perampanel. The patient's medical status improved significantly within 5 days of discontinuing all antiepileptic agents, neurologic function returned to baseline, and she was discharged home after a 3 week hospitalization.

A serious and life-threatening psychiatric event with behavioral changes is associated with the use of perampanel. Exercise great caution when using perampanel in patients with pre-existing aggressive behavior or psychosis, which may be present in patients with schizophrenia, schizoaffective disorder, bipolar disorder, chronic hallucinatory psychosis, or delusional disorder. During clinical trials, reactions such as hostility, agitation, irritability, aggression, anxiety, anger, belligerence, affect lability, and homicidal ideation or threats were observed. Patients with and without prior neuropsychiatric history or concomitant use of medications associated with aggression and hostility experienced these effects. Hostility and aggressive behavior effects are dose-related. In clinical trials, these effects generally appeared within the first 6 weeks of therapy; however, new events continued to occur through more than 37 weeks of therapy. Counsel patients, caregivers, and families about the risk of psychiatric and behavioral reactions with perampanel. Closely monitor patients during treatment, particularly during dose increases and treatment with higher doses, and for a minimum of 1 month after discontinuation. If symptoms occur, reduce the dose. If persistent severe or worsening symptoms occur, perampanel should be discontinued and the patient should be referred for psychiatric evaluation.

There is an increased risk of suicidal ideation and behavior in patients receiving antiepileptic drugs (AEDs). Suicidal ideation or behavior has occurred as early as 1 week after AED initiation and may occur any time during treatment. All patients beginning treatment with perampanel should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Inform patients, caregivers, and families of the increased risk of suicidal thoughts and behaviors and advise them to immediately report the emergence or worsening of depression, the emergence of suicidal thoughts or behavior, thoughts of self-harm, or other unusual changes in mood or behavior. AEDs should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose. A pooled analysis of 199 placebo-controlled clinical studies with a total of 27,863 patients in drug treatment groups and 16,029 patients in placebo groups (5 years of age and older) was conducted. There were 4 completed suicides among patients in drug treatment groups versus none in the placebo groups. Patients receiving AEDs had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo (0.43% vs. 0.24%, respectively; RR 1.8, 95% CI: 1.2 to 2.7). The relative risk for suicidality was higher in patients with epilepsy compared to those with other conditions; however, the absolute risk differences were similar in trials for epilepsy and psychiatric indications. Age was not a determining factor.

Patients taking perampanel should avoid activities requiring coordination and concentration (e.g., gymnastics, riding a bicycle, operation of vehicles) until they are aware of how this medication affects them. An increased risk of falls, in some cases leading to serious injury, occurred in patients taking perampanel during clinical trials. Dose-dependent adverse reactions such as dizziness, gait disturbances, vertigo, abnormal coordination, balance disorder, somnolence, and fatigue have been most often observed during dose titration. A study evaluating the effects of perampanel on psychomotor performance demonstrated that single and multiple doses of 8 mg and 12 mg impaired psychomotor performance in a dose-related manner. Car handling ability was impaired after dosing of 12 mg, but no significant impairment of postural stability was noted. Single and multiple doses of perampanel 4 mg did not impair activities such as driving performance, sensori-motor coordination, or simple psychomotor tasks. Performance results returned to baseline 2 weeks after drug discontinuation.

Like with other antiepileptic drugs (AEDs), the abrupt discontinuation of perampanel may lead to increased seizure activity. When possible, dosage reduction, substitution in therapy, or drug discontinuation should be gradual. Serious adverse reactions may require rapid discontinuation. Perampanel has a half-life of approximately 105 hours and was withdrawn during clinical trials without down-titration; however, small numbers of patients experienced seizures after drug discontinuation. Specific recommendations regarding withdrawal schedules are not available due to insufficient data; gradual withdrawal is recommended by the manufacturer.

Perampanel should not be used in patients with severe hepatic disease. In patients with mild or moderate hepatic impairment, dosage adjustments are recommended.

Perampanel should not be used in patients with renal failure or in those undergoing hemodialysis. In patients with moderate renal impairment, enhanced patient monitoring and slower titration may be necessary.

Perampanel is a controlled substance that can cause physical and psychological dependence and should be used with caution in patients with known, suspected, or a history of substance abuse or drug addiction. During studies of human abuse potential, supra-therapeutic doses of perampanel 24 or 36 mg produced euphoria similar to ketamine 100 mg and alprazolam 3 mg among recreational drug users. Patients taking perampanel 24 mg, 36 mg or ketamine 100 mg had comparable responses on visual analog scales for feeling "high", and those taking perampanel had significantly greater responses than those taking alprazolam 1.5 or 3 mg. Dissociative phenomena, including sensations of "floating", being "spaced out" and "detached" were similar between supra-therapeutic doses of perampanel and ketamine 100 mg, and greater than alprazolam 1.5 or 3 mg.

Description: Perampanel is a selective, non-competitive ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) glutamate receptor antagonist approved for the treatment of partial-onset and primary generalized tonic-clonic seizures. The AMPA receptor is present in nearly all excitatory neurons. Because of perampanel's novel mechanism of action, it may be an effective adjunct medication in patients with refractory partial-onset seizures. Also, though further research is needed, animal models have suggested AMPA receptor antagonist efficacy for status epilepticus resistant to benzodiazepines. Perampanel carries a boxed warning for neuropsychiatric adverse events, which can be life-threatening; the drug is also associated with a high incidence of adverse effects that may affect balance and coordination. Perampanel is FDA-approved for use in patients 4 years and older for partial-onset seizures and 12 years and older for generalized tonic-clonic seizures.

For monotherapy or adjunctive treatment of partial seizures with or without secondary generalization:
Oral dosage:
Children and Adolescents 4 to 17 years: 2 mg PO once daily at bedtime initially; titrate by 2 mg/day increments at weekly intervals based on clinical response and tolerability. The recommended maintenance dosage is 8 to 12 mg/day, although some patients may respond to 4 mg/day. Doses of 12 mg/day have produced greater seizure reduction compared to 8 mg/day; however, substantial increases in adverse events occurred with 12 mg/day dosing. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the adjunctive treatment of primary generalized tonic-clonic seizures:
Oral dosage:
Children and Adolescents 12 to 17 years: 2 mg PO once daily at bedtime initially; titrate by 2 mg/day increments at weekly intervals based on clinical response and tolerability. The recommended maintenance dose is 8 mg/day. If a patient is tolerating 8 mg/day well and requires further seizure control, the dosage may be increased up to 12 mg/day as tolerated. Doses of 12 mg/day have produced greater seizure reduction compared to 8 mg/day; however, substantial increases in adverse events occurred with the higher dosage. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established.
-Infants
Safety and efficacy have not been established.
-Children
1 to 3 years: Safety and efficacy have not been established.
4 to 12 years: 12 mg/day PO.
-Adolescents
12 mg/day PO.

Patients with Hepatic Impairment Dosing
For patients with mild to moderate hepatic impairment, begin with 2 mg/day PO and titrate by 2 mg/day increments no more frequently than every 2 weeks based on clinical response and tolerability. Max: 6 mg/day for mild impairment and 4 mg/day for moderate impairment. Use in patients with severe hepatic impairment is not recommended.

Patients with Renal Impairment Dosing
No dosage adjustment is required in patients with mild renal impairment. Enhanced patient monitoring and slower dosage titration may be necessary in patients with moderate renal impairment. Use is not recommended in patients with severe renal impairment or those undergoing hemodialysis.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Perampanel is a selective, non-competitive antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor that is present on post-synaptic neurons within the central nervous system (CNS). AMPA receptors mediate fast, excitatory neurotransmission and have a critical role in seizure development and spreading. Glutamate, released from pre-synaptic neurons, binds to AMPA receptors, subsequently allowing cations to travel across the post-synaptic membrane and create brief depolarizations termed excitatory post-synaptic potentials. Electrical activity is produced by additive excitatory potentials that generate action potentials fired by the post-synaptic neuron. Although the precise mechanism of perampanel's antiepileptic effects in humans is unknown, the drug has demonstrated inhibition of calcium influx into cultured cortical neurons in a concentration dependent manner; it has been suggested that perampanel reduces neuroexcitation, but does not eliminate it.

Excitatory neurons generally express both AMPA and N-methyl-D-aspartate (NMDA) receptors. Through research of glutamate receptors as therapeutic targets for epilepsy and investigation of NMDA receptors, it was discovered that AMPA receptors are the predominant mediators of synaptic response. AMPA receptor antagonists demonstrate a broader spectrum of anticonvulsant activity than investigational N-methyl-D-aspartate (NMDA) antagonists, display fewer adverse effects, and are effective against fully kindled seizures. Perampanel has demonstrated no effect on kainate or NMDA receptors.

Pharmacokinetics: Perampanel is administered orally. Perampanel is approximately 95% bound to plasma proteins, primarily albumin and alpha 1-acid glycoprotein. Perampanel is primarily metabolized via oxidation primarily mediated by CYP3A4 and/or CYP3A5. Sequential glucuronidation occurs. Elimination occurs in the urine and feces. After a single dose, 22% and 48% of the dose was recovered in the urine and feces, respectively, mainly as a mixture of oxidative and conjugated metabolites. The half-life of perampanel is approximately 105 hours; apparent clearance is approximately 12 mL/minute.

Affected cytochrome P450 isoenzymes: CYP3A4/5, CYP1A2, CYP2B6
Oxidative metabolism of perampanel is mediated primarily by CYP3A4/5 and to a lesser extent CYP1A2 and CYP2B6 based on results of in vitro studies. Other CYP enzymes may also be involved. The concomitant use of known CYP enzyme inducers may decrease perampanel plasma concentrations by approximately 50% to 67%.


-Route-Specific Pharmacokinetics
Oral Route
Perampanel absorption is rapid and complete after oral administration. The bioavailability of the oral suspension is comparable to the tablets under steady state; the formulations may be used interchangeably. Food does not effect the AUC (extent of absorption), but may decrease the rate of absorption. Median Tmax was 0.5 to 2.5 hours under fasting conditions. When co-administered with a high fat meal, Tmax was delayed by 1 to 3 hours, and Cmax was reduced by 11% to 40% when compared to values observed during fasting conditions. The AUC of perampanel increases in a dose-proportional manner after single and multiple doses.


-Special Populations
Pediatrics
There is no significant effect of age or body weight on perampanel clearance.

Hepatic Impairment
After a single dose of perampanel, the AUC of both free and protein bound drug was 50% greater in patients with mild hepatic impairment (Child-Pugh A) and 2.25-fold greater in those with moderate impairment (Child-Pugh B) compared to healthy controls. The AUC of free perampanel in patients with mild or moderate hepatic impairment was 1.8-fold and 3.3-fold higher, respectively, than the AUC in healthy controls. Half-life lengthened from 125 to 306 hours in those with mild hepatic impairment and from 139 to 295 hours in those with moderate hepatic impairment. Patients with severe hepatic impairment have not been studied.

Renal Impairment
Pooled data from patients with partial-onset seizures receiving perampanel up to 12 mg/day during clinical trials indicate that the renal clearance of perampanel decreased by 27% and the AUC increased by 37% in patients with mild renal impairment (CrCl 50 to 80 mL/minute) compared to patients with normal renal function (CrCl > 80 mL/minute). Perampanel has not been studied in patients with severe renal impairment or in those undergoing hemodialysis.

Gender Differences
Perampanel clearance in females (9 mL/minute) was 18% lower than in males (11 mL/minute) in a population pharmacokinetic analysis of patients receiving perampanel during clinical trials; however, no dosage adjustment is necessary based on gender.