Chemical formula: C₂₃H₁₅N₃O Molecular mass: 349.393 g/mol PubChem compound: 9924495
Perampanel interacts in the following cases:
In healthy subjects, the CYP3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased perampanel AUC by 20% and prolonged perampanel half-life by 15% (67.8 h vs 58.4 h). Larger effects cannot be excluded when perampanel is combined with a CYP3A inhibitor with longer half-life than ketoconazole or when the inhibitor is given for a longer treatment duration.
In healthy subjects, perampanel (6 mg once daily for 20 days) decreased midazolam AUC by 13%. A larger decrease in exposure of midazolam (or other sensitive CYP3A substrates) at higher perampanel doses cannot be excluded.
The effects of perampanel on tasks involving alertness and vigilance such as driving ability were additive or supra-additive to the effects of alcohol itself, as found in a pharmacodynamic interaction study in healthy subjects. Multiple dosing of perampanel 12 mg/day increased levels of anger, confusion, and depression as assessed using the Profile of Mood State 5-point rating scale. These effects may also be seen when perampanel is used in combination with other central nervous system (CNS) depressants.
Use in patients with moderate or severe renal impairment or patients undergoing haemodialysis is not recommended.
Dose increases in patients with mild and moderate hepatic impairment should be based on clinical response and tolerability. For patients with mild or moderate hepatic impairment, dosing can be initiated at 2 mg. Patients should be up-titrated using 2 mg doses no faster than every 2 weeks based on tolerability and effectiveness.
Perampanel dosing for patients with mild and moderate impairment should not exceed 8 mg.
Use in patients with severe hepatic impairment is not recommended.
In healthy women receiving 12 mg (but not 4 or 8 mg/day) for 21 days concomitantly with a combined oral contraceptive, perampanel was shown to decrease the levonorgestrel exposure (mean Cmax and AUC values were each decreased by 40%). Ethinylestradiol AUC was not affected by perampanel 12 mg whereas Cmax was decreased by 18%. Therefore, the possibility of decreased efficacy of hormonal progestative-containing contraceptives should be considered for women needing perampanel 12 mg/day and an additional reliable method (intra-uterine device (IUD), condom) is to be used.
Some anti-epileptic drugs known as CYP450 3A enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to increase perampanel clearance and consequently to decrease plasma concentrations of perampanel. Conversely, withdrawal of a concomitant CYP450 3A enzyme inducer can be expected to increase plasma concentrations of perampanel and dose reduction may be required.
Carbamazepine, a known potent enzyme inducer, reduced perampanel levels by two-thirds in a study performed on healthy subjects.
A similar result was seen in a population pharmacokinetic analysis of patients with partial-onset seizures receiving perampanel up to 12 mg/day and patients with primary generalised tonic-clonic seizures receiving perampanel up to 8 mg/day in placebo-controlled clinical trials. The total clearance of Fycompa was increased when administered with carbamazepine (2.75-fold), phenytoin (1.7-fold) and oxcarbazepine (1.9-fold), which are known inducers of enzymes of metabolism. This effect should be taken into account and managed when adding or withdrawing these anti-epileptic drugs from a patient’s treatment regimen.
In the epilepsy population pharmacokinetic analysis, perampanel was found to decrease the clearance of oxcarbazepine by 26%. Oxcarbazepine is rapidly metabolised by cytosolic reductase enzyme to the active metabolite, monohydroxycarbazepine. The effect of perampanel on monohydroxycarbazepine concentrations is not known.
Strong inducers of cytochrome P450, such as rifampicin and hypericum, are expected to decrease perampanel concentrations and the potential for higher plasma concentrations of reactive metabolites in their presence has not been excluded. Felbamate has been shown to decrease the concentrations of some medicinal products and may also reduce perampanel concentrations.
Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown) in association with perampanel treatment.
At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions.
Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident.
Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) <10%, erythematous skin (confluent), rapid progression, painful atypical target-like lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes.
If signs and symptoms suggestive of these reactions appear, perampanel should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or DRESS with the use of perampanel, treatment with perampanel must not be restarted in this patient at any time.
There appears to be an increased risk of falls, particularly in the elderly; the underlying reason is unclear.
Cases of hepatotoxicity (mainly hepatic enzyme increased) with perampanel in combination with other antiepileptic drugs have been reported. If hepatic enzymes elevation is observed, monitoring of liver function should be considered.
Aggressive and hostile behaviour has been reported in patients receiving perampanel therapy. In perampanel-treated patients in clinical trials, aggression, anger and irritability were reported more frequently at higher doses. Most of the reported events were either mild or moderate and patients recovered either spontaneously or with dose adjustment. However, thoughts of harming others, physical assault or threatening behaviour were observed in some patients (<1% in perampanel clinical studies). Patients and caregivers should be counselled to alert a healthcare professional immediately if significant changes in mood or patterns of behaviour are noted. The dosage of perampanel should be reduced if such symptoms occur and should be discontinued immediately if symptoms are severe.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic medicinal products in several indications. A meta-analysis of randomised placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for perampanel.
Therefore, patients should be monitored for signs of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.
There are limited amounts of data (less than 300 pregnancy outcomes) from the use of perampanel in pregnant women. Studies in animals did not indicate any teratogenic effects in rats or rabbits, but embryotoxicity was observed in rats at maternally toxic doses. Perampanel is not recommended during pregnancy.
Studies in lactating rats have shown excretion of perampanel and/or its metabolites in milk. It is not known whether perampanel is excreted in human milk. A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from perampanel therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Perampanel is not recommended in women of childbearing potential not using contraception unless clearly necessary. Perampanel may decrease the effectiveness of progestative-containing hormonal contraceptives. An additional non-hormonal form of contraception is, therefore recommended.
In the fertility study in rats, prolonged and irregular oestrous cycles were observed at high-dose (30 mg/kg) in females; however, these changes did not affect the fertility and early embryonic development. There were no effects on male fertility. The effect of perampanel on human fertility has not been established.
Perampanel has moderate influence on the ability to drive and use machines. Perampanel may cause dizziness and somnolence and, therefore, may influence the ability to drive or use machines. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities until it is known whether perampanel affects their ability to perform these tasks.
In all controlled and uncontrolled trials in patients with partial-onset seizures, 1,639 subjects have received perampanel of whom 1,147 have been treated for 6 months and 703 for longer than 12 months.
In the controlled and uncontrolled trial in patients with primary generalised tonic-clonic seizures, 114 subjects have received perampanel of whom 68 have been treated for 6 months and 36 for longer than 12 months.
Adverse reactions leading to discontinuation: In the controlled Phase 3 partial-onset seizures clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7%, 4.2% and 13.7% in patients randomised to receive perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% in patients randomised to receive placebo. The adverse reactions most commonly (≥1% in the total perampanel group and greater than placebo) leading to discontinuation were dizziness and somnolence.
In the controlled Phase 3 primary generalised tonic-clonic seizures clinical trial, the rate of discontinuation as a result of an adverse reaction was 4.9% in patients randomised to receive perampanel 8 mg, and 1.2% in patients randomised to receive placebo. The adverse reaction most commonly leading to discontinuation (≥2% in the perampanel group and greater than placebo) was dizziness.
Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association with perampanel treatment.
In the list below, adverse reactions, which were identified based on review of the full perampanel clinical studies safety database, are listed by System Organ Class and frequency. The following convention has been used for the classification of adverse reactions: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), not known (cannot be estimated from the available data).
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
Common: Decreased appetite, Increased appetite
Common: Aggression, Anger, Anxiety, Confusional state
Uncommon: Suicidal ideation, Suicide attempt
Very common: Dizziness, Somnolence
Common: Ataxia, Dysarthria, Balance disorder, Irritability
Common: Diplopia, Vision blurred
Common: Vertigo
Common: Nausea
Not known: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson Syndrome (SJS)
Common: Back pain
Common: Gait disturbance, Fatigue
Common: Weight increased
Common: Fall
Based on the clinical trial database of 196 adolescents exposed to perampanel from double-blind studies for partial-onset seizures and primary generalised tonic-clonic seizures, the overall safety profile in adolescents was similar to that of adults, except for aggression, which was observed more frequently in adolescents than in adults.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
