Usage
Perampanel is an anticonvulsant medication prescribed for the adjunctive treatment of partial-onset seizures (with or without secondary generalization) in patients aged 4 years and older, and primary generalized tonic-clonic seizures in patients aged 12 years and older with epilepsy. Its pharmacological classification is anticonvulsant. Perampanel works by selectively antagonizing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, a subtype of ionotropic glutamate receptors. This action reduces neuronal excitation and helps prevent seizures.
Alternate Names
The International Nonproprietary Name (INN) is perampanel. A common brand name is Fycompa.
How It Works
Pharmacodynamics: Perampanel acts primarily by non-competitively antagonizing AMPA receptors, inhibiting the excitatory neurotransmitter glutamate. This mechanism reduces neuronal hyperexcitability associated with seizures.
Pharmacokinetics:
- Absorption: Perampanel is almost completely absorbed after oral administration, with or without food. Peak plasma concentration is reached in approximately 1 to 4.5 hours (median: 2.5 hrs) after a single dose.
- Distribution: Perampanel has a large volume of distribution, indicating extensive tissue binding.
- Metabolism: It is extensively metabolized primarily by CYP3A4 hepatic enzymes, with minor contributions from CYP2A6 and CYP2B6.
- Elimination: Perampanel is primarily eliminated through hepatic metabolism with renal excretion playing a minor role (approximately 30% as metabolites and less than 2% as unchanged drug). The elimination half-life is approximately 50 to 130 hours, allowing for once-daily dosing. The half-life can be shortened by concomitant use of strong CYP3A4 inducers (like carbamazepine, phenytoin, oxcarbazepine).
Mode of Action: Perampanel’s primary mode of action is the selective non-competitive antagonism of post-synaptic AMPA receptors. It doesn’t directly bind to the glutamate binding site but to an allosteric site on the AMPA receptor. This binding inhibits glutamate-mediated excitatory currents, thus decreasing neuronal excitability.
Receptor Binding, Enzyme Inhibition, or Neurotransmitter Modulation: The primary mechanism is AMPA receptor antagonism. It does not significantly affect other glutamate receptor subtypes or common voltage-gated ion channels.
Elimination Pathways: Perampanel is predominantly eliminated via hepatic metabolism by CYP3A4 and to a lesser extent by CYP2A6 and CYP2B6. Less than 2% is excreted unchanged in urine. Metabolites are mainly excreted in urine with a small fraction in feces.
Dosage
Standard Dosage
Adults:
Initial dose: 2 mg orally once daily at bedtime. Dosage is titrated upward in 2 mg increments no more frequently than weekly intervals (or every 2 weeks in patients on drugs that do not affect perampanel half-life), based on clinical response and tolerability. The maintenance dose range is 8-12 mg/day. Some patients may respond to 4 mg/day, while others may need up to 12 mg/day.
Children (4 years and older):
- Partial-Onset Seizures: Initial dose: 2 mg orally once daily at bedtime. The dose can be increased by 2 mg/day increments no more frequently than weekly intervals based on individual clinical response and tolerability. The maximum dose is 12 mg/day. Some patients may respond to 4 mg/day.
- Primary Generalized Tonic-Clonic Seizures (12 years and older): Same as adult dosing.
Special Cases:
- Elderly Patients: Dose titration should not occur more frequently than every 2 weeks, beginning at 2 mg.
- Patients with Renal Impairment: No dose adjustment is necessary.
- Patients with Hepatic Dysfunction:
- Mild Impairment: Maximum dose 6 mg/day. Titrate every 2 weeks.
- Moderate Impairment: Maximum dose 4 mg/day. Titrate every 2 weeks.
- Severe Impairment: Use not recommended.
- Patients with Comorbid Conditions: Dosage adjustments should be made based on the specific comorbidity and potential drug interactions.
Clinical Use Cases
Perampanel’s use is exclusively focused on the aforementioned seizure types as an add-on therapy. It is not indicated for use in clinical scenarios like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dose titration and adjustments should be made based on clinical response and tolerability, particularly in patients with hepatic impairment or those taking concomitant medications that affect CYP3A4 activity.
Dose modification frequency should be weekly or bi-weekly depending on concomitant medications that may affect half-life.
Side Effects
Common Side Effects
Dizziness, somnolence, fatigue, irritability, nausea, headache, vertigo, ataxia, diplopia, blurred vision, weight gain, and falls.
Rare but Serious Side Effects
Severe psychiatric and behavioral reactions (e.g., aggression, hostility, anger, homicidal ideation, and psychotic symptoms), hyponatremia, and severe allergic reactions (e.g. angioedema).
Long-Term Effects
Potential long-term effects include cognitive impairment and behavioral changes. These require close monitoring.
Adverse Drug Reactions (ADR)
Serious psychiatric and behavioral ADRs may occur. These include aggression, hostility, anger, and homicidal ideation. Any such symptoms require immediate medical evaluation and possible discontinuation of perampanel.
Contraindications
Hypersensitivity to perampanel or any component of the formulation is the only absolute contraindication.
Drug Interactions
- CYP450 Interactions: Strong CYP3A4 inducers (e.g., carbamazepine, phenytoin, rifampin, and St. John’s wort) can decrease perampanel plasma concentrations, requiring dosage adjustments. CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) may increase perampanel plasma concentrations.
- Other Medications: Perampanel may enhance the CNS depressant effects of alcohol and other CNS depressants (e.g., benzodiazepines, opioids). It may also decrease the effectiveness of levonorgestrel-containing hormonal contraceptives.
- Food and Lifestyle Factors: Alcohol should be avoided due to additive CNS depression.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Pregnancy Category C. Perampanel has been shown to be teratogenic in some animal studies. It should only be used during pregnancy if the benefits clearly outweigh the potential risks.
- Fetal Risks: Potential developmental risks exist. Consider enrollment in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
- Breastfeeding: Perampanel and/or its metabolites are present in rat milk at concentrations higher than in maternal plasma. It is unknown if the drug is found in human breast milk. If perampanel is required, monitor the infant for drowsiness, agitation, and adequate weight gain.
Drug Profile Summary
- Mechanism of Action: Non-competitive AMPA receptor antagonist.
- Side Effects: Dizziness, somnolence, fatigue, irritability, nausea, falls, and serious psychiatric and behavioral reactions.
- Contraindications: Hypersensitivity to perampanel.
- Drug Interactions: CYP3A4 inducers and inhibitors, CNS depressants, and levonorgestrel-containing contraceptives.
- Pregnancy & Breastfeeding: Potential developmental risks. Monitor infants for adverse effects if perampanel is used during breastfeeding.
- Dosage: Adults and children 4 years and older: Start at 2 mg once daily at bedtime, titrate up to 8-12 mg/day as needed and tolerated. Adjustments needed for hepatic impairment and concomitant medications.
- Monitoring Parameters: Seizure frequency, mood changes, behavioral changes, and signs of hyponatremia.
Popular Combinations
Perampanel is often combined with other antiepileptic drugs (AEDs) like levetiracetam, lamotrigine, and valproic acid. However, the specific combinations are determined based on the individual patient’s seizure type and response to therapy. Concomitant use of CYP3A4 inducing AEDs like carbamazepine, phenytoin and oxcarbazepine requires careful dosage adjustment of perampanel.
Precautions
- General Precautions: Assess for hypersensitivity, hepatic and renal function, and psychiatric history before initiating therapy. Monitor closely for mood and behavioral changes.
- Specific Populations: Use with caution in the elderly and patients with hepatic impairment. It is not recommended in patients with severe hepatic impairment. Assess risks versus benefits carefully in pregnant and breastfeeding women. Safety and efficacy have not been established in children younger than 4 years for partial-onset seizures or younger than 12 years for primary generalized tonic-clonic seizures.
- Lifestyle Considerations: Advise patients to avoid alcohol and operate machinery or drive until the effects of the drug are known.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Perampanel?
A: Adults and children 4 years and older: Initial dose is 2 mg orally once daily at bedtime, titrated upward in 2 mg increments no more frequently than weekly intervals (or bi-weekly as appropriate) up to a maximum of 12 mg/day based on individual clinical response and tolerability. Adjustments are necessary for hepatic impairment and concomitant CYP3A4-modulating medications.
Q2: What is the mechanism of action of Perampanel?
A: Perampanel is a selective, non-competitive AMPA receptor antagonist. It binds to an allosteric site on the receptor, inhibiting glutamate-mediated neuronal excitation and reducing seizure activity.
Q3: What are the most common side effects of Perampanel?
A: Common side effects include dizziness, somnolence, fatigue, irritability, nausea, headache, vertigo, ataxia, diplopia, blurred vision, weight gain, and falls.
Q4: What are the serious side effects of Perampanel?
A: Serious side effects include neuropsychiatric events (e.g., aggression, hostility, anger, homicidal ideation, psychosis), hyponatremia, and allergic reactions.
Q5: What are the contraindications to Perampanel?
A: Hypersensitivity to perampanel is the only absolute contraindication.
Q6: What are the key drug interactions with Perampanel?
A: Perampanel interacts with strong CYP3A4 inducers (e.g., carbamazepine, phenytoin) and inhibitors (e.g., ketoconazole), CNS depressants (e.g., alcohol, benzodiazepines), and hormonal contraceptives containing levonorgestrel.
Q7: Can Perampanel be used during pregnancy and breastfeeding?
A: Perampanel is Pregnancy Category C. It has potential fetal risks and should only be used during pregnancy if the benefits clearly outweigh the risks. Its presence in human breast milk is unknown. Monitor infants for adverse effects if use is necessary during breastfeeding.
Q8: How should Perampanel be administered?
A: Administer orally once daily at bedtime with or without food. Swallow tablets whole; do not chew or crush.
Q9: What monitoring parameters are important for patients on Perampanel?
A: Monitor for seizure frequency, changes in mood and behavior (especially signs of aggression, hostility, or depression), signs of hyponatremia (e.g., confusion, nausea, vomiting), and adverse reactions.
Q10: How are doses adjusted for patients with hepatic impairment?
A: For patients with mild hepatic impairment, the maximum dose is 6 mg/day. For moderate impairment, the maximum is 4 mg/day. Titrate dosage every two weeks. Perampanel is not recommended for patients with severe hepatic impairment.
