Suicidal ideation: Suicidal ideation and behavior have been reported in patients treated with anti-epileptic agents including FYCOMPA. 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 FYCOMPA.
Therefore patients 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.
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 FYCOMPA 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If signs and symptoms suggestive of these reactions appear, FYCOMPA should be withdrawn immediately and an alternative treatment considered (as appropriate).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 FYCOMPA, treatment with FYCOMPA must not be restarted in this patient at any time.
Neurologic effects: Dizziness, Disturbance in Gait and Coordination and Falls: FYCOMPA caused dose-related increases in events related to dizziness, disturbance in gait or coordination, and falls. In the absence of enzyme-inducing AEDS, the rate of coordination-related events at FYCOMPA doses of 8 to 12 mg/day was 54% for FYCOMPA vs 15% for placebo. In the presence of enzyme-inducing AEDs, the rates were 47% and 13% respectively.
These adverse reactions occurred mostly during the titration phase and led to discontinuation more frequently in FYCOMPA-treated patients than in placebo-treated. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents. An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with FYCOMPA (with and without concurrent seizures).
Somnolence- and Fatigue-Related Events: FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the absence of enzyme-inducing AEDS, the rate of somnolence/fatigue-related events at FYCOMPA doses of 8 to 12 mg/day was 39% for FYCOMPA vs 11% for placebo. In the presence of enzyme-inducing AEDs, the rates were 24% and 13% respectively.
Somnolence or fatigue-related events led to discontinuation more frequently in FYCOMPA-treated patients than placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and adolescents.
Hormonal contraceptives: At doses of 12 mg/day FYCOMPA may decrease the effectiveness of progestative-containing hormonal contraceptives; in this circumstance additional non-hormonal forms of contraception are recommended when using FYCOMPA.
End of treatment: It is recommended that discontinuation be undertaken gradually to minimize the potential for rebound seizures. However, due to its long half life and subsequent slow decline in plasma concentrations, FYCOMPA can be discontinued abruptly if absolutely needed.
Falls: There appears to be an increased risk of falls, particularly in the elderly; the underlying reason is unclear and may in part be related to the underlying diseases studied.
Aggression: Aggressive and hostile behavior has been reported in patients receiving FYCOMPA therapy. In FYCOMPA-treated patients in clinical trials, aggression, anger and irritability 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 behavior were observed in some patients (< 1% in FYCOMPA clinical studies). 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 FYCOMPA should be reduced if such symptoms occur and should be discontinued immediately if symptoms are severe.
Abuse potential: Caution should be exercised in patients with a history of substance abuse and the patient should be monitored for symptoms of FYCOMPA abuse.
Substantial Decrease in Mean FYCOMPA Blood Levels for Patients on Concomitant CYP3A Enzyme-Inducing AEDs (Carbamazepine, Oxcarbazepine, Phenytoin): Carbamazepine, oxcarbazepine, and phenytoin (all strong cytochrome P450 inducers) decrease FYCOMPA plasma concentrations and efficacy to a clinically significant extent, as compared to patients not on these AEDs. The rate of occurrence of adverse events in clinical trials was often greater in the absence of concomitant enzyme-inducing AEDs (EI-AEDs), apparently reflecting higher mean FYCOMPA blood levels in that condition of use.
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.
Endrocrine and Metabolism: FYCOMPA 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 these medicines.
Hepatotoxicity: Cases of hepatotoxicity (mainly hepatic enzyme increased) with FYCOMPA in combination with other antiepileptic drugs have been reported. If hepatic enzymes elevation is observed, monitoring of liver function should be considered.
Caution with Driving and Use of Machinery: FYCOMPA 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 requiring mental alertness, until the effect of FYCOMPA is known.