Perampanel

1.1 Partial-Onset Seizures

Perampanel is indicated as adjunctive therapy for the treatment of partial-onset seizures with or without secondarily generalized seizures in patients with epilepsy 12 years of age and older.

1.2 Primary Generalized Tonic-Clonic Seizures

​Perampanel is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.

Perampanel (Perampanel) is an anticonvulsant used to treat seizures in adults and children who are at least 12 years old.

Perampanel is a prescription medicine that is used with other medications to treat partial-onset seizures with or without secondarily generalized seizures, and to treat primary generalized tonic-clonic (PGTC) seizures, in adults and children who are at least 12 years old.

Perampanel may also be used for purposes not listed in this medication guide.

Adults and Adolescents: Perampanel must be titrated, according to individual patient response, in order to optimise the balance between efficacy and tolerability.

Perampanel should be taken orally once daily before bedtime.

Perampanel at doses of 4-12 mg/day has been shown to be effective therapy in partial-onset seizures.

Treatment with Perampanel should be initiated with a dose of 2 mg/day. The dose may be increased based on clinical response and tolerability by increments of 2 mg/day to a maintenance dose of 4-8 mg/day. Depending upon individual clinical response and tolerability at a dose of 8 mg/day, the dose may be increased by increments of 2-12 mg/day. Patients who are taking concomitant medicinal products that do not shorten the t_½ of Perampanel should be titrated no more frequently than at 2-week intervals. Patients who are taking concomitant medicinal products that shorten the half-life of Perampanel should be titrated no more frequently than at 1-week intervals.

When withdrawing Perampanel, the dose should be gradually reduced.

Single Missed Dose: As Perampanel has a long t_½, the patient should wait and take their next dose as scheduled.

If >1 dose has been missed, for a continuous period of <5 t_½ [3 weeks for patients not taking Perampanel metabolism-inducing anti-epileptic drugs (AED), 1 week for patients taking Perampanel metabolism-inducing AEDs ], consideration should be given to restart treatment from the last dose level.

If a patient has discontinued Perampanel for a continuous period of >5 t_½, it is recommended that initial dosing recommendations given above should be followed.

Elderly (≥65 Years): Clinical studies of Perampanel in epilepsy did not include sufficient numbers of subjects ≥ 65 years to determine whether they respond differently from younger subjects. Analysis of safety information in 905 Perampanel-treated elderly subjects (in double-blind studies conducted in non-epilepsy indications) revealed no age-related differences in the safety profile. In combination with the lack of age-related difference in Perampanel exposure, the results indicate that dose adjustment in the elderly is not required. Perampanel should be used with caution in elderly taking into account the drug interaction potential in polymedicated patients.

Renal Impairment: Dose adjustment is not required in patients with mild renal impairment. Use in patients with moderate or severe renal impairment or patients undergoing haemodialysis is not recommended.

Hepatic Impairment: 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.

Administration: Perampanel should be taken as single oral dose at bedtime. It may be taken with or without food. The tablet should be swallowed whole with a glass of water. It should not be chewed, crushed or split. The tablets cannot be split accurately as there is no break line. To ensure the patient receives the entire dose, the tablets should be swallowed whole without chewing or crushing.

See also:
What is the most important information I should know about Perampanel?

Some people taking Perampanel have had serious psychotic effects, especially when starting the medication.

Call your doctor right away if you have any changes in mood or behavior changes, personality changes, thoughts about suicide, or thoughts about hurting others. Your family or other caregivers should also be alert to changes in your mood or symptoms.

Before you take Perampanel, tell your doctor if you have liver or kidney disease, or a history of depression, mental illness, or addiction to drugs or alcohol.

Tell your doctor right away if you become pregnant while taking Perampanel for seizures. Do not start or stop taking Perampanel during pregnancy without your doctor's advice.

Do not stop using any other seizure medication suddenly, even if you feel fine. Stopping suddenly may cause increased seizures. Follow your doctor's instructions about tapering your dose.

Never share Perampanel with another person, especially someone with a history of drug abuse or addiction. Keep the medication in a place where others cannot get to it.

Use Perampanel as directed by your doctor. Check the label on the medicine for exact dosing instructions.

• Perampanel comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Perampanel refilled.
• Take Perampanel by mouth with or without food.
• Taking Perampanel at the same time each day will help you remember to take it.
• Continue to take Perampanel even if you feel well. Do not miss any doses.
• Do not suddenly stop taking Perampanel. You may have an increased risk of seizures. If you need to stop Perampanel, your doctor will gradually lower your dose.
• If you miss a dose of Perampanel, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once. Contact your doctor if you miss more than 1 dose of Perampanel.

Ask your health care provider any questions you may have about how to use Perampanel.

Use: Labeled Indications

Partial-onset seizures: Treatment of partial-onset seizures with or without secondarily generalized seizures as adjunct or monotherapy in patients with epilepsy who are ≥4 years of age.

Primary generalized tonic-clonic seizures: Treatment of primary generalized tonic-clonic seizures as adjunct therapy in patients with epilepsy who are ≥12 years of age.

See also:
What other drugs will affect Perampanel?

Perampanel is not considered a strong inducer or inhibitor of cytochrome P450 or UGT enzymes.

Oral Contraceptives:

Interactions Between Perampanel and Other Anti-Epileptic Medicinal Products: Potential interactions between Perampanel (up to 12 mg once daily) and other anti-epileptic drugs (AEDs) were assessed in clinical studies and evaluated in the population PK analysis of 3 pooled phase 3 studies. The effect of these interactions on average steady state concentration is summarised in the table as follows.

Some anti-epileptic drugs known as enzyme inducers (carbamazepine, phenytoin, oxcarbazepine) have been shown to increase Perampanel clearance and consequently to decrease plasma concentrations of Perampanel.

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 in placebo-controlled clinical trials. The total clearance of Perampanel was increased when administered with carbamazepine (3-fold), phenytoin (2-fold) and oxcarbazepine (2-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 a population pharmacokinetic analysis of patients with partial-onset seizures receiving Perampanel up to 12 mg/day in placebo-controlled clinical trials, Perampanel did not affect to a clinically relevant manner the clearance of clonazepam, levetiracetam, phenobarbital, phenytoin, topiramate, zonisamide, carbamazepine, clobazam, lamotrigine and valproic acid, at the highest Perampanel dose evaluated (12 mg/day).

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.

Perampanel is dosed to clinical effect regardless of other AEDs.

Effect of Perampanel on CYP3A Substrates: 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.

Effect of Cytochrome P450 Inducers on Perampanel Pharmacokinetics: Strong inducers of cytochrome P450 eg, rifampicin and hypericum, are expected to decrease Perampanel concentrations. Felbamate has been shown to decrease the concentrations of some drugs and may also reduce Perampanel concentrations.

Effect of Cytochrome P450 Inhibitors on Perampanel Pharmacokinetics: In healthy subjects, the CPY3A4 inhibitor ketoconazole (400 mg once daily for 10 days) increased Perampanel AUC by 20% and prolonged Perampanel t_½ by 15% (67.8 hr vs 58.4 hr). Larger effects cannot be excluded when Perampanel is combined with a CYP3A inhibitor with longer t_½ than ketoconazole or when the inhibitor is given for a longer treatment duration. Strong inhibitors of other cytochrome P450 isoforms could potentially also increase Perampanel concentrations.

Levodopa: In healthy subjects, Perampanel (4 mg once daily for 19 days) had no effect on C_max or AUC of levodopa.

Alcohol: 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 pharmacodynamics 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 CNS depressants.

Paediatric Population: Interaction studies have only been performed in adults. In a population pharmacokinetic analysis of the adolescent patients in the phase 3 clinical studies, there were no notable differences between this population and the overall population.

Incompatibilities: Not applicable.

See also:
What are the possible side effects of Perampanel?

Summary of Safety Profile: In all controlled and uncontrolled trials in patients with partial-onset seizures, 1639 subjects have received Perampanel, of whom 1174 have been treated for 6 months and 703 for longer than 12 months.

Adverse Reactions Leading to Discontinuation: In controlled phase 3 clinical trials, the rate of discontinuation as a result of an adverse reaction was 1.7%, 4.2% and 13.7% in patients randomized to receive Perampanel at the recommended doses of 4 mg, 8 mg and 12 mg/day, respectively, and 1.4% in patients randomized 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.

The list of adverse reactions are as follows. 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 initial review was done by considering all treatment emergent adverse events (TEAEs) in the double-blind phase 3 epilepsy studies that occurred in ≥2% of patients in the total Perampanel group. The following were also considered: Incidence rates higher than with placebo; severity, seriousness, and rates of discontinuation due to the events; analyses of exposure and dose-response; and consistency with Perampanel pharmacology. Treatment emergent adverse events that occurred in less frequency and met the same criteria as for the more frequent TEAEs were also considered. The following convention has been used for the classification of adverse reactions: Very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000).

The dose of 2 mg/day was not included in this assessment because it is not considered to be an effective dose, and the rates of TEAEs in that dose group were generally comparable to, or lower than, those in the placebo group. Within each frequency category, adverse reactions are presented in order of decreasing seriousness.

Metabolism and Nutrition Disorders: Common: Decreased/increased appetite.

Psychiatric Disorders: Common: Aggression, anger, anxiety, confusional state.

Nervous System Disorders: Very Common: Dizziness, somnolence. Common: Ataxia, dysathria, balance disorder, irritability.

Eye Disorders: Common: Diplopia, blurred vision.

Ear and Labyrinth Disorders: Common: Vertigo.

Gastrointestinal Disorders: Very common: Nausea.

Musculoskeletal and Connective Tissue Disorders: Very Common: Back pain.

General Disorders: Very Common: Gait disturbance, fatigue.

Investigations: Very Common: Increased weight.

Injury, Poisoning and Procedural Complications: Very Common: Fall.

Paediatric Population: Based on the clinical trial database of 143 adolescents, the frequency, type and severity of adverse reactions in adolescents are expected to be the same as in adults.

Each film-coated tablet contains 2, 4, 6, 8, 10 or 12 mg Perampanel.

It also contains the following excipients: Core: Lactose monohydrate, low-substitute hydroxypropyl cellulose, povidone, magnesium stearate (all presentations), microcrystalline cellulose (6, 8, 10 and 12 mg only). Film Coating: Opadry orange (2 mg), opadry red (4 mg), opadry pink (6 mg), opadry purple (8 mg), opadry green (10 mg), opadry blue (12 mg) (containing) hypromellose 2910, talc, macrogol 8000, titanium dioxide, yellow ferric oxide (2 mg, 10 mg), red ferric oxide (2 mg, 4 mg, 6 mg, 8 mg), black ferric oxide (8 mg), FD&C blue #2 indigo carmine aluminum lake (E132) (10 mg, 12 mg).