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  • CLASSES

    Anticonvulsants, Miscellaneous

    BOXED WARNING

    Behavioral changes, bipolar disorder, psychiatric event, psychosis, schizophrenia

    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. 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 following 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.

    DEA CLASS

    Rx, schedule III

    DESCRIPTION

    Alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) receptor antagonist
    Used for partial-onset and primary generalized tonic-clonic seizures
    Black box warning for neuropsychiatric events

    COMMON BRAND NAMES

    FYCOMPA

    HOW SUPPLIED

    FYCOMPA Oral Susp: 0.5mg, 1mL
    FYCOMPA Oral Tab: 2mg, 4mg, 6mg, 8mg, 10mg, 12mg

    DOSAGE & INDICATIONS

    For monotherapy or adjunctive treatment of partial seizures with or without secondary generalization.
    Oral dosage
    Adults

    2 mg PO once daily at bedtime initially; titrate by 2 mg/day increments at weekly intervals based on clinical response and tolerability. Dose titration should occur no more frequently than every 2 weeks in geriatric patients. 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.

    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
    Adults

    2 mg PO once daily at bedtime initially; titrate by 2 mg/day increments at weekly intervals based on clinical response and tolerability. Dose titration should occur no more than every 2 weeks in geriatric patients. 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.

    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

    Adults

    12 mg/day PO.

    Geriatric

    12 mg/day PO.

    Adolescents

    12 mg/day PO.

    Children

    4 to 12 years: 12 mg/day PO.
    1 to 3 years: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    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.

    Renal Impairment

    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.

    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.

    STORAGE

    FYCOMPA:
    - Avoid temperatures above 86 degrees F
    - Discard opened bottle after 90 days
    - Do not freeze

    CONTRAINDICATIONS / PRECAUTIONS

    Behavioral changes, bipolar disorder, psychiatric event, psychosis, schizophrenia

    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. 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 following 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.

    Depression, suicidal ideation

    Antiepileptic drugs increase the risk of suicidal ideation and behavior in patients receiving the drugs to treat epilepsy, psychiatric disorders, or other conditions (e.g., migraine, neuropathic pain). In pooled analyses of placebo-controlled trials, patients receiving antiepileptics had approximately twice the risk of suicidal behavior or ideation as patients receiving placebo. Data suggest that these risks apply to all antiepileptic drugs used for any indication in patients of any age (5 to 100 years). Suicidal ideation or behavior has occurred as early as 1 week after treatment initiation, and may occur any time during treatment. All patients beginning treatment with antiepileptics or currently receiving perampanel should be closely monitored for emerging or worsening depression or suicidal thoughts/behavior. Patients, caregivers, and families 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. Antiepileptics should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Driving or operating machinery

    Patients should avoid driving or operating machinery or participating in other activities requiring mental alertness until the neurologic effects of perampanel in the patient are known. Dose-dependent adverse reactions such as dizziness, gait disturbances, vertigo, somnolence, and fatigue have been observed during treatment. 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.

    Abrupt discontinuation

    Patients receiving perampanel should generally undergo gradual withdrawal to avoid abrupt discontinuation; however, abrupt discontinuation may occur in response to serious adverse reactions. Following abrupt discontinuation of perampanel, small numbers of patients have experienced seizures. Specific recommendations regarding withdrawal schedules are not available due to insufficient data.

    Hepatic disease

    Perampanel is not recommended for use in patients with severe hepatic disease. Dose adjustments should be used in patients with mild or moderate hepatic impairment.

    Renal failure, renal impairment

    Perampanel is not recommended in patients with severe renal failure or in those undergoing hemodialysis. Caution should be exercised and dose adjustments considered when using perampanel in patients with moderate renal impairment. Mild renal impairment does not require dose adjustment.

    Substance abuse

    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 substance abuse potential among recreational drug users, supra-therapeutic doses of perampanel 24 or 36 mg produced euphoria similar to ketamine 100 mg and alprazolam 3 mg. Patients taking perampanel 24 or 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.

    Geriatric

    Sufficient numbers of geriatric patients were not enrolled in clinical trials of perampanel; therefore, the safety and efficacy of perampanel in this patient population is not established. Geriatric patients may be at increased risk for many of the adverse reactions associated with perampanel, so dose titration should occur slowly if use is necessary. According to the Beers Criteria, anticonvulsants are considered potentially inappropriate medications (PIMs) in geriatric patients with a history of falls or fractures and should be avoided in these patient populations, except for treating seizure and mood disorders, since anticonvulsants can produce ataxia, impaired psychomotor function, syncope, and additional falls. If perampanel must be used, consider reducing the use of other CNS-active medications that increase the risk of falls and fractures and implement strategies to reduce fall risk.[63923] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities; the use of any anticonvulsant for any condition should be based on confirmation of the condition and its potential cause(s). Determine effectiveness and tolerability by evaluating symptoms, and use these as the basis for dosage adjustment for most patients. Therapeutic drug monitoring is not required or available for most anticonvulsants. Serum medication concentrations (when available) may assist in identifying toxicity. Monitor the treated patient for drug efficacy and side effects. Anticonvulsants can cause a variety of side effects; some adverse reactions can increase the risk of falls. When an anticonvulsant is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt periodic tapering of the medication or provide documentation of medical necessity as outlined in the OBRA guidelines.[60742]

    Pregnancy

    There are no adequate data on the developmental risk associated with perampanel use during pregnancy in women. Animal data suggest that perampanel may be associated with fetal harm, as developmental toxicity occurred in pregnant rats and rabbits given perampanel. Perampanel doses of 1, 3, or 10 mg/kg/day administered to rats resulted in an increase in visceral abnormalities (diverticulum of the intestine); a dose of 1 mg/kg/day is similar to a human dose of 8 mg/day based on body surface area. Fetal death and delayed sexual maturation in male and female offspring were reported with mid to high doses. Doses of 30 or 60 mg/kg/day resulted in embryolethality and reduced fetal body weight. Embryolethality was also observed in rabbits given doses of 3 or 10 mg/kg/day. To monitor human fetal outcomes, pregnant women taking perampanel are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must enroll themselves by calling the registry at 1-888-233-2334.

    Breast-feeding

    There are no data describing the presence of perampanel in human milk or the effects of perampanel on the breast-fed infant or milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for perampanel and any potential adverse effects on the breast-fed infant from perampanel or the underlying maternal condition.

    Contraception requirements, reproductive risk

    Discuss reproductive risk and contraception requirements with female patients who are using levonorgestrel-containing contraceptives. Perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel and a levonorgestrel-containing hormonal contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation.

    ADVERSE REACTIONS

    Severe

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / 0-1.0
    suicidal ideation / Delayed / Incidence not known

    Moderate

    hostility / Early / 12.0-20.0
    ataxia / Delayed / 1.0-8.0
    dysarthria / Delayed / 1.0-4.0
    blurred vision / Early / 1.0-4.0
    constipation / Delayed / 2.0-3.0
    memory impairment / Delayed / 0-2.0
    confusion / Early / 1.0-2.0
    euphoria / Early / 0-2.0
    hyponatremia / Delayed / 0-2.0
    peripheral edema / Delayed / 1.0-2.0
    hallucinations / Early / Incidence not known
    psychosis / Early / Incidence not known
    delirium / Early / Incidence not known
    depression / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known

    Mild

    vertigo / Early / 3.0-47.0
    dizziness / Early / 16.0-43.0
    drowsiness / Early / 9.0-18.0
    fatigue / Early / 8.0-15.0
    headache / Early / 11.0-13.0
    irritability / Delayed / 4.0-12.0
    vomiting / Early / 2.0-9.0
    nausea / Early / 3.0-8.0
    weight gain / Delayed / 4.0-7.0
    anxiety / Delayed / 2.0-5.0
    abdominal pain / Early / 5.0-5.0
    back pain / Delayed / 2.0-5.0
    cough / Delayed / 1.0-4.0
    infection / Delayed / 3.0-4.0
    rash / Early / 4.0-4.0
    hypoesthesia / Delayed / 0-3.0
    diplopia / Early / 1.0-3.0
    myalgia / Early / 1.0-3.0
    arthralgia / Delayed / 0-3.0
    paresthesias / Delayed / 0-2.0
    asthenia / Delayed / 1.0-2.0
    musculoskeletal pain / Early / 1.0-2.0
    throat irritation / Early / 2.0-2.0
    agitation / Early / Incidence not known
    lethargy / Early / Incidence not known
    paranoia / Early / Incidence not known
    emotional lability / Early / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin; Diphenhydramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Caffeine; Pyrilamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Chlorpheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Chlorpheniramine; Dextromethorphan: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Chlorpheniramine; Phenylephrine : (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Chlorpheniramine; Phenylephrine; Phenyltoloxamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Diphenhydramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Acetaminophen; Pamabrom; Pyrilamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Acrivastine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Alfentanil: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aliskiren; Amlodipine: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Alprazolam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Amitriptyline: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as amitriptyline. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold. Monitor patients for changes in efficacy of perampanel.
    Amlodipine: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Atorvastatin: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Benazepril: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Celecoxib: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Olmesartan: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amlodipine; Valsartan; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Amobarbital: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Amoxapine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as amoxapine. In addition, cyclic antidepressants, when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Amoxicillin; Clarithromycin; Omeprazole: (Moderate) Concurrent use of perampanel with clarithromycin may increase exposure to perampanel and increase plasma concentrations. Clarithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Apalutamide: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to apalutamide therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If apalutamide is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and apalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased perampanel exposure by 50% to 67%.
    Aprepitant, Fosaprepitant: (Moderate) Use caution if perampanel and aprepitant, fosaprepitant are used concurrently and monitor for an increase in perampanel-related adverse effects for several days after administration of a multi-day aprepitant regimen. Perampanel is a CYP3A4 substrate in vitro. Aprepitant, when administered as a 3-day oral regimen (125 mg/80 mg/80 mg), is a moderate CYP3A4 inhibitor and inducer and may increase plasma concentrations of perampanel. For example, a 5-day oral aprepitant regimen increased the AUC of another CYP3A4 substrate, midazolam (single dose), by 2.3-fold on day 1 and by 3.3-fold on day 5. After a 3-day oral aprepitant regimen, the AUC of midazolam (given on days 1, 4, 8, and 15) increased by 25% on day 4, and then decreased by 19% and 4% on days 8 and 15, respectively. As a single 125 mg or 40 mg oral dose, the inhibitory effect of aprepitant on CYP3A4 is weak, with the AUC of midazolam increased by 1.5-fold and 1.2-fold, respectively. After administration, fosaprepitant is rapidly converted to aprepitant and shares many of the same drug interactions. However, as a single 150 mg intravenous dose, fosaprepitant only weakly inhibits CYP3A4 for a duration of 2 days; there is no evidence of CYP3A4 induction. Fosaprepitant 150 mg IV as a single dose increased the AUC of midazolam (given on days 1 and 4) by approximately 1.8-fold on day 1; there was no effect on day 4. Less than a 2-fold increase in the midazolam AUC is not considered clinically important. Perampanel is also a weak in vitro CYP3A4 inhibitor and aprepitant is a CYP3A4 substrate. Coadministration of daily oral aprepitant (230 mg, or 1.8 times the recommended single dose) with a moderate CYP3A4 inhibitor, diltiazem, increased the aprepitant AUC 2-fold with a concomitant 1.7-fold increase in the diltiazem AUC; clinically meaningful changes in ECG, heart rate, or blood pressure beyond those induced by diltiazem alone did not occur. Information is not available regarding the use of aprepitant with weak CYP3A4 inhibitors.
    Armodafinil: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with armodafinil due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of armodafinil occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Armodafinil is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Carisoprodol: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as carisoprodol.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as carisoprodol. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Atazanavir: (Major) Caution is warranted when atazanavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Atazanavir is a CYP3A4 substrate and inhibitor.
    Atazanavir; Cobicistat: (Major) Caution is warranted when atazanavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of atazanavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Atazanavir is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor.
    Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with perampanel can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Patients should limit activity and not drive or operate machinery until they know how concomitant use of perampanel and CNS depressants, such as phenobarbital, affects them. Coadministration of perampanel with phenobarbital may increase CNS depression. The combination of perampanel with CNS depressants has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression.
    Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Benzodiazepines: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Bexarotene: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with bexarotene due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of bexarotene occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Bexarotene is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Boceprevir: (Moderate) Concurrent use of perampanel with boceprevir, may increase exposure to perampanel and lead to elevated plasma concentrations. Boceprevir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Bosentan: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with bosentan due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of bosentan occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Bosentan is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Brompheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Brompheniramine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Brompheniramine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Brompheniramine; Pseudoephedrine; Dextromethorphan: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Buspirone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as buspirone.
    Butabarbital: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Butalbital; Acetaminophen: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Butalbital; Acetaminophen; Caffeine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Butalbital; Acetaminophen; Caffeine; Codeine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and perampanel. CNS depressants can potentiate the effects of cannabidiol.
    Carbamazepine: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with carbamazepine due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of carbamazepine occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Carbamazepine is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate. Steady state administration of carbamazepine 300 mg twice daily with a single dose of perampanel 2 mg reduced the Cmax of perampanel by 26% and AUC by 67%. The half-life of perampanel decreased from 56.8 hours to 25 hours.
    Carbetapentane; Chlorpheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbetapentane; Pyrilamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbidopa; Levodopa; Entacapone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as entacapone.
    Carbinoxamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Carbinoxamine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carbinoxamine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Carisoprodol: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as carisoprodol.
    Celecoxib; Tramadol: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cenobamate: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to cenobamate therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If cenobamate is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and cenobamate is a moderate CYP3A4 inducer. Coadministration may decrease perampanel plasma concentrations. Additionally, monitor for excessive sedation and somnolence during coadministration of cenobamate and perampanel. Concurrent use may result in additive CNS depression.
    Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with perampanel should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with perampanel should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Chlophedianol; Dexbrompheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chloral Hydrate: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as chloral hydrate.
    Chlorcyclizine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlordiazepoxide: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Chlordiazepoxide; Amitriptyline: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as amitriptyline. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold. Monitor patients for changes in efficacy of perampanel. (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Chlordiazepoxide; Clidinium: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Chlorpheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpheniramine; Codeine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dextromethorphan: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpheniramine; Dextromethorphan; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Chlorpheniramine; Ibuprofen; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpheniramine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpheniramine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Chlorpromazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Clarithromycin: (Moderate) Concurrent use of perampanel with clarithromycin may increase exposure to perampanel and increase plasma concentrations. Clarithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Clemastine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Clomipramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as clomipramine. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Clonazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Clorazepate: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Clozapine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as clozapine.
    Cobicistat: (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor.
    Cobimetinib: (Moderate) If concurrent use of cobimetinib and perampanel is necessary, use caution and monitor for decreased efficacy of cobimetinib. Cobimetinib is a CYP3A substrate in vitro, and perampanel is a weak in vitro inducer of CYP3A. The manufacturer of cobimetinib recommends avoiding coadministration of cobimetinib with moderate or strong CYP3A inducers based on simulations demonstrating that cobimetinib exposure would decrease by 73% or 83% when coadministered with a moderate or strong CYP3A inducer, respectively. Guidance is not available regarding concomitant use of cobimetinib with weak CYP3A inducers.
    Codeine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Phenylephrine; Promethazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Codeine; Promethazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Cyclizine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Cyproheptadine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Dabrafenib: (Major) Consider alternative therapy or start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with dabrafenib due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of dabrafenib occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Dabrafenib is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Darunavir: (Major) Caution is warranted when darunavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
    Darunavir; Cobicistat: (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when darunavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
    Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when darunavir is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of darunavir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Darunavir is a CYP3A4 substrate and inhibitor.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of perampanel with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated perampanel plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Perampanel is a weak inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, perampanel is a CYP3A4 substrate; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent use of perampanel with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated perampanel plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Perampanel is a weak inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, perampanel is a CYP3A4 substrate; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Delavirdine: (Moderate) The use of perampanel with delavirdine, a non-nucleoside reverse transcriptase inhibitor of CYP3A4, may increase perampanel plasma concentrations. Perampanel is a substrate of CYP3A4. Monitor patients taking potent CYP3A4 inhibitors for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Deutetrabenazine: (Moderate) Concurrent use of deutetrabenazine and drugs that can cause CNS depression, such as perampanel, may have additive effects and worsen drowsiness or sedation. Advise patients about worsened somnolence and not to drive or perform other tasks requiring mental alertness until they know how deutetrabenazine affects them.
    Dexamethasone: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with dexamethasone due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of dexamethasone occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Dexamethasone is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Dexbrompheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Dexbrompheniramine; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Dexchlorpheniramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Dextromethorphan; Diphenhydramine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Diazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Difelikefalin: (Moderate) Monitor for dizziness, somnolence, mental status changes, and gait disturbances if concomitant use of difelikefalin with CNS depressants is necessary. Concomitant use may increase the risk for these adverse reactions.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Dimenhydrinate: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Diphenhydramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Diphenhydramine; Ibuprofen: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Diphenhydramine; Naproxen: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Diphenhydramine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Diphenoxylate; Atropine: (Moderate) Concurrent administration of diphenoxylate/difenoxin with perampanel can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.
    Doxepin: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as doxepin. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Doxorubicin Liposomal: (Major) In vitro, perampanel is a mild CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of perampanel and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Doxorubicin: (Major) In vitro, perampanel is a mild CYP3A4 inhibitor; doxorubicin is a major substrate of CYP3A4. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP3A4, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of perampanel and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Doxylamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Doxylamine; Pyridoxine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Dronabinol: (Moderate) Use caution if coadministration of dronabinol with perampanel is necessary, and monitor for a decrease in the efficacy of dronabinol. Additive dizziness, confusion, somnolence, and other CNS effects may also occur. Dronabinol is a CYP2C9 and 3A4 substrate; perampanel is a weak in vitro inducer of CYP3A4. Concomitant use may result in decreased plasma concentrations of dronabinol.
    Droperidol: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as droperidol.
    Efavirenz: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with efavirenz due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of efavirenz occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Efavirenz is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Efavirenz; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with efavirenz due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of efavirenz occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Efavirenz is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with efavirenz due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of efavirenz occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Efavirenz is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Elagolix: (Major) Consider alternative therapy or start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with elagolix due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of elagolix occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. elagolix is a weak to moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Elagolix; Estradiol; Norethindrone acetate: (Major) Consider alternative therapy or start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with elagolix due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of elagolix occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. elagolix is a weak to moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Elbasvir; Grazoprevir: (Moderate) Caution is advised when administering elbasvir; grazoprevir with perampanel. Perampanel is a mild CYP3A inducer, while both elbasvir and grazoprevir are substrates of CYP3A. Use of these drugs together may decrease the plasma concentrations of both elbasvir and grazoprevir, and could result in decreased virologic response. Conversely, concentrations of perampanel (also a CYP3A substrate) may be increased when given with grazoprevir (a weak CYP3A inhibitor).
    Elvitegravir: (Major) Caution is warranted when elvitegravir is administered with perampanel as there is a potential for decreased concentrations of elvitegravir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is an inducer of CYP3A4. Elvitegravir is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when elvitegravir is administered with perampanel as there is a potential for decreased concentrations of elvitegravir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is an inducer of CYP3A4. Elvitegravir is a CYP3A4 substrate.
    Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) Caution is warranted when cobicistat is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of cobicistat. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is a substrate and inducer of CYP3A4. Cobicistat is a CYP3A4 substrate and inhibitor. (Major) Caution is warranted when elvitegravir is administered with perampanel as there is a potential for decreased concentrations of elvitegravir. Decreased antiretroviral concentrations may lead to a reduction of antiretroviral efficacy and the potential development of viral resistance. Perampanel is an inducer of CYP3A4. Elvitegravir is a CYP3A4 substrate.
    Entacapone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as entacapone.
    Enzalutamide: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to enzalutamide therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If enzalutamide is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and enzalutamide is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased perampanel exposure by 50% to 67%.
    Esketamine: (Moderate) Closely monitor patients receiving esketamine and perampanel for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.
    Eslicarbazepine: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with eslicarbazepine due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of eslicarbazepine occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Eslicarbazepine is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Estazolam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Estradiol; Levonorgestrel: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel and a levonorgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Eszopiclone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as eszopiclone.
    Ethanol: (Major) Advise patients to avoid alcohol consumption while taking CNS depressants. Alcohol consumption may result in additive CNS depression.
    Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel and a levonorgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Ethinyl Estradiol; Norgestrel: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing norgestrel (which contains levonorgestrel as an active isomer). Advise women taking perampanel and a norgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Etravirine: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with etravirine due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of etravirine occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Etravirine is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and perampanel. Concurrent use may result in additive CNS depression.
    Fentanyl: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Fluphenazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Flurazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Food: (Major) Advise patients to avoid cannabis use while taking CNS depressants due to the risk for additive CNS depression and potential for other cognitive adverse reactions.
    Fosamprenavir: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with fosamprenavir due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of fosamprenavir occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Fosamprenavir is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Fosphenytoin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with fosphenytoin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of fosphenytoin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate. After administration, fosphenytoin is converted to phenytoin. Phenytoin is a strong CYP3A4 inducer. The AUC of perampanel was reduced by 43% in patients taking phenytoin compared to patients not taking enzyme-inducing antiepileptic drugs.
    Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of perampanel and gabapentin. Concurrent use may result in additive CNS depression.
    Griseofulvin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with griseofulvin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of griseofulvin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Griseofulvin is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Haloperidol: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as haloperidol.
    Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking perampanel. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydromorphone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Hydroxychloroquine: (Moderate) Caution is warranted with the coadministration of hydroxychloroquine and antiepileptic drugs, such as perampanel. Hydroxychloroquine can lower the seizure threshold; therefore, the activity of antiepileptic drugs may be impaired with concomitant use.
    Hydroxyzine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Idelalisib: (Major) Avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with perampanel, a CYP3A substrate, as perampanel toxicities may be significantly increased. The AUC of a sensitive CYP3A substrate was increased 5.4-fold when coadministered with idelalisib.
    Imipramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as imipramine. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Indinavir: (Moderate) Concurrent use of perampanel with indinavir, may increase exposure to perampanel and lead to elevated plasma concentrations. Indinavir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Isavuconazonium: (Major) Caution and close monitoring are warranted when isavuconazonium is administered with perampanel as there is a potential for elevated perampanel concentrations and decreased concentrations of isavuconazonium. Decreased isavuconazonium concentrations may lead to a reduction of antifungal efficacy and the potential for treatment failure. Perampanel is a substrate and inducer of the hepatic isoenzyme CYP3A4. Isavuconazole, the active moiety of isavuconazonium, is a sensitive substrate and moderate inhibitor of this enzyme.
    Isocarboxazid: (Moderate) Use of perampanel with CNS depressants, including monoamine oxidase inhibitors (MAOIs), may increase CNS depression. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient taking perampanel for epilepsy is required.
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifampin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifampin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifampin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Isoniazid, INH; Rifampin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifampin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifampin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifampin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Itraconazole: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary. Caution should also be used during concomitant use of perampanel with itraconazole, as it inhibits CYP3A4.
    Ketoconazole: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary.
    Lansoprazole; Amoxicillin; Clarithromycin: (Moderate) Concurrent use of perampanel with clarithromycin may increase exposure to perampanel and increase plasma concentrations. Clarithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and perampanel. Concurrent use may result in additive CNS depression.
    Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and perampanel. Dosage adjustments of lemborexant and perampanel may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.
    Levamlodipine: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with perampanel should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.
    Levoketoconazole: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary.
    Levonorgestrel: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel and a levonorgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Levonorgestrel; Ethinyl Estradiol: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel and a levonorgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Levonorgestrel; Ethinyl Estradiol; Ferrous Bisglycinate: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing levonorgestrel. Advise women taking perampanel and a levonorgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Levorphanol: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Lofexidine: (Moderate) Monitor for excessive sedation and somnolence during coadministration. Perampanel may potentiate the sedative effects of lofexidine.
    Lopinavir; Ritonavir: (Moderate) Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Lorazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Lorlatinib: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to lorlatinib therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If lorlatinib is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and lorlatinib is a moderate CYP3A4 inducer. Coadministration may decrease perampanel plasma concentrations.
    Lumacaftor; Ivacaftor: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with lumacaftor due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of lumacaftor occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Lumacaftor is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Lumateperone: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and perampanel. Concurrent use may result in additive CNS depression.
    Maprotiline: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as maprotiline. In addition, maprotiline, when used concomitantly with anticonvulsants may lower the seizure threshold, leading to pharmacodynamic interactions.
    Maraviroc: (Minor) Use caution if coadministration of maraviroc with perampanel is necessary, due to a possible decrease in maraviroc exposure. Maraviroc is a CYP3A substrate and perampanel is a weak CYP3A4 inducer. Monitor for a decrease in efficacy with concomitant use.
    Mavacamten: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to mavacamten therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If mavacamten is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A substrate and mavacamten is a moderate CYP3A inducer.
    Meclizine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Meperidine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Meperidine; Promethazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines. (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Mephobarbital: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Meprobamate: (Contraindicated) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as meprobamate.
    Mesoridazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Methadone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Methocarbamol: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as methocarbamol.
    Midazolam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Mirtazapine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as mirtazapine.
    Mitotane: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with mitotane due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of mitotane occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Mitotane is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Modafinil: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with modafinil due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of modafinil occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Modafinil is a moderate CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Molindone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as molindone. In addition, seizures have been reported during the use of molindone which is of particular significance in patients with a seizure disorder receiving anticonvulsants.
    Monoamine oxidase inhibitors: (Moderate) Use of perampanel with CNS depressants, including monoamine oxidase inhibitors (MAOIs), may increase CNS depression. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient taking perampanel for epilepsy is required.
    Morphine: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Nabilone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as nabilone.
    Nafcillin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with nafcillin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of nafcillin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Nafcillin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Nefazodone: (Moderate) Concomitant use of perampanel and nefazodone, a potent CYP3A4 inhibitor, may increase exposure to perampanel, a CYP3A4 substrate. Monitor patients for increases in adverse effects such as anger anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Nelfinavir: (Moderate) Concurrent use of perampanel with nelfinavir, may increase exposure to perampanel and lead to elevated plasma concentrations. Nelfinavir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Nevirapine: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with nevirapine due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of nevirapine occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Nevirapine is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Nirmatrelvir; Ritonavir: (Moderate) Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Norgestrel: (Major) Perampanel may reduce the efficacy of hormonal contraceptives containing norgestrel (which contains levonorgestrel as an active isomer). Advise women taking perampanel and a norgesterol-containing contraceptive to use additional non-hormonal contraception while using perampanel and for a month after discontinuation. With concomitant use, perampanel 12 mg/day decreased the Cmax and AUC of levonorgestrel by 42% and 40%, respectively. No significant effect on oral contraception exposure was noted when lower perampanel dosing regimens (4 to 8 mg/day) were used.
    Nortriptyline: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as nortriptyline. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Olanzapine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as olanzapine.
    Olanzapine; Fluoxetine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as olanzapine.
    Olanzapine; Samidorphan: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as olanzapine.
    Oliceridine: (Moderate) Concomitant use of oliceridine with perampanel may cause excessive sedation and somnolence. Limit the use of oliceridine with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.
    Olmesartan; Amlodipine; Hydrochlorothiazide, HCTZ: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of perampanel with dasabuvir; ombitasvir; paritaprevir; ritonavir may result in elevated perampanel plasma concentrations and decreased concentrations of dasabuvir, paritaprevir, and ritonavir. Perampanel is a weak inducer of the hepatic isoenzyme CYP3A4; ritonavir, paritaprevir, and dasabuvir (minor) are CYP3A4 substrates. In addition, perampanel is a CYP3A4 substrate; ritonavir is a potent inhibitor of this enzyme. Caution and close monitoring are advised if these drugs are administered together. (Moderate) Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Omeprazole; Amoxicillin; Rifabutin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifabutin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifabutin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifabutin is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Opicapone: (Moderate) Opicapone should be given cautiously with other agents that cause CNS depression, including perampanel, due to the possibility of additive sedation. COMT inhibitors, such as opicapone, have also been associated with sudden sleep onset during activities of daily living such as driving, which has resulted in accidents in some cases. Prescribers should re-assess patients for drowsiness or sleepiness regularly throughout treatment, especially since events may occur well after the start of treatment. Patients should be advised to avoid driving or other tasks requiring mental alertness until they know how the combination affects them.
    Oxazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Oxcarbazepine: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with oxcarbazepine due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of oxcarbazepine occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A substrate and oxcarbazepine is a CYP3A inducer. Oxcarbazepine has been observed to reduce the AUC of perampanel by approximately 48%.
    Oxycodone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Oxymorphone: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Pentobarbital: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Perindopril; Amlodipine: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Perphenazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Perphenazine; Amitriptyline: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as amitriptyline. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold. Monitor patients for changes in efficacy of perampanel. (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Pexidartinib: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to pexidartinib therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If pexidartinib is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and pexidartinib is a moderate CYP3A4 inducer.
    Phenelzine: (Moderate) Use of perampanel with CNS depressants, including monoamine oxidase inhibitors (MAOIs), may increase CNS depression. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient taking perampanel for epilepsy is required.
    Phenobarbital: (Moderate) Patients should limit activity and not drive or operate machinery until they know how concomitant use of perampanel and CNS depressants, such as phenobarbital, affects them. Coadministration of perampanel with phenobarbital may increase CNS depression. The combination of perampanel with CNS depressants has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression.
    Phenobarbital; Hyoscyamine; Atropine; Scopolamine: (Moderate) Patients should limit activity and not drive or operate machinery until they know how concomitant use of perampanel and CNS depressants, such as phenobarbital, affects them. Coadministration of perampanel with phenobarbital may increase CNS depression. The combination of perampanel with CNS depressants has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression.
    Phenothiazines: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Phentermine; Topiramate: (Moderate) During clinical trials, co-administration of topiramate and perampanel to patients led to a 20% decrease in the AUC of perampanel compared to patients not taking enzyme-inducing antiepileptic drugs. Topiramate is an inducer of CYP3A4, while perampanel is a substrate of this enzyme. Patients taking topiramate who begin treatment with perampanel should be closely monitored for adverse effects and receive a higher initial dose of perampanel. Addition or withdrawal of enzyme-inducing antiepileptic drugs may require a perampanel dose adjustment.
    Phenytoin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with phenytoin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of phenytoin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Phenytoin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate. The AUC of perampanel was reduced by 43% in patients taking phenytoin compared to patients not taking enzyme-inducing antiepileptic drugs.
    Pimozide: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as pimozide.
    Posaconazole: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary. Caution should also be used during concomitant use of perampanel with posaconazole as this drug inhibits CYP3A4.
    Pramipexole: (Moderate) Use of perampanel with CNS depressants may increase CNS depression. Perampanel (particularly at high doses) has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; these effects may be additive to the concomitant use of other CNS depressants, such as pramipexole.
    Praziquantel: (Major) In vitro and drug interactions studies suggest that the CYP3A4 isoenzyme is the major enzyme involved in praziquantel metabolism. Therefore, use of praziquantel with perampanel, a weak CYP3A4 inducer in vitro, should be done with caution as concomitant use may produce therapeutically ineffective concentrations of praziquantel.
    Pregabalin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of perampanel and pregabalin. Concurrent use may result in additive CNS depression.
    Primidone: (Moderate) Patients should limit activity and not drive or operate machinery until they know how concomitant use of perampanel and CNS depressants, such as primidone, affects them. Coadministration of perampanel with primidone may increase CNS depression. The combination of perampanel with CNS depressants has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression.
    Prochlorperazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Promethazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Promethazine; Dextromethorphan: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Promethazine; Phenylephrine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Pseudoephedrine; Triprolidine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Pyrilamine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Quazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Quetiapine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as quetiapine.
    Ramelteon: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as ramelteon.
    Remifentanil: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Remimazolam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Rifabutin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifabutin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifabutin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifabutin is a CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Rifampin: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with rifampin due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of rifampin occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Rifampin is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Rifapentine: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to rifapentine therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If rifapentine is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and rifapentine is a strong CYP3A4 inducer. Coadministration with other strong CYP3A4 inducers decreased perampanel exposure by 50% to 67%.
    Risperidone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as risperidone.
    Ritonavir: (Moderate) Concurrent use of perampanel with ritonavir may decrease ritonavir concentrations and increase perampanel concentrations. Both drugs are metabolized by CYP3A4. Ritonavir is also a CYP3A4 inhibitor, while perampanel is a weak inducer of CYP3A4. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Rivaroxaban: (Minor) Coadministration of rivaroxaban and perampanel may result in decreased rivaroxaban exposure and may decrease the efficacy of rivaroxaban. Perampanel is an inducer of CYP3A4, and rivaroxaban is a substrate of CYP3A4. If these drugs are administered concurrently, monitor the patient for signs of lack of efficacy of rivaroxaban.
    Ropinirole: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as ropinirole.
    Saquinavir: (Moderate) Concurrent use of perampanel with saquinavir, may increase exposure to perampanel and lead to elevated plasma concentrations. Saquinavir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Secobarbital: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Sedating H1-blockers: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Selegiline: (Moderate) Monitor for excessive sedation and somnolence during coadministration of selegiline and perampanel. Concurrent use may result in additive CNS depression.
    Simeprevir: (Moderate) Simeprevir, a mild intestinal CYP3A4 inhibitor, may increase the side effects of perampanel, which is a CYP3A4 substrate. Monitor patients for adverse effects of perampanel, such as CNS and psychiatric events.
    Sofosbuvir; Velpatasvir: (Major) Use caution when administering velpatasvir with perampanel. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; perampanel is a weak in vitro inducer of CYP3A4.
    Sofosbuvir; Velpatasvir; Voxilaprevir: (Major) Use caution when administering velpatasvir with perampanel. Taking these drugs together may decrease velpatasvir plasma concentrations, potentially resulting in loss of antiviral efficacy. Velpatasvir is a CYP3A4 substrate; perampanel is a weak in vitro inducer of CYP3A4.
    Sotorasib: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime if perampanel is added to sotorasib therapy; increase the dose as tolerated in 2 mg increments no more than weekly, based on clinical response. If sotorasib is added or withdrawn from perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. Perampanel is a CYP3A4 substrate and sotorasib is a moderate CYP3A4 inducer.
    St. John's Wort, Hypericum perforatum: (Major) Start perampanel at a higher initial dose of 4 mg once daily at bedtime when using concurrently with St. John's Wort due to a potential reduction in perampanel plasma concentration. If introduction or withdrawal of St. John's Wort occurs during perampanel therapy, closely monitor patient response; a dosage adjustment may be necessary. St. John's Wort is a strong CYP3A4 inducer, and perampanel is a CYP3A4 substrate.
    Sufentanil: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tapentadol: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Telaprevir: (Moderate) Concurrent use of perampanel with telaprevir, may increase exposure to perampanel and lead to elevated plasma concentrations. Telaprevir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Telithromycin: (Moderate) Concurrent use of perampanel with telithromycin may increase exposure to perampanel and increase plasma concentrations. Telithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Telmisartan; Amlodipine: (Moderate) Coadministration of CYP3A4 inducers with amlodipine can theoretically increase the hepatic metabolism of amlodipine (a CYP3A4 substrate). Caution should be used when CYP3A4 inducers, such as perampanel, are coadministered with amlodipine. Monitor therapeutic response; the dosage requirements of amlodipine may be increased.
    Temazepam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Terbinafine: (Moderate) Due to the risk for breakthrough fungal infections, caution is advised when administering terbinafine with perampanel. Although this interaction has not been studied by the manufacturer, and published literature suggests the potential for interactions to be low, taking these drugs together may decrease the systemic exposure of terbinafine. Predictions about the interaction can be made based on the metabolic pathways of both drugs. Terbinafine is metabolized by at least 7 CYP isoenyzmes, with major contributions coming from CYP3A4; perampanel induces this enzyme. Monitor patients for breakthrough fungal infections.
    Thiethylperazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Thiopental: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as barbiturates.
    Thioridazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Tipranavir: (Moderate) Concurrent use of perampanel with tipranavir, may increase exposure to perampanel and lead to elevated plasma concentrations. Tipranavir is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Tolcapone: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as tolcapone.
    Topiramate: (Moderate) During clinical trials, co-administration of topiramate and perampanel to patients led to a 20% decrease in the AUC of perampanel compared to patients not taking enzyme-inducing antiepileptic drugs. Topiramate is an inducer of CYP3A4, while perampanel is a substrate of this enzyme. Patients taking topiramate who begin treatment with perampanel should be closely monitored for adverse effects and receive a higher initial dose of perampanel. Addition or withdrawal of enzyme-inducing antiepileptic drugs may require a perampanel dose adjustment.
    Tramadol: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tramadol; Acetaminophen: (Moderate) Concomitant use of opioid agonists with perampanel may cause excessive sedation and somnolence. Limit the use of opioid pain medications with perampanel to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.
    Tranylcypromine: (Moderate) Use of perampanel with CNS depressants, including monoamine oxidase inhibitors (MAOIs), may increase CNS depression. MAOIs can also cause a variable change in seizure patterns, so careful monitoring of the patient taking perampanel for epilepsy is required.
    Triazolam: (Moderate) Patients taking benzodiazepines with perampanel may experience increased CNS depression. Monitor patients for adverse effects; dose adjustment of either drug may be necessary. Use of midazolam in healthy subjects who received perampanel 6 mg once daily for 20 days decreased the AUC and Cmax of midazolam by 13% and 15%, respectively, possibly due to weak induction of CYP3A4 by perampanel; the specific clinical significance of this interaction is unknown.
    Trifluoperazine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as phenothiazines.
    Trimipramine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as trimipramine. In addition, tricyclic antidepressants (TCAs), when used concomitantly with anticonvulsants, may also lower the seizure threshold, leading to pharmacodynamic interactions.
    Triprolidine: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as sedating H1-blockers.
    Vincristine Liposomal: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including perampanel (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vincristine: (Moderate) Vincristine is a substrate for cytochrome P450 (CYP) 3A4. Agents that induce CYP3A4 may increase the metabolism of vincristine and decrease the efficacy of the drug, including perampanel (in vitro). Patients receiving these drugs concurrently with vincristine should be monitored for possible loss of vincristine efficacy.
    Vonoprazan; Amoxicillin; Clarithromycin: (Moderate) Concurrent use of perampanel with clarithromycin may increase exposure to perampanel and increase plasma concentrations. Clarithromycin is a potent inhibitor of CYP3A4, an enzyme responsible for perampanel metabolism. Monitor patients for increases in adverse effects such as anger, anxiety, irritability, somnolence, dizziness, or nausea. Dose adjustment may be required.
    Vorapaxar: (Moderate) Use caution during concurrent use of vorapaxar and perampanel. Decreased serum concentrations of vorapaxar and thus decreased efficacy are possible when vorapaxar, a CYP3A4 substrate, is coadministered with perampanel, an inducer of CYP3A4 in vitro.
    Voriconazole: (Moderate) Ketoconazole, a potent CYP3A4 inhibitor, can prolong the half-life of perampanel and decrease perampanel metabolism. Administration of a single dose of perampanel 1 mg with ketoconazole 400 mg once daily for 8 days in healthy subjects increased perampanel half-life from 58.4 to 67.8 hours, and increased perampanel AUC by 20%. Patients taking ketoconazole and perampanel should be closely monitored for adverse effects; a perampanel dose adjustment may be necessary. Caution should also be used during concomitant use of perampanel with voriconazole, as it inhibits CYP3A4.
    Zaleplon: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as zaleplon.
    Zolpidem: (Moderate) Co-administration of perampanel with CNS depressants, including ethanol, may increase CNS depression. The combination of perampanel (particularly at high doses) with ethanol has led to decreased mental alertness and ability to perform complex tasks (such as driving), as well as increased levels of anger, confusion, and depression; similar reactions should be expected with concomitant use of other CNS depressants, such as zolpidem.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate data on the developmental risk associated with perampanel use during pregnancy in women. Animal data suggest that perampanel may be associated with fetal harm, as developmental toxicity occurred in pregnant rats and rabbits given perampanel. Perampanel doses of 1, 3, or 10 mg/kg/day administered to rats resulted in an increase in visceral abnormalities (diverticulum of the intestine); a dose of 1 mg/kg/day is similar to a human dose of 8 mg/day based on body surface area. Fetal death and delayed sexual maturation in male and female offspring were reported with mid to high doses. Doses of 30 or 60 mg/kg/day resulted in embryolethality and reduced fetal body weight. Embryolethality was also observed in rabbits given doses of 3 or 10 mg/kg/day. To monitor human fetal outcomes, pregnant women taking perampanel are encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Patients must enroll themselves by calling the registry at 1-888-233-2334.

    There are no data describing the presence of perampanel in human milk or the effects of perampanel on the breast-fed infant or milk production. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for perampanel and any potential adverse effects on the breast-fed infant from perampanel or the underlying maternal condition.

    MECHANISM OF ACTION

    Perampanel is a non-competitive, selective antagonist of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor that is present on post-synaptic neurons within the 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. 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 by 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%.

    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.