Perampanel (perampanel)

Initial dosage recommendations for perampanel vary based on whether a moderate or potent cytochrome P-450 (CYP) 3A4 enzyme-inducing drug (e.g., carbamazepine, oxcarbazepine, phenytoin) is used concomitantly. Such CYP3A4-inducing drugs can reduce plasma concentrations, and thus efficacy, of perampanel. (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Perampanel is administered orally as tablets or oral suspension. The drug usually is administered once daily at bedtime and may be given without regard to food. (See Description.) Bioavailability of the commercially available oral suspension is comparable to that of the tablets, and the dosage forms may be used interchangeably.

When discontinuing any anticonvulsant therapy, gradual withdrawal is recommended to minimize the potential for increased seizure frequency in patients with seizure disorders. However, the manufacturer states that there are insufficient data to make specific recommendations regarding withdrawing perampanel. Because of its prolonged half-life (approximately 105 hours), plasma concentrations are expected to decline gradually even after abrupt discontinuance. If discontinuance of perampanel is necessary because of adverse effects, prompt withdrawal of the drug may be considered. (See Discontinuance of Anticonvulsants under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Patients currently receiving or beginning therapy with perampanel and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior. (See Suicidality Risk under Warnings/Precautions: Other Warnings and Precautions, in Cautions.)

Monitoring for adverse neuropsychiatric effects is recommended in patients receiving perampanel, especially during the initial titration period (or any other time dosage is increased) and when high dosages (e.g., 12 mg daily) of the drug are used. If any neuropsychiatric manifestations occur, dosage of perampanel should be reduced or therapy discontinued, depending on the severity of the reaction. (See Serious Psychiatric and Behavioral Reactions under Warnings/Precautions: Warnings, in Cautions.)

Perampanel is principally metabolized by cytochrome P-450 (CYP) isoenzyme 3A4/5 and, to a lesser extent, by CYP1A2 and CYP2B6, although other CYP-mediated pathways may be involved.

Perampanel is a weak inhibitor of CYP2C8 and 3A4, and a weak inducer of CYP2B6 and 3A4/5 in vitro. The drug does not appear to inhibit CYP1A2, 2A6, 2B6, 2C9, 2C19, 2D6, and 2E1 nor induce CYP1A2.

Perampanel is neither a substrate nor substantial inhibitor of the efflux transporters P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP); organic anion transport proteins (OATP) 1B1 and 1B3; organic anion transporters 1, 2, 3, and 4; and organic cation transporters 1, 2, and 3. Perampanel has weak inhibitory effects on uridine diphosphate-glucuronosyltransferase (UGT) 1A9 and 2B7 and does not appear to inhibit UGT1A1, 1A4, and 1A6. The drug has been shown to induce UGT1A1 and 1A4.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Brivaracetam; Lamotrigine; Perampanel/Rifampin; Rifapentine

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Rifampin and rifapentine may induce the metabolism of brivaracetam by CYP2C19(1) and lamotrigine(2,3) and perampanel(4) by CYP3A4.

CLINICAL EFFECTS: The concurrent use of rifampin or rifapentine with brivaracetam,(1) lamotrigine,(2,3) or perampanel(4) may result in decreased levels and clinical effectiveness of the anticonvulsant.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients receiving rifampin or rifapentine concurrently with brivaracetam, lamotrigine, or perampanel should be observed for decreased anticonvulsant levels and clinical effectiveness. The dose of the anticonvulsant may need to be adjusted if the rifamycin is added to or removed from therapy. Refer to the current anticonvulsant prescribing information for information on dosage adjustments.

DISCUSSION: Concurrent rifampin decreases brivaracetam levels by 45%.(1) A study in 10 healthy subjects examined the effects of rifampin (600 mg daily for five days) on a single dose of lamotrigine (25 mg). Pretreatment with rifampin decreased the lamotrigine area-under-curve (AUC) and half-life (T1/2) by 43.7% and 40.8%, respectively. Lamotrigine clearance over bioavailability increased 98.3%. The amount of lamotrigine excreted as the glucuronide metabolite increased 36%.(2) A study in 10 healthy subjects examining the effects of rifampin (600 mg daily for 5 days) on a single dose of lamotrigine (25 mg) showed that rifampin increased the apparent clearance of lamotrigine by approximately 2-fold and decreased the AUC by 40%.(3) Rifampin and rifapentine are expected to decrease perampanel concentrations.(4)

Selected Anticonvulsants/Ulipristal

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, and topiramate may induce the metabolism of ulipristal by CYP3A4.(1,2)

CLINICAL EFFECTS: Concurrent use or use of eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate within the previous 2-3 weeks may result in decreased levels and effectiveness of ulipristal.(1,2) In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.(3)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US and UK manufacturers of ulipristal states that concurrent use with CYP3A4 inducers such as eslicarbazepine, mephenytoin, oxcarbazepine, rufinamide, or topiramate is not recommended. Decreased effectiveness of ulipristal may occur even 2-3 weeks after discontinuation of these agents.(1,2)

DISCUSSION: CYP3A4 inducers may decrease levels and effectiveness of ulipristal. Enzyme induction may take 2-3 weeks to wear off. Plasma levels of ulipristal may be reduced even if the CYP3A4 inducer was discontinued in the previous 2-3 weeks.(1) Concurrent administration of ulipristal 30 mg and rifampin 600 mg, another CYP3A4 inducer, for 9 days decreased the maximum concentration (Cmax) and area-under-the-curve (AUC) by 90% and 93%, respectively. The Cmax and AUC of monodemethyl-ulipristal decreased by 84% and 90%, respectively.(2)

Selected Anticonvulsants; Barbiturates/Contraceptives

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Barbiturates, hydantoins, and primidone may increase the metabolism of the contraceptives via CYP3A4 induction.

CLINICAL EFFECTS: May observe reduced contraceptive effects such as breakthrough bleeding, spotting, or pregnancy. Effects may be seen several days after discontinuation of the anticonvulsant or barbiturate. In addition, topiramate has been associated with an increased risk of birth defects, including cleft palate.

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: To avoid pregnancy, additional or alternative means of non-hormonal contraception should be utilized. Depo medroxyprogesterone may be an alternative, since its effectiveness is not decreased by anticonvulsants. Patients receiving perampanel at doses of 12 mg/day should use alternative contraception methods, such as an intra-uterine device or condom. Patients receiving topiramate may observe decreased contraceptive efficacy and increased breakthrough bleeding, especially at doses greater than 200 mg per day. Patients taking topiramate and estrogen containing or progestin-only contraceptives should be asked to report any change in their bleeding patterns.(20) Patients taking the combination of phentermine/topiramate for weight loss should be counseled that break-through bleeding may occur but is not expected to increase the risk of pregnancy. Instruct patients to report changes in bleeding patterns to their physician and to continue to take their hormonal contraceptive. Patients should not rely on hormonal contraceptives (other than implants or IUD) alone, but may use them in combination with a barrier contraceptive. It is necessary to use effective contraception with phentermine/topiramate, because the topiramate content of the product can cause birth defects. For emergency contraception, the UK's Medicines & Healthcare Products Regulatory Agency (MHRA) recommends that women who have used a CYP3A4 inducer in the previous 4 weeks should consider a non-hormonal emergency contraceptive (ie a copper IUD). If a non-hormonal emergency contraceptive is not an option, double the usual dose of levonorgestrel from 1.5 to 3 mg. Advise the patient to have a pregnancy test to exclude pregnancy after use and to seek medical advice if they do become pregnant.

DISCUSSION: Decreased effectiveness of oral contraceptives, characterized by breakthrough bleeding and amenorrhea have been documented. Through August, 2010, Australia's Therapeutic Goods Association had received 32 reports of contraceptive failure leading to pregnancy as a result of a suspected interaction between etonogestrel implants and carbamazepine. In a randomized, open-label study in healthy women, concurrent topiramate (50 mg daily to 200 mg daily) and Ortho Novum 1/35 (ethinyl estradiol and norethindrone) resulted in no changes in levels of ethinyl estradiol or norethindrone. However, in another study, concurrent topiramate at doses of 200 mg daily, 400 mg daily, and 800 mg daily with valproic acid decreased the area-under-curve (AUC) of ethinyl estradiol by 18%, 21%, and 30%, respectively. There were no changes in norethindrone levels. The US manufacturer of topiramate states that the possibility of decreased contraceptive effectiveness should be considered. At doses of 12 mg/day, perampanel decreased the maximum concentration (Cmax) and AUC of levonorgestrel by 40% each. The Cmax of ethinyl estradiol was decreased by 18%. There were no effects on ethinyl estradiol AUC. Doses of perampanel of 4 mg/day and 8 mg/day had no effect on contraceptive levels. The combination of phentermine/topiramate (15 mg/92 mg for 15 days) increased the Cmax and AUC of norethindrone by 22% and 16%, respectively. The Cmax and AUC of ethinyl estradiol decreased 8% and 16%, respectively. Because contraceptive efficacy is primarily determined by the progestin component, no effect on contraceptive efficacy is expected, although breakthrough bleeding may occur. The effectiveness of depo medroxyprogesterone is not decreased by anticonvulsants or barbiturates.

Moderate Interaction: Assess the risk to the patient and take action as needed.

Perampanel/Strong And Moderate Cyp3a4 Inducers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Strong and moderate CYP3A4 inducers may induce the metabolism of perampanel by CYP3A4.(1)

CLINICAL EFFECTS: The concurrent use of strong and moderate CYP3A4 inducers and perampanel may result in decreased levels and clinical effectiveness of perampanel.(1)

PREDISPOSING FACTORS: Induction effects may be more likely with regular use of the inducer for longer than 1-2 weeks.

PATIENT MANAGEMENT: Patients receiving concurrent therapy with strong and moderate CYP3A4 inducers and perampanel should be observed for decreased anticonvulsant levels and clinical effectiveness. The manufacturer of perampanel recommends a starting dose of 4 mg once daily at bedtime in patients receiving concurrent therapy with CYP3A4 inducers. Dose increases are recommended by 2 mg increments once daily based on clinical response and tolerability, no more frequently than at weekly intervals. The highest studied dose with concurrent enzyme-inducing antiepileptic drugs was 12 mg once daily.(1) The dose of the anticonvulsant may need to be adjusted if a strong or moderate CYP3A4 inducer is added to or removed from therapy.(1)

DISCUSSION: In a study in healthy subjects, carbamazepine 300 mg BID decreased the maximum concentration (Cmax) and area-under-curve (AUC) of a single 2 mg tablet dose of perampanel by 26% and 67%, respectively. The half-life (t1/2) of perampanel was shortened from 56.8 hours to 25 hours. In clinical studies examining partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 64% in patients on carbamazepine compared to the AUC in patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 48% in patients on oxcarbazepine compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures, a population pharmacokinetic analysis showed that perampanel AUC was reduced by 43% in patients on phenytoin compared to patients not on enzyme-inducing antiepileptic drugs.(1) In a study in partial-onset and primary generalized tonic-clonic seizures in clinical trials (40 patients co-administered phenobarbital and 9 patients co-administered primidone), no significant effect on perampanel AUC was found. A modest effect of phenobarbital and primidone on perampanel concentrations cannot be excluded.(1) In a study in 76 patients, concentration-to-dose (CD) ratio of perampanel was assessed with and without concurrent antiepileptic agents. In patients only on perampanel the mean CD ratio was 3963 ng/mL/mg/kg (range: 1793-13,299) compared to the mean CD ratio in patients using enzyme-inducing AEDs [1760 (range: 892-3090), 2256 (range: 700-4703), and 1120 (range: 473-1853) ng/mL/mg/kg in patients taking phenytoin, phenobarbital, and carbamazepine, respectively], and carbamazepine had a significantly greater reduction in the CD ratio compared with phenytoin or phenobarbital (P < 0.001).(3) Strong and moderate CYP3A4 inducers linked to this monograph include: apalutamide, barbiturates, bosentan, carbamazepine, cenobamate, dabrafenib, efavirenz, elagolix, encorafenib, enzalutamide, eslicarbazepine, etravirine, fexinidazole, fosphenytoin, ivosidenib, lorlatinib, lumacaftor, mavacamten, mitapivat, mitotane, modafinil, nafcillin, oxcarbazepine, pacritinib, pexidartinib, phenobarbital, phenytoin, primidone, repotrectinib, rifabutin, sotorasib, telotristat, thioridazine, and tovorafenib.(1,2)

The manufacturer states that there are no known contraindications to the use of perampanel.

There are no contraindication contraindications for this drug.

• Aggressive behavior
• Alcohol intoxication
• Alcohol use disorder
• Child-pugh class A hepatic impairment
• Child-pugh class B hepatic impairment
• Chronic kidney disease stage 3A (moderate) GFR 45-59 ml/min
• Chronic kidney disease stage 3B (moderate) GFR 30-44 ml/min
• Disease of liver
• Homicidal ideation
• Suicidal ideation

• Gait abnormality

Adverse effects reported in at least 4% of patients with partial-onset seizures receiving perampanel in 3 controlled clinical trials and more frequently with the drug than with placebo include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, and balance disorder.

Adverse effects reported in at least 10% of patients with primary generalized tonic-clonic seizures receiving perampanel in a controlled clinical trial and more frequently with the drug than with placebo include dizziness, fatigue, headache, somnolence, and irritability.

More Frequent

• Hostility

Less Frequent

• Hyponatremia

Rare or Very Rare

• Accidental fall
• Delirium
• DRESS syndrome
• Drug-induced psychosis
• Eosinophilia
• Hallucinations
• Homicidal ideation
• Suicidal
• Suicidal ideation

More Frequent

• Acute abdominal pain
• Aggressive behavior
• Ataxia
• Bruising
• Dizziness
• Drowsy
• Fatigue
• Gait abnormality
• General weakness
• Irritability
• Nausea
• Vertigo
• Vomiting
• Weight gain

Less Frequent

• Acute cognitive impairment
• Agitation
• Arthralgia
• Back pain
• Blurred vision
• Constipation
• Delusional disorder
• Diplopia
• Dysarthria
• Euphoria
• Hypoesthesia
• Memory impairment
• Mood changes
• Myalgia
• Paranoid disorder
• Peripheral edema
• Sedation
• Symptoms of anxiety

Rare or Very Rare

• Behavioral disorders
• Personality disorders
• Skin rash

No enhanced messaging available.

Safety and efficacy of perampanel have not been established in pediatric patients younger than 12 years of age. A total of 72 adolescents 12-16 years of age were included in the controlled partial-onset seizure trials and 11 adolescents 12-16 years of age were included in the study evaluating primary generalized tonic-clonic seizures with an additional 6 pediatric patients in the open-label extension of the study. In the 3 placebo-controlled studies of perampanel in patients with partial seizures, aggression was observed more frequently in adolescents than in adults receiving the drug. (See Serious Psychiatric and Behavioral Reactions under Warnings/Precautions: Warnings, in Cautions.)

There are no adequate data in humans to determine if there is any risk associated with the use of perampanel during pregnancy; in animal reproductive studies, developmental toxicity (e.g., visceral abnormalities, decreased fetal weight gain, delayed sexual maturation) was observed at clinically relevant doses.

Women who are taking perampanel during pregnancy should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 or http://www.aedpregnancyregistry.org.

Perampanel and/or its metabolites are distributed into milk in rats at concentrations higher than those in maternal plasma; it is not known whether the drug is distributed into human milk. The effects of perampanel on the nursing infant or on milk production also are not known. The known benefits of breast-feeding should be considered along with the mother's clinical need for perampanel and any potential adverse effects on the infant from the drug or underlying maternal condition.

There is insufficient experience in patients 65 years of age and older to establish efficacy and safety of perampanel in this population. Geriatric patients treated with the drug appear to be at increased risk of adverse neurologic effects (e.g., dizziness, gait disturbances, somnolence, fatigue) compared with younger adults and adolescents. In addition, the risk of falls appears to be greater in geriatric patients. Because of a greater likelihood of such adverse reactions in geriatric patients, dosage of perampanel should be titrated gradually in patients 65 years of age and older.