perampanel (Rx)

>10%

Dizziness (16-43%)

Somnolence (9-18%)

Headache (11-13%)

Fatigue (8-12%)

Irritability (4-12%)

1-10%

Falls (2-10%)

Nausea (6-8%)

Ataxia (1-8%)

Vertigo (3-5%)

Balance disorder (3-5%)

Back pain (2-5%)

Weight gain (4%)

Vomiting (2-4%)

Anxiety (3-4%)

Blurred vision (1-4%)

Dysarthria (1-4%)

Cough (1-4%)

Hypoaesthesia (3%)

Constipation (2-3%)

Arthralgia (2-3%)

Extremity pain (2-3%)

Aggression (1-3%)

Anger (1-3%)

Myalgia (1-3%)

Diplopia (1-3%)

Injuries due to falls (1-3%)

Hypersomnia (1-3%)

Hyponatremia (2%)

Contusions (2%)

Oropharyngeal pain (2%)

Asthenia (1-2%)

Confusional state (1-2%)

Euphoric mood (1-2%)

Altered mood (1-2%)

Abnormal coordination (1-2%)

Musculoskeletal pain (1-2%)

Peripheral edema (1-2%)

Memory impairment (1-2%)

Paraesthesia (1-2%)

Postmarketing Reports

Acute psychosis, hallucinations, delusions, paranoia, delirium, disorientation, drug reaction with eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity

Contraindications

None

Cautions

Serious psychiatric and behavioral reactions

• Aggression-related adverse reactions reported at doses of 8 mg and 12 mg per day, these effects were dose-related and generally appeared within first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks
• Other symptoms included belligerence, affect lability, agitation, and physical assault; some events were reported as serious and life-threatening; homicidal ideation and/or threat also reported postmarketing
• These events occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression
• Some patients experienced worsening of their pre-existing psychiatric conditions; patients with active psychotic disorders and unstable recurrent affective disorders have not been studied
• Combination with alcohol significantly worsened mood and increased anger; patients receiving therapy should avoid use of alcohol
• Similar serious psychiatric and behavioral events also reported in patients with primary generalized tonic-clonic seizure; psychiatric events included paranoia, euphoric mood, agitation, anger,mental status changes, and disorientation/confusional state
• in the postmarketing setting, there have also been reports of psychosis (acute psychosis, hallucinations, delusions, paranoia)and delirium (delirium, confusional state, disorientation, memory impairment) in patients receiving therapy
• Patients, their caregivers, and families should be informed that the drug may increase risk of psychiatric events; patients should be monitored during treatment and for at least 1 month after last dose, and especially when taking higher doses and during initial few weeks of drug therapy (titration period) or at other times of dose increases; dose should be reduced if these symptoms occur
• Permanently discontinue therapy for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation

Suicidal behavior and ideation

• Antiepileptic drugs (AEDs) increase risk of suicidal thoughts or behavior in patients taking these drugs for any indication; patients treated with any AED for any indication should be monitored for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior
• The increased risk of suicidal thoughts or behavior with AEDs reported as early as 1 week after starting drug treatment with AEDs and persisted for duration of treatment assessed; because assessment did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be determined
• Anyone considering prescribing this drug or any other AED must balance risk of suicidal thoughts or behavior with risk of untreated illness; epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior; should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to illness being treated

Neurologic effects

• Dose-related increases in dizziness and disturbance in gait or coordination reported among patients with partial-onset seizure; these adverse reactions also observed in patients with primary generalized tonic-clonic seizures
• Dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy) also reported; adverse reactions occurred mostly during titration phase; also reported with primary generalized tonic-clonic seizures
• An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, reported in patients being treated with this drug (with and without concurrent seizures); elderly patients reported to have increased risk of falls compared to younger adults and pediatric patients
• Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until effect known; patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when drug is used with other drugs with sedative properties because of potential additive effect

Drug reaction with eosinophilia and systemic symptoms (DRESS)

• Also known as multiorgan hypersensitivity, DRESS has been reported in patients receiving therapy; DRESS may be fatal or life-threatening; DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection; eosinophilia is often present
• Because this disorder is variable in its expression, other organ systems not noted here may be involved; important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident; if such signs or symptoms are present, the patient should be evaluated immediately
• Therapy should be discontinued if an alternative etiology for signs or symptoms cannot be established

Withdrawal of antiepileptic drugs

• There is potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly; this drug has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually; in epilepsy clinical trials was withdrawn without down-titration; although a small number of patients exhibited seizures following discontinuation, the data were not sufficient to allow any recommendations regarding appropriate withdrawal regimens
• A gradual withdrawal is generally recommended with antiepileptic drugs, but if withdrawal is a response to adverse events, prompt withdrawal can be considered

Drug interaction overview

• Moderate to strong CYP3A4 inducers (eg, carbamazepine, oxcarbazepine, phenytoin, phenobarbital, primidone, topiramate) may greatly increase clearance, resulting in reduced perampanel plasma concentrations (see Dosage Modifications)

Pregnancy

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs); encourage women to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org

There are no adequate data on the developmental risk associated with use in pregnant women; in animal studies, perampanel induced developmental toxicity in pregnant rat and rabbit at clinically relevant doses

Contraception

• Advise women who are using a levonorgestrel-containing contraceptive to use an additional non-hormonal form (eg, condoms) of contraception while in therapy and for a month after discontinuation

Lactation

Perampanel and/or its metabolites are present in rat milk, and are detected at concentrations higher than that in maternal plasma

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on the breastfed child from therapy or from the underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Noncompetitive antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor on post-synaptic neurons; glutamate is a primary excitatory neurotransmitter in the CNS and is implicated in various neurological disorders caused by neuronal over excitation

The mechanism for its antiepileptic effects in humans is still unknown

Absorption

Rapid and complete absorption

Bioavailability: Oral suspension has comparable bioavailability to tablets under steady state; both formulations may be used interchangeably

Peak Plasma Time: 0.5-2.5 hr (fasting)

Food does not affect extent of absorption, but slows rate of absorption; Cmax decreased by 11-40% and Tmax delayed by 1-3 hr compared to fasted conditions

Distribution

Protein Bound: 95-96% (mainly albumin and alfa1-acid glycoprotein)

Blood to plasma ratio: 0.55-0.59

Metabolism

Extensively metabolized in liver via primary oxidation and sequential glucuronidation

In vitro studies indicated, oxidative metabolism mediated mainly by CYP3A4 and/or CYP3A5; lesser extent by CYP1A2 and CYP2B6

Elimination

Half-life: 105 hr

Renal clearance: 12 mL/min

Excretion: Feces (48%); urine (22%)

Oral Administration

May take tablet or oral suspension with or without food

Tablet and oral suspension may be used interchangeably on a mg-per-mg basis

Oral suspension

• Shake well before measuring dose for each administrations
• Use provided adapter and graduated oral dosing syringe to accurately administer the oral suspension; household teaspoons or tablespoons are not an adequate measuring device
• The adapter, which is supplied in the product carton, should be inserted firmly into the neck of the bottle before use and remain in place for the duration of the usage of the bottle
• The dosing syringe should be inserted into the adapter and the dose withdrawn from the inverted bottle
• The cap should be replaced after each use; the cap fits properly when the adapter is in place
• Discard any unused oral suspension remaing 90 days after first opening the bottle

Storage

Tablet

• Store at room temperature: 68 - 77°F (20- 25°C); excursions permitted to 59-86°F (15-30°C)

Oral suspension

• Do not store above 86°F (30°C). Do not freeze. Use within 90 days after the first opening of the bottle.