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PERAMPANEL

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Perampanel, an anticonvulsant, is a non-competitive antagonist of the AMPA glutamate receptors on post-synaptic neurons.

Specific Substances

    1) 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile hydrate (4:3)
    2) CAS 380917-97-5
    1.2.1) MOLECULAR FORMULA
    1) C23-H15-N3-O.3/4(H2-O)

Available Forms Sources

    A) FORMS
    1) Perampanel is available as 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg film-coated tablets (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) USES
    1) Perampanel is approved for use as adjunctive treatment of partial-onset seizures, with or without secondary development of generalized seizures, in patients with epilepsy aged 12 years or older(Prod Info FYCOMPA(TM) oral tablets, 2012).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Perampanel is approved for use as adjunctive treatment of partial-onset seizures in patients with epilepsy, 12 years of age or older, with or without development of generalized seizures secondarily.
    B) PHARMACOLOGY: Although the exact mechanism of action of perampanel has not been fully determined, it exerts its antiepileptic effects by reducing neuronal excitation via the noncompetitive antagonism of the ionotropic-AMPA-glutamate receptor on postsynaptic neurons.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects following therapeutic administration, with an incidence of at least 4% and occurring at least 1% higher than in the placebo group, include dizziness, somnolence, fatigue, irritability, dysarthria, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, and balance disorder.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include: diplopia, blurred vision, constipation, vomiting, upper respiratory tract infection, contusion, head injury, limb injury, skin laceration, hyponatremia, arthralgia, back pain, musculoskeletal pain, myalgia, pain in extremity, peripheral edema, asthenia, abnormal coordination, headache, hypersomnia, hypesthesia, memory impairment, paresthesia, aggression, anger, anxiety, confusion, euphoria, altered mental status, cough, and oropharyngeal pain.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic administration. Ingestion of 264 mg resulted in altered mental status, agitation, and aggressive behavior. A woman developed dysarthria, mild tiredness, impairment of consciousness, including intermittent agitation, misperception, disorientation of the situation after ingesting 204 mg (25.5 times her daily dose) of perampanel.
    0.2.20) REPRODUCTIVE
    A) There are no adequate and well-controlled studies of perampanel use in pregnant women. Perampanel may cause fetal harm when administered during pregnancy. Developmental toxicity, including visceral abnormalities, and embryolethality have been reported in animal studies. It is unknown whether perampanel is excreted into human breast milk or has adverse effects on milk production or the breastfed infant. Use in lactating women only after considering the mother's need for the drug, potential risk to the breastfed infant, and developmental and health benefits of breastfeeding.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Plasma concentrations of perampanel are not readily available or clinically useful in the management of overdose.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF TOXICITY
    1) Treatment is symptomatic and supportive. Control agitation and confusion with benzodiazepines. Correct any significant fluid and/or electrolyte abnormalities in patients with severe vomiting.
    B) DECONTAMINATION
    1) PREHOSPITAL: Prehospital gastrointestinal decontamination is generally not recommended because of the potential for CNS depression and subsequent aspiration.
    2) HOSPITAL: Consider activated charcoal if the overdose is recent, the patient is not vomiting, and is alert and able to maintain airway.
    C) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with significant CNS depression.
    D) ANTIDOTE
    1) None
    E) ENHANCED ELIMINATION
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding (approximately 96%).
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: Asymptomatic adults who inadvertently ingest an extra dose, or asymptomatic children who ingest a few pills can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be referred to a healthcare facility to be monitored for several hours. Signs and symptoms may be prolonged due to the long half-life of perampanel. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    G) PITFALLS
    1) Prolonged observation may be needed in patients who become symptomatic after overdose due to the long half life of perampanel. When managing a suspected perampanel overdose, the possibility of multidrug involvement should be considered. Symptoms of overdose are similar to reported side effects of the medication.
    H) PHARMACOKINETICS
    1) Rapidly and completely absorbed following oral administration. Approximately 96% bound to plasma proteins. Extensively metabolized via primary oxidation and sequential glucuronidation, with oxidative metabolism mediated by CYP3A4 and/or CYP3A5 based on in vitro studies. Following administration of radiolabeled perampanel to healthy elderly subjects (n=8), 22% and 48% were recovered in the urine and feces, respectively, and mainly composed of a mixture of oxidative and conjugated metabolites Half-life is approximately 105 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Other chemicals or drugs that cause CNS depression or altered mental status (eg, toxic alcohols, benzodiazepines, opiates/opioids, antipsychotic medications).

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established. A reported intentional ingestion of approximately 264 mg resulted in altered mental status, agitation, and aggressive behavior. A woman developed dysarthria, mild tiredness, impairment of consciousness, including intermittent agitation, misperception, disorientation and misjudging of situations after ingesting 204 mg (25.5 times her daily dose) of perampanel.
    B) THERAPEUTIC DOSE: Patients 12 years and older, the recommended initial dose is 2 to 4 mg once daily at bedtime, up to a maximum dose of 12 mg once daily at bedtime. Patients 11 years and younger, safety and efficacy have not been established.

Clinical Effects

Summary Of Exposure

    A) USES: Perampanel is approved for use as adjunctive treatment of partial-onset seizures in patients with epilepsy, 12 years of age or older, with or without development of generalized seizures secondarily.
    B) PHARMACOLOGY: Although the exact mechanism of action of perampanel has not been fully determined, it exerts its antiepileptic effects by reducing neuronal excitation via the noncompetitive antagonism of the ionotropic-AMPA-glutamate receptor on postsynaptic neurons.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) COMMON: The most commonly reported adverse effects following therapeutic administration, with an incidence of at least 4% and occurring at least 1% higher than in the placebo group, include dizziness, somnolence, fatigue, irritability, dysarthria, falls, nausea, weight gain, vertigo, ataxia, gait disturbance, and balance disorder.
    2) LESS FREQUENT: Other adverse effects that have occurred less frequently include: diplopia, blurred vision, constipation, vomiting, upper respiratory tract infection, contusion, head injury, limb injury, skin laceration, hyponatremia, arthralgia, back pain, musculoskeletal pain, myalgia, pain in extremity, peripheral edema, asthenia, abnormal coordination, headache, hypersomnia, hypesthesia, memory impairment, paresthesia, aggression, anger, anxiety, confusion, euphoria, altered mental status, cough, and oropharyngeal pain.
    E) WITH POISONING/EXPOSURE
    1) Overdose data are limited. In general, overdose effects are anticipated to be an extension of adverse effects following therapeutic administration. Ingestion of 264 mg resulted in altered mental status, agitation, and aggressive behavior. A woman developed dysarthria, mild tiredness, impairment of consciousness, including intermittent agitation, misperception, disorientation of the situation after ingesting 204 mg (25.5 times her daily dose) of perampanel.

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) DIPLOPIA: Diplopia occurred in 1%, 1%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    2) BLURRED VISION: Blurred vision occurred in 1%, 3%, and 4% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials. Blurred vision led to treatment discontinuation in 1% or more of patients in the perampanel 8 mg or 12 mg treatment groups (Prod Info FYCOMPA(TM) oral tablets, 2012).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) Oropharyngeal pain occurred in 2%, 2%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) PERIPHERAL EDEMA
    1) WITH THERAPEUTIC USE
    a) Peripheral edema occurred in 1%, 1%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) UPPER RESPIRATORY INFECTION
    1) WITH THERAPEUTIC USE
    a) Upper respiratory tract infection occurred in 3%, 3%, and 4% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 3% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) COUGH
    1) WITH THERAPEUTIC USE
    a) Cough occurred in 1%, 1%, and 4% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 3% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ASTHENIA
    1) WITH THERAPEUTIC USE
    a) Asthenia occurred in 1%, 2%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) ATAXIA
    1) WITH THERAPEUTIC USE
    a) Ataxia occurred in 1%, 3%, and 8% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 0% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials. Ataxia led to treatment discontinuation in 1% or more of patients in the perampanel 8 mg or 12 mg treatment groups (Prod Info FYCOMPA(TM) oral tablets, 2012).
    C) LOSS OF EQUILIBRIUM
    1) WITH THERAPEUTIC USE
    a) Balance disorder occurred in 0%, 5%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    D) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Dizziness occurred in 16%, 32%, and 43% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 9% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials. Dizziness led to treatment discontinuation in 1% or more of patients in the perampanel 8 mg or 12 mg treatment groups (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) Dizziness and vertigo occurred in 35% and 47% of patients with epilepsy randomized to receive perampanel 8 mg/day or 12 mg/day doses, respectively, compared with 10% of placebo-treated patients in controlled phase 3 trials. Toxicity usually developed during the titration phase, with therapy discontinued due to dizziness, gait disturbance, or vertigo in 3% of perampanel-treated patients and 1% of placebo-treated patients. Elderly patients were at increased risk for toxicity compared with adolescents and young adults (Prod Info FYCOMPA(TM) oral tablets, 2012).
    E) DYSARTHRIA
    1) WITH THERAPEUTIC USE
    a) Dysarthria occurred in 1%, 3%, and 4% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 0% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials. Dysarthria led to treatment discontinuation in 1% or more of patients in the perampanel 8 mg or 12 mg treatment groups (Prod Info FYCOMPA(TM) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 34-year-old woman with a medical history of symptomatic focal epilepsy due to tuberous sclerosis, with complex focal and generalized tonic-clonic seizures, presented with dysarthria and mild tiredness after intentionally ingesting 204 mg (25.5 times her daily dose) of perampanel. She started receiving perampanel 2 weeks before presentation as a participant in a double-blind, randomized phase III study. Her other medications for epilepsy included levetiracetam, topiramate, and pregabalin. She later developed profound deep sleep and had withdrawal symptoms in response to painful stimuli. She was transported to an intermediate care unit with Glasgow Coma Scale of 8, weak reflexes, and PERRLA (pupils equal, round, and reacted to light and accommodation) pupils. At this time, she developed impairment of consciousness, including intermittent agitation, misperception, and disorientation and misjudging situations. All of her medications were continued, but lamotrigine replaced perampanel (discontinued). It was determined that the suicide attempt was due to either substance-induced depressive syndrome or an organic depressive syndrome. She was transported to a psychiatric facility 2 days later (Hoppner et al, 2013).
    F) ABNORMAL GAIT
    1) WITH THERAPEUTIC USE
    a) Gait disturbance occurred in 1%, 4%, and 4% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) Gait disturbance related events (also including abnormal coordination, balance disorder, and ataxia) occurred in 12% and 16% of patients with epilepsy randomized to receive perampanel 8 mg/day or 12 mg/day doses, respectively, compared with 2% of placebo-treated patients in controlled phase 3 trials. Toxicity usually developed during the titration phase, with therapy discontinued due to dizziness, gait disturbance, or vertigo in 3% of perampanel-treated patients and 1% of placebo-treated patients. Elderly patients were at increased risk for toxicity compared with adolescents and young adults (Prod Info FYCOMPA(TM) oral tablets, 2012).
    G) HEADACHE
    1) WITH THERAPEUTIC USE
    a) Headache occurred in 11%, 11%, and 13% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 11% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    H) HYPERSOMNIA
    1) WITH THERAPEUTIC USE
    a) Hypersomnia occurred in 1%, 2%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 0% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    I) HYPESTHESIA
    1) WITH THERAPEUTIC USE
    a) Hypesthesia occurred in 0%, 0%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    J) MEMORY IMPAIRMENT
    1) WITH THERAPEUTIC USE
    a) Memory impairment occurred in 0%, 1%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    K) PARESTHESIA
    1) WITH THERAPEUTIC USE
    a) Paresthesia occurred in 0%, 1%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    L) DROWSY
    1) WITH THERAPEUTIC USE
    a) Somnolence occurred in 9%, 16%, and 18% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 7% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials. Treatment was discontinued due to somnolence or fatigue-related events in 2% of perampanel 8 mg or 12 mg/day-treated patients and 0.5% of placebo-treated patients. Elderly patients were at increased risk for somnolence and fatigue-related events compared to adolescents and young adults (Prod Info FYCOMPA(TM) oral tablets, 2012).
    M) CLOUDED CONSCIOUSNESS
    1) WITH THERAPEUTIC USE
    a) Confusional state occurred in 1%, 1%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with less than 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) Psychiatric events, including disorientation/confusional state, paranoia, agitation, euphoric mood, anger, and mental status changes, were reported in healthy volunteers with perampanel therapy. Disorientation occurred more frequently with perampanel therapy than with placebo treatment in non-epilepsy trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    2) WITH POISONING/EXPOSURE
    a) CASE REPORT: A 34-year-old woman with a medical history of symptomatic focal epilepsy due to tuberous sclerosis, with complex focal and generalized tonic-clonic seizures, presented with dysarthria and mild tiredness after intentionally ingesting 204 mg (25.5 times her daily dose) of perampanel. She started receiving perampanel 2 weeks before presentation as a participant in a double-blind, randomized phase III study. Her other medications for epilepsy included levetiracetam, topiramate, and pregabalin. She later developed profound deep sleep and had withdrawal symptoms in response to painful stimuli. She was transported to an intermediate care unit with Glasgow Coma Scale of 8, weak reflexes, and PERRLA (pupils equal, round, and reacted to light and accommodation) pupils. At this time, she developed impairment of consciousness, including intermittent agitation, misperception, and disorientation and misjudging of situations. All of her medications were continued, but lamotrigine replaced perampanel (discontinued). It was determined that the suicide attempt was due to either substance-induced depressive syndrome or an organic depressive syndrome. She was transported to a psychiatric facility 2 days later (Hoppner et al, 2013).
    N) FATIGUE
    1) WITH THERAPEUTIC USE
    a) Fatigue occurred in 8%, 8%, and 12% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 5% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) Fatigue-related events occurred in 12% and 15% of patients with epilepsy randomized to receive perampanel 8 mg/day or 12 mg/day doses, respectively, compared with 5% of placebo-treated patients in controlled phase 3 trials. Treatment was discontinued due to fatigue-related events or somnolence in 2% of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients were at increased risk of fatigue-related events and somnolence compared with adolescents and young adults (Prod Info FYCOMPA(TM) oral tablets, 2012).
    O) VERTIGO
    1) WITH THERAPEUTIC USE
    a) Vertigo occurred in 4%, 3%, and 5% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials. Vertigo led to treatment discontinuation in 1% or more of patients in the perampanel 8 mg or 12 mg treatment groups (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) Vertigo and dizziness occurred in 35% and 47% of patients with epilepsy randomized to receive perampanel 8 mg/day or 12 mg/day doses, respectively, compared to 10% of placebo-treated patients in controlled phase 3 trials. Toxicity usually developed during the titration phase, with therapy discontinued due to dizziness, gait disturbance, or vertigo in 3% of perampanel-treated patients and 1% of placebo-treated patients. Elderly patients were at increased risk for toxicity compared with adolescents and young adults (Prod Info FYCOMPA(TM) oral tablets, 2012).
    P) PSYCHOMOTOR AGITATION
    1) WITH POISONING/EXPOSURE
    a) A patient intentionally ingested 264 mg of perampanel and subsequently experienced altered mental status, agitation, and aggressive behavior. The patient recovered without sequelae (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) CASE REPORT: A 34-year-old woman with a medical history of symptomatic focal epilepsy due to tuberous sclerosis, with complex focal and generalized tonic-clonic seizures, presented with dysarthria and mild tiredness after intentionally ingesting 204 mg (25.5 times her daily dose) of perampanel. She started receiving perampanel 2 weeks before presentation as a participant in a double-blind, randomized phase III study. Her other medications for epilepsy included levetiracetam, topiramate, and pregabalin. She later developed profound deep sleep and had withdrawal symptoms in response to painful stimuli. She was transported to an intermediate care unit with Glasgow Coma Scale of 8, weak reflexes, and PERRLA (pupils equal, round, and reacted to light and accommodation) pupils. At this time, she developed impairment of consciousness, including intermittent agitation, misperception, and disorientation and misjudging situations. All of her medications were continued but lamotrigine replaced perampanel (discontinued). It was determined that the suicide attempt was due to either substance-induced depressive syndrome or an organic depressive syndrome. She was transported to a psychiatric facility 2 days later (Hoppner et al, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea occurred in 3%, 6%, and 8% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 5% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    b) Vomiting occurred in 2%, 3%, and 4% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 3% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) CONSTIPATION
    1) WITH THERAPEUTIC USE
    a) Constipation occurred in 2%, 2%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 2% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) CONTUSION
    1) WITH THERAPEUTIC USE
    a) Contusion occurred in 0%, 2%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) LACERATION OF SKIN
    1) WITH THERAPEUTIC USE
    a) Skin laceration occurred in 0%, 2%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) DISORDER OF EXTREMITY
    1) WITH THERAPEUTIC USE
    a) Limb injury occurred in 1%, 1%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with less than 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) Arthralgia occurred in 0%, 3%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    C) BACKACHE
    1) WITH THERAPEUTIC USE
    a) Back pain occurred in 2%, 2%, and 5% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 2% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    D) MUSCULOSKELETAL PAIN
    1) WITH THERAPEUTIC USE
    a) Musculoskeletal pain occurred in 1%, 1%, and 2% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    E) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) Myalgia occurred in 1%, 1%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 2% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).
    F) PAIN IN LIMB
    1) WITH THERAPEUTIC USE
    a) Pain in extremity occurred in 0%, 2%, and 3% of patients with partial-onset seizures (mean age, 35 years, 51% female) treated with perampanel 4 mg (n=172), 8 mg (n=431), or 12 mg (n=255) once daily, respectively, compared with 1% of placebo-treated patients (n=442) in phase 3 double-blind clinical trials (Prod Info FYCOMPA(TM) oral tablets, 2012).

Reproductive

    3.20.1) SUMMARY
    A) There are no adequate and well-controlled studies of perampanel use in pregnant women. Perampanel may cause fetal harm when administered during pregnancy. Developmental toxicity, including visceral abnormalities, and embryolethality have been reported in animal studies. It is unknown whether perampanel is excreted into human breast milk or has adverse effects on milk production or the breastfed infant. Use in lactating women only after considering the mother's need for the drug, potential risk to the breastfed infant, and developmental and health benefits of breastfeeding.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) An increase in visceral abnormalities (diverticulum of the intestine) was observed at all doses tested when pregnant rats were given oral perampanel 1, 3, or 10 mg/kg/day throughout organogenesis (1 mg/kg/day is similar to a human dose of 8 mg/day based on body surface area) (Prod Info FYCOMPA(R) oral tablets, suspension, 2016).
    3.20.3) EFFECTS IN PREGNANCY
    A) RISK SUMMARY
    1) There are no adequate and well-controlled studies of perampanel use in pregnant women. Advise pregnant women of the potential for fetal harm if perampanel is used during pregnancy. The North American Antiepileptic Drug (NAAED) Pregnancy Registry has been established to monitor the effects of in utero exposure to antiepileptic drugs, such as perampanel, and patients are encouraged to enroll themselves by calling 1-888-233-2334. Patients may also obtain information on the NAAED at www.aedpregnancyregistry.org/ (Prod Info FYCOMPA(R) oral tablets, suspension, 2016).
    B) ANIMAL STUDIES
    1) Embryolethality and reduced fetal body weight occurred when rats were given perampanel 30 or 60 mg/kg/day. A second study indicated fetal and pup deaths occurred when pregnant rats were given oral perampanel 3 or 10 mg/kg/day throughout gestation and lactation, while delayed male and female sexual maturation occurred at a dose of 10 mg/kg/day. Embryolethality was reported when pregnant rabbits were given oral perampanel 3 or 10 mg/kg/day throughout organogenesis (1 mg/kg/day approximately equals 2 times a human dose of 8 mg/day based on body surface area) (Prod Info FYCOMPA(R) oral tablets, suspension, 2016).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) LACK OF INFORMATION
    1) It is unknown whether perampanel is excreted into human breast milk or has adverse effects on milk production or the breastfed infant. Use in lactating women only after considering the mother's need for the drug, potential risk to the breastfed infant, and developmental and health benefits of breastfeeding (Prod Info FYCOMPA(R) oral tablets, suspension, 2016).
    B) ANIMAL STUDIES
    1) Perampanel and its metabolites have been detected in rat milk at higher concentrations than those in maternal plasma (Prod Info FYCOMPA(R) oral tablets, suspension, 2016).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) Although there were no clear effects on fertility in male and female rats administered oral perampanel 1, 10, or 30 mg/kg/day prior to and throughout mating and in females to gestation day 6, prolonged and/or irregular estrus cycles were noted at all doses tested. Plasma perampanel AUC exposures were lower at all tested doses than in humans administered 8 mg/day (Prod Info FYCOMPA(R) oral tablets, suspension, 2016).

Carcinogenicity

    3.21.4) ANIMAL STUDIES
    A) LACK OF EFFECT
    1) According to studies conducted in mice and rats, there was no evidence of drug-related tumors developing in either species following perampanel oral administration at doses up to 30 mg/kg/day in mice, and up to 30 mg/kg/day and 100 mg/kg/day in female and male rats, respectively. Plasma perampanel AUC exposures at the highest doses tested were less than that in humans dosed at 8 mg/day (Prod Info FYCOMPA(TM) oral tablets, 2012).

Genotoxicity

    A) There was no evidence of mutagenicity according to the in vitro Ames and mouse lymphoma tk assays, and in the in vivo rat micronucleus assay (Prod Info FYCOMPA(TM) oral tablets, 2012).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Plasma concentrations of perampanel are not readily available or clinically useful in the management of overdose.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) Asymptomatic adults who inadvertently ingest an extra dose, or asymptomatic children who ingest a few pills can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a Poison Center or medical toxicologist for assistance in managing patients with severe toxicity or for whom diagnosis is unclear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be referred to a healthcare facility to be monitored for several hours. Signs and symptoms may be prolonged due to the long half-life of perampanel. Patients that remain asymptomatic can be discharged.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Monitor vital signs and mental status.
    C) Monitor serum electrolytes in patients with significant vomiting.
    D) Plasma concentrations of perampanel are not readily available or clinically useful in the management of overdose.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Prehospital gastrointestinal decontamination is not recommended because of the potential for CNS depression and subsequent aspiration.
    6.5.2) PREVENTION OF ABSORPTION
    A) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive.
    B) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Monitor vital signs and mental status.
    3) Monitor serum electrolytes in patients with significant vomiting.
    4) Plasma concentrations of perampanel are not readily available or clinically useful in the management of overdose.

Enhanced Elimination

    A) HEMODIALYSIS
    1) Hemodialysis is UNLIKELY to be of value because of the high degree of protein binding.

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established. A reported intentional ingestion of approximately 264 mg resulted in altered mental status, agitation, and aggressive behavior. A woman developed dysarthria, mild tiredness, impairment of consciousness, including intermittent agitation, misperception, disorientation and misjudging of situations after ingesting 204 mg (25.5 times her daily dose) of perampanel.
    B) THERAPEUTIC DOSE: Patients 12 years and older, the recommended initial dose is 2 to 4 mg once daily at bedtime, up to a maximum dose of 12 mg once daily at bedtime. Patients 11 years and younger, safety and efficacy have not been established.

Therapeutic Dose

    7.2.1) ADULT
    A) WITHOUT ENZYME-INDUCING ANTIEPILEPTIC DRUGS: The recommended initial dose is 2 mg orally once daily at bedtime. The dose may be increased by increments of 2 mg/day once weekly to a dose of 4 to 8 mg once daily at bedtime; MAX recommended daily dose of 12 mg at bedtime (Prod Info FYCOMPA(R) oral tablets, 2014).
    B) WITH ENZYME-INDUCING ANTIEPILEPTIC DRUGS: The recommended initial dose is 4 mg orally once daily at bedtime. The dose may be increased by increments of 2 mg/day once weekly, up to a MAX recommended daily dose of 12 mg at bedtime (Prod Info FYCOMPA(R) oral tablets, 2014).
    7.2.2) PEDIATRIC
    A) 12 YEARS OR OLDER: WITHOUT ENZYME-INDUCING ANTIEPILEPTIC DRUGS: The recommended initial dose is 2 mg orally once daily at bedtime. The dose may be increased by increments of 2 mg/day once weekly to a dose of 4 to 8 mg once daily at bedtime; MAX recommended daily dose of 12 mg at bedtime (Prod Info FYCOMPA(R) oral tablets, 2014).
    B) 12 YEARS OR OLDER: WITH ENZYME-INDUCING ANTIEPILEPTIC DRUGS: The recommended initial dose is 4 mg orally once daily at bedtime. The dose may be increased by increments of 2 mg/day once weekly, up to a MAX recommended daily dose of 12 mg at bedtime (Prod Info FYCOMPA(R) oral tablets, 2014).
    C) 11 YEARS AND YOUNGER: Safety and efficacy have not been established (Prod Info FYCOMPA(R) oral tablets, 2014).

Maximum Tolerated Exposure

    A) CASE REPORT: A patient intentionally ingested approximately 264 mg of perampanel and subsequently experienced altered mental status, agitation, and aggressive behavior. The patient recovered without sequelae (Prod Info FYCOMPA(TM) oral tablets, 2012).
    B) CASE REPORT: A 34-year-old woman with a medical history of symptomatic focal epilepsy due to tuberous sclerosis, with complex focal and generalized tonic-clonic seizures, developed dysarthria and mild tiredness and later impairment of consciousness, including intermittent agitation, misperception, and disorientation and misjudging of situations, after ingesting 204 mg (25.5 times her daily dose) of perampanel. Lamotrigine was started after the discontinuation of perampanel. She was transported to a psychiatric facility 2 days later. It was determined that the suicide attempt was due to either substance-induced depressive syndrome or an organic depressive syndrome (Hoppner et al, 2013).

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Although the exact mechanism of action of perampanel has not been fully determined, it exerts its antiepileptic effects by reducing neuronal excitation via the noncompetitive antagonism of the ionotropic-AMPA-glutamate receptor on postsynaptic neurons (Prod Info FYCOMPA(TM) oral tablets, 2012).

Physicochemical

Physical Characteristics

    A) Perampanel is a white to yellowish white powder, freely soluble in N-methylpyrrolidone, sparingly soluble in acetonitrile and acetone, slightly soluble in methanol, ethanol, and ethyl acetate, and practically insoluble in heptane and water (Prod Info FYCOMPA(TM) oral tablets, 2012).

Molecular Weight

    A) 362.90 (3/4 hydrate) (Prod Info FYCOMPA(TM) oral tablets, 2012)

References

General Bibliography

    1) Chyka PA, Seger D, Krenzelok EP, et al: Position paper: Single-dose activated charcoal. Clin Toxicol (Phila) 2005; 43(2):61-87.
    2) Elliot CG, Colby TV, & Kelly TM: Charcoal lung. Bronchiolitis obliterans after aspiration of activated charcoal. Chest 1989; 96:672-674.
    3) FDA: Poison treatment drug product for over-the-counter human use; tentative final monograph. FDA: Fed Register 1985; 50:2244-2262.
    4) Golej J, Boigner H, Burda G, et al: Severe respiratory failure following charcoal application in a toddler. Resuscitation 2001; 49:315-318.
    5) Graff GR, Stark J, & Berkenbosch JW: Chronic lung disease after activated charcoal aspiration. Pediatrics 2002; 109:959-961.
    6) Harris CR & Filandrinos D: Accidental administration of activated charcoal into the lung: aspiration by proxy. Ann Emerg Med 1993; 22:1470-1473.
    7) Hoppner AC, Fauser S, & Kerling F: Clinical course of intoxication with the new anticonvulsant drug perampanel. Epileptic Disord 2013; 15(3):362-364.
    8) None Listed: Position paper: cathartics. J Toxicol Clin Toxicol 2004; 42(3):243-253.
    9) Pollack MM, Dunbar BS, & Holbrook PR: Aspiration of activated charcoal and gastric contents. Ann Emerg Med 1981; 10:528-529.
    10) Product Information: FYCOMPA(R) oral tablets, perampanel oral tablets. Eisai Inc. (per FDA), Woodcliff Lake, NJ, 2014.
    11) Product Information: FYCOMPA(R) oral tablets, suspension, perampanel oral tablets, suspension. Eisai Inc (per manufacturer), Woodcliff Lake, NJ, 2016.
    12) Product Information: FYCOMPA(TM) oral tablets, perampanel oral tablets. Eisai Inc. (per Manufacturer), Woodcliff Lake, NJ, 2012.
    13) Rau NR, Nagaraj MV, Prakash PS, et al: Fatal pulmonary aspiration of oral activated charcoal. Br Med J 1988; 297:918-919.