Precautions

Important Precautions Precaution on Special Populations Precaution Concerning Dosage & Administration Precaution Concerning Use (N/A)

Important Precautions

Effects on Ability to Drive and Use Machines

Perampanel has moderate influence on the ability to drive and use machines. Perampanel may cause dizziness and somnolence and therefore may influence the ability to drive or use machines. Patients are advised not to drive a vehicle, operate complex machinery or engage in other potentially hazardous activities until it is known whether perampanel affects their ability to perform these tasks.

Aggression, Psychotic disorder

Aggressive and hostile behavior has been reported in patients receiving perampanel therapy. In perampanel-treated patients in clinical trials, aggression, irritability, and psychotic disorder were reported more frequently at higher doses. Most of the reported events were either mild or moderate and patients recovered either spontaneously or with dose adjustment. However, thoughts of harming others, physical assault or threatening behaviour were observed in some patients (< 1% in perampanel clinical studies). Homicidal ideation has been reported in patients. Patients and caregivers should be counseled to alert a health care professional immediately if significant changes in mood or patterns of behavior are noted. The dosage of perampanel should be reduced if such symptoms occur and should be discontinued immediately if symptoms are severe.

Suicidal ideation

Suicidal ideation and behavior have been reported in patients treated with antiepileptic medicinal products in several indications. A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has also shown a small increased risk of suicidal ideation and behavior. The mechanism of this risk is not known and the available data do not exclude the possibility of an increased risk for perampanel. Therefore, patients (children, adolescents, and adults) should be monitored for signs of suicidal ideation and behaviors and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behavior emerge.

Nervous system disorders

Perampanel may cause dizziness and somnolence and therefore may influence the ability to drive or use machines.

Severe cutaneous adverse reactions (SCARs)

Severe cutaneous adverse reactions (SCARs) including drug reaction with eosinophilia and systemic symptoms (DRESS) and Stevens – Johnson Syndrome (SJS), which can be life-threatening or fatal, have been reported (frequency unknown; in association with perampanel treatment. At the time of prescription patients should be advised of the signs and symptoms and monitored closely for skin reactions. Symptoms of DRESS include typically, although not exclusively, fever, rash associated with other organ system involvement, lymphadenopathy, liver function tests abnormalities and eosinophilia. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. Symptoms of SJS include typically although not exclusively, skin detachment (epidermal necrosis/blister) < 10%, erythematous skin (confluent), rapid progression, painful atypical target-like lesions and/or purpuric macules in wide dissemination or large erythema (confluent), bullous/erosive involvement of more than 2 mucous membranes. If signs and symptoms suggestive of these reactions appear, perampanel should be withdrawn immediately and an alternative treatment considered (as appropriate). If the patient has developed a serious reaction such as SJS or DRESS with the use of perampanel, treatment with perampanel must not be restarted in this patient at any time.

Hormonal contraceptives

At doses of 12 mg/day perampanel may decrease the effectiveness of progestative containing hormonal contraceptives; in this circumstance additional non-hormonal forms of contraception are recommended when using perampanel.

Falls

There appears to be an increased risk of falls, particularly in the elderly; the underlying reason is unclear.

Abuse potential

Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of perampanel abuse.

Concomitant CYP3A inducing anti-epileptic medicinal products

Response rates after addition of perampanel at fixed doses were lower when patients received concomitant CYP3A enzyme-inducing anti-epileptic medicinal products (carbamazepine, phenytoin, oxcarbazepine) as compared to response rates in patient who received concomitant nonenzyme–inducing anti-epileptic medicinal products. Patient’s response should be monitored when they are switching from concomitant non-inducer antiepileptic medicinal products to enzyme-inducing medicinal products and vice versa. Depending upon individual clinical response and tolerability, the dose may be increased or decreased 2 mg at a time.

Other concomitant (non- anti-epileptic) cytochrome P450 inducing or inhibiting medicinal products

Patients should be closely monitored for tolerability and clinical response when adding or removing cytochrome P450 inducers or inhibitors, since perampanel plasma levels can be decreased or increased; the dose of perampanel may need to be adjusted accordingly.

 Absence and myoclonic seizures

Absence and myoclonic seizures are two common generalised seizure types that frequently occur in IGE patients. Other AEDs are known to induce or aggravate these seizure types. Patients with myoclonic seizures and absence seizures should be monitored while on Perampanel.

Hepatotoxicity

Cases of hepatotoxicity (mainly hepatic enzyme increased) with perampanel in combination with other antiepileptic drugs have been reported. If hepatic enzymes elevation is observed, monitoring of liver function should be considered.

Excipients

Lactose intolerance

Perampanel film-coated tablets contain lactose, therefore patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.


Precautions on Special Populations

Elderly (65 years of age and above)

Clinical studies of perampanel in epilepsy did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Analysis of safety information in 905 perampanel-treated elderly patients (in double-blind studies conducted in non-epilepsy indications) revealed no age-related differences in the safety profile. In combination with the lack of age-related difference in perampanel exposure, the results indicate that dose adjustment in the elderly is not required. Perampanel should be used with caution in elderly taking into account the drug interaction potential in polymedicated patients.

Renal impairment

Dose adjustment is not required in patients with mild renal impairment. Use in patients with moderate or severe renal impairment or patients undergoing hemodialysis is not recommended.

Hepatic impairment

Dose increases in patients with mild and moderate hepatic impairment should be based on clinical response and tolerability. For patients with mild or moderate hepatic impairment, dosing can be initiated at 2 mg. Patients should be up-titrated using 2 mg doses no faster than every 2 weeks based on tolerability and effectiveness. Perampanel dosing for patients with mild and moderate impairment should not exceed 8 mg. Use in patients with severe hepatic impairment is not recommended.

Paediatric patients

The safety and efficacy of perampanel have not yet been established in children below 4 years of age in the POS indication or in children below 7 years of age in the PGTCS indication.


 Precaution Concerning Dosage & Administration

Withdrawal

It is recommended that discontinuation be undertaken gradually to minimise the potential for rebound seizures. However, due to its long half-life and subsequent slow decline in plasma concentrations, perampanel can be discontinued abruptly if absolutely needed.

Missed doses

Single missed dose: As perampanel has a long half-life, the patient should wait and take their next dose as scheduled.If more than 1 dose has been missed, for a continuous period of less than 5 half-lives (3 weeks for patients not taking perampanel metabolism-inducing AEDs, 1 week for patients taking perampanel metabolism inducing AEDs, consideration should be given to re-start treatment from the last dose level.

If a patient has discontinued perampanel for a continuous period of more than 5 half-lives, it is recommended that initial dosing recommendations given above should be followed.