Perampanel (Fycompa) 


Indication: Perampanel (Fycompa) is indicated for use as an adjuvant in treating partial onset seizures with or without secondary generalization in patients with epilepsy ≥12 years of age.1

Pharmacology: Perampanel is a noncompetitive antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors located on postsynaptic neurons.  Glutamate is one of the major neurotransmitters involved in excitatory neurotransmission as well as neurologic disorders due to excessive neuronal excitation. Excessive activation of glutamate receptors, specifically AMPA, has been associated in the pathophysiology of epilepsy.1,2

Clinical Trials: Perampanel’s approval followed the release of three international, multicenter, phase-3 randomized, controlled trials that revealed substantial and statistically significant reductions in seizure frequency in patients with partial onset seizures with or without secondarily generalized seizures. Study 306 identified the minimal effective dose and included four treatment arms (placebo vs perampanel 2 mg, 4 mg, and 8 mg).3 Studies 304 and 305 evaluated an extended-dose range and included three treatment arms (placebo vs perampanel 8 mg and 12 mg).4,5

In the first trial (306), patients in both the 4-mg (P=0.013) and 8-mg (P=0.001) perampanel groups were found to have a higher response rate as well as a decrease in seizure frequency (P=.003 and P<.001, respectively).3 In the second trial (305), response rates of 50% were achieved in 14.7% in the placebo group vs 33.3% in the 8-mg treatment arm and 33.9% in the 12-mg treatment arm. Average percent change in seizure frequency per 28 days during the study was -9.7% for placebo, 30.5% for perampanel 8 mg, and -17.6% for patients on 12 mg perampanel. Ultimately, 15.5% of patients receiving 8 mg of perampanel and 16.5% of patients receiving 12 mg perampanel experienced >75% seizure reduction.5

The last trial (304) recruited 180 patients from different geographic locations and followed the same format as study 305. Response rates were found to be 26.4% for placebo, 36.1% for patients on perampanel 12 mg and 37.6% for patients on perampanel 8 mg. Average percent change in seizure frequency per 28 days during the study was -21% for placebo, -34.5% for patients on 12 mg perampanel, and -26.3% for perampanel 8 mg.4 

The latest extension of the previous trials showed that 1037 of 1186 (87.4%) patients reported at least one treatment-related adverse effect with 73% of those patients classifying the adverse effect as mild to moderate. Higher rates of treatment-related adverse effects were noticed in patients taking higher dose ranges (4 mg-12 mg), specifically those in the >8 mg-12 mg dose range. Serious adverse events occurred in 157 patients of which three died in manners not related to treatment. Ultimately, 346 patients (29.2%) would discontinue therapy primarily as a result of adverse events (125 patients) or due to choice (107 patients).6

Seizure frequency was found to decrease within the first 26 weeks of adjuvant perampanel therapy and was maintained throughout the study. Patients on perampanel adjuvant therapy for at least 1 year (n=588) were found to have a response rate of 47.6%, while those on perampanel therapy for at least 2 years (n=19) had a response rate of 63.2%.6

Warnings/Precautions: Perampanel is not recommended for use in patients with severe hepatic impairment or patients with renal impairment or on hemodialysis. Perampanel is associated with adverse CNS effects, including but not limited to gait disturbances and dizziness. Patients should be advised to use caution when performing tasks that require alertness. Perampanel has been associated with suicidal ideation; monitor patients for any changes in behavior or indications of suicidal ideation. Perampanel has also been associated with serious dose-related behavioral and psychiatric reactions such as aggression, and homicidal thoughts in patients with and without prior psychiatric history.1 As per the Food and Drug Administration’s Black Box warning; “Dose-related serious and/or life-threatening neuropsychiatric events (including aggression, anger, homicidal thoughts, hostility, and irritability) have been reported most often occurring in the first 6 weeks of therapy in patients with or without preexisting psychiatric disease; monitor patients closely, especially during dosage adjustments and when receiving higher doses. Adjust dose or immediately discontinue use if severe or worsening symptoms occur. Inform patients and caregivers to contact their health care provider immediately if they experience any atypical behavioral and/or mood changes.”1

Pregnancy: Perampanel is a pregnancy category C drug. Adverse events were observed in animal studies equivalent to the human dose. Patients taking perampanel should be encouraged to enroll in the North America Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or by going to: http://www.aedpregnancyregistry.org/1

Adverse Reactions: The most common adverse effects associated with perampanel are irritability (4%-12%), headache (13%), fatigue (8%-12%), somnolence (9%-18%), and dizziness (16%-43%). Other adverse effects include psychiatric and behavioral reactions, suicidal ideation, and weight gain.1

Drug Interactions: Perampanel is a CYP3A4 substrate. As such caution should be used when using strong CYP3A inducers as they can decrease perampanel plasma levels, specifically enzyme-inducing AEDs. Concomitant use of enzyme-inducing antiepileptic drugs (AEDs) such as phenytoin, oxcarbazepine, and carbamazepine with perampanel, decreased perampanel plasma concentrations by an estimated 50%-67%; therefore, it is suggested when introducing or withdrawing enzyme-inducing AEDs in therapy that patients be monitored for tolerability and clinical response, with appropriate perampanel dose adjustment if necessary. Contraceptives containing levonorgestrel were found to be less effective when coadministered with perampanel. 1

Dosage and Administration: The recommended starting dose for perampanel is 2 mg by mouth every night at bedtime, with weekly increments of 2 mg based on tolerability and response. The recommended dose range is 8 mg to 12 mg. Patients receiving enzyme-inducing AEDs, the recommended starting dose is 4 mg by mouth every night at bedtime with weekly increments of 2 mg based on tolerability and response. The recommended dose range is 8 mg to 12 mg.1


References

  1. Fycompa [package insert]. Woodcliff Lake, NJ: Eisai Inc.: 2012. http://us.eisai.com/package_inserts/FycompaPI.pdf.
  2. Rogawski MA, Kurzman PS, Yamaguchi SI, Li H. Role of AMPA and GluR5 kainate receptors in the development and expression of amygdala kindling in the mouse. Neuropharmacology. 2000;40(1):28-35.
  3. Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:1408-1415.
  4. French JA, Krauss GL, Biton V, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology. 2012;79:589-596.
  5. French JA, Krauss GL, Steinhoff BJ, et al. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia. 2012;doi: 10.1111/j.1528-1167.2012.03638.x
  6. Krauss GL, Perucca E, Ben-Menachem E, et al. Perampanel, a selective, noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, as adjunctive therapy for refractory partial-onset seizures: interim results from phase III, extension study 307. Epilepsia. 2013;54(1):126-134.


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