Perspectives for the Pharmacist in Epilepsy Management: Considerations for the Use of FYCOMPA(R) (perampanel) Tablets and Oral Suspension, CIII

SEPTEMBER 13, 2017
This article is brought to you by Eisai Inc.

According to the National Institutes of Health, epilepsy affects approximately 3 million Americans, with an incidence highest in early childhood. There is an estimated 3% lifetime risk for developing a new case of epilepsy by the age of 80 years.1 Seizures that occur in association with epilepsy are generally classified as focal (partial) seizures, which affect a limited area of the brain, or as generalized seizures, which may affect the entire brain.2,3 Some patients may experience nonconvulsive seizures, while other patients may experience convulsive seizures, such as tonic-clonic seizures, which may involve loss of consciousness and repeated muscle contractions.3

Currently, approximately one-third of patients continue to have uncontrolled epilepsy despite pharmacotherapy.3,4 Pharmacists have a crucial role in ensuring the appropriate use of therapy of antiepileptic medications and in detecting and managing drug-drug interactions with these medications.3,5 Additionally, considering that an estimated 30% to 60% of patients with epilepsy are not adherent with their treatment regimen, pharmacists have an important role in promoting treatment adherence.6

FYCOMPA has Established Efficacy in Treating Convulsive Seizures Regardless of Origin
FYCOMPA (perampanel) is a treatment option for seizure management with indications for use in both partial-onset seizures and primary generalized tonic-clonic seizures. FYCOMPA is indicated for the treatment of partial-onset seizures with or without secondarily generalized seizures, and as adjunctive therapy for treatment of primary generalized tonic-clonic seizures in patients with epilepsy 12 years of age and older.7 Across studies, FYCOMPA demonstrated established efficacy in treating convulsive seizures, including partial-onset seizures with secondarily generalized seizures and primary generalized tonic-clonic seizures (TABLE7-9).


Mechanism of Action
FYCOMPA is the first and only noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist specifically engineered to block glutamate activity at postsynaptic AMPA receptors. Glutamate imbalance is implicated in nervous system disorders related to overexcitation, including seizures. FYCOMPA is thought to exert its effects by antagonizing glutamate, the primary excitatory neurotransmitter in the central nervous system. The precise mechanism by which FYCOMPA exerts its antiepileptic effects in humans is unknown. Importantly, with its long half-life of approximately 105 hours, doses of FYCOMPA should be administered once daily, at bedtime. As a result of its long half-life, blood levels reach steady state gradually over approximately 2 to 3 weeks and fall gradually with discontinuation.7

Dose Titration With FYCOMPA
Appropriate dose titration is critical to the success of patients taking FYCOMPA, as some adverse reactions may be more likely during the dose titration period and at higher doses of FYCOMPA treatment.7
 
SELECTED SAFETY INFORMATION
  
WARNING: SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS
  • Serious or life-threatening psychiatric and behavioral adverse reactions including aggression, hostility, irritability, anger, and homicidal ideation and threats have been reported in patients taking FYCOMPA
  • These reactions occurred in patients with and without prior psychiatric history, prior aggressive behavior, or concomitant use of medications associated with hostility and aggression
  • Advise patients and caregivers to contact a healthcare provider immediately if any of these reactions or changes in mood, behavior, or personality that are not typical for the patient are observed while taking FYCOMPA or after discontinuing FYCOMPA
  • Closely monitor patients particularly during the titration period and at higher doses
  • FYCOMPA should be reduced if these symptoms occur and should be discontinued immediately if symptoms are severe or are worsening






















Click here for additional Selected Safety Information.

FYCOMPA is available in 2 forms: as tablets and as an oral suspension. Tablets of FYCOMPA are available in 2 mg, 4 mg, 6 mg, 8 mg, 10 mg, and 12 mg strengths, and the oral suspension is available in a 0.5 mg/mL concentration.7

FYCOMPA should be initiated at a dose of 2 mg daily in patients not receiving antiepileptic drugs that induce CYP3A4. FYCOMPA should be initiated at a dose of 4 mg daily in patients receiving moderate or strong CYP3A4 inducers, such as carbamazepine, phenytoin, or oxcarbazepine (FIGURE7). Increase no more frequently  than at weekly intervals. For example, intervals between dose increases may be every 2 or 3 weeks, or even every 4 weeks. Gradual dose titration is especially important in patients with hepatic impairment, renal impairment, or in elderly patients.7



It is important to direct patients to take medication at bedtime, with or without food. Patients should also be aware that FYCOMPA may reduce the effectiveness of oral contraceptives containing levonorgestrel. Both pharmacists and patients should be aware that FYCOMPA is a Schedule III controlled substance.7

Role of the Pharmacist
FYCOMPA is classified as a Schedule III medication, so it is important to plan the days’ supply with both the physician and the patient to avoid interruptions of therapy. It is also important for pharmacists to remember that patients should initiate therapy at a 2-mg daily dose in patients who are not taking moderate or strong CYP3A4 inducers, or a 4-mg daily dose in patients who are also taking moderate or strong CYP3A4 inducers. During titration, the dose of FYCOMPA should be increased at a maximum of 2-mg increments, no more frequently than at weekly intervals. For example, intervals between dose increases may be every 2 or 3 weeks, or even every 4 weeks.7

 Through appropriate counseling and advice for patients and caregivers, pharmacists can help optimize therapy in patients with epilepsy to promote optimal patient outcomes.

INDICATION
FYCOMPA® (perampanel) is indicated in patients with epilepsy 12 years of age and older for the treatment of partial-onset seizures (POS) with or without secondarily generalized seizures and adjunctive therapy in the treatment of primary generalized tonic-clonic (PGTC) seizures.
 
SELECTED SAFETY INFORMATION

SERIOUS PSYCHIATRIC AND BEHAVIORAL REACTIONS
In the partial-onset seizures clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 6% of patients in the placebo group. These effects were dose-related and generally appeared within the first 6 weeks of treatment, although new events continued to be observed through more than 37 weeks. These effects in FYCOMPA-treated patients led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Homicidal ideation and/or threat have also been reported postmarketing in patients treated with FYCOMPA. The combination of alcohol and FYCOMPA significantly worsened mood and increased anger. Patients taking FYCOMPA should avoid the use of alcohol. Patients, their caregivers, and families should be informed that FYCOMPA may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least one month after the last dose of FYCOMPA, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic (PGTC) seizure clinical trial.
 
SUICIDAL BEHAVIOR AND IDEATION
Antiepileptic drugs (AEDs), including FYCOMPA, increase the risk of suicidal  thoughts or behavior in patients. Anyone considering prescribing FYCOMPA or any other AED must balance the risk of suicidal thoughts or behavior with the 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. Patients, their caregivers, and families should be informed of the risk and advised to monitor and immediately report the emergence or worsening of depression, suicidal thoughts or behavior, thoughts about self-harm and/or any unusual changes in mood or behavior. Should suicidal thoughts and behavior emerge during treatment, consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
 
DIZZINESS AND GAIT DISTURBANCE
FYCOMPA caused dose-related increases in events related to dizziness and disturbance in gait or coordination. Dizziness and vertigo were reported in 35% and 47% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 10% of placebo-treated patients. Gait disturbance related events were reported in 12% and 16% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 2% of placebo-treated patients. These adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the PGTC seizure clinical trial.
 
SOMNOLENCE AND FATIGUE
FYCOMPA caused dose-dependent increases in somnolence and fatigue-related events. Somnolence was reported in 16% and 18% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 7% of placebo patients. Fatigue-related events were reported in 12% and 15% of patients in the partial-onset seizure trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 5% of placebo patients. These adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the PGTC seizure clinical trial. Patients should be advised against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of FYCOMPA is known.
 
FALLS
Falls were reported in 5% and 10% of patients in the partial-onset seizure clinical trials randomized to receive FYCOMPA at doses of 8 mg and 12 mg per day, respectively, compared to 3% of placebo-treated patients.

DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS (DRESS)
DRESS, also known as multiorgan hypersensitivity, has been reported in patients taking AEDs, including FYCOMPA. 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. If signs or symptoms are present, immediately evaluate the patient and discontinue FYCOMPA if an alternative etiology for signs or symptoms cannot be established.

WITHDRAWAL OF AEDs
A gradual withdrawal is generally recommended with AEDs to minimize the potential of increased seizure frequency, but if withdrawal is a response to adverse events, prompt withdrawal can be considered.
 
MOST COMMON ADVERSE REACTIONS
The most common adverse reactions in patients receiving FYCOMPA (≥5% and ≥1% higher than placebo) include dizziness, somnolence, fatigue, irritability, falls, nausea, weight gain, vertigo, ataxia, headache, vomiting, contusion, abdominal pain, and anxiety.
 
DRUG INTERACTIONS
FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. Plasma levels of FYCOMPA may decrease the efficacy of contraceptives containing levonorgestrel. Plasma levels of FYCOMPA were decreased when administered with moderate and strong CYP3A4 inducers, including, carbamazepine, phenytoin, or oxcarbazepine. Multiple dosing of FYCOMPA 12 mg per day enhanced the effects of alcohol on vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when FYCOMPA is used in combination with other CNS depressants.
 
PREGNANCY AND LACTATION
Physicians are advised to recommend that pregnant patients taking FYCOMPA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. Caution should be exercised when FYCOMPA is administered to pregnant or nursing women as there are no adequate data on the developmental risk associated with use in pregnant women, and no data on the presence of perampanel in human milk, the effects on the breastfed child, or the effects of the drug on milk production.
 
HEPATIC AND RENAL IMPAIRMENT
Use in patients with severe hepatic or severe renal impairment is not recommended. Dosage adjustments are recommended in patients with mild or moderate hepatic impairment. Use with caution in patients with moderate renal impairment.
 
DRUG ABUSE AND DEPENDENCE
FYCOMPA is a Schedule III controlled substance and has the potential to be abused and lead to drug dependence.
 
Please see full US Prescribing Information for FYCOMPA.

References
  1. National Institutes of Health (NIH). Epilepsy fact sheet. NIH website. https://report.nih.gov/nihfactsheets/Pdfs/Epilepsy(NINDS).pdf. Updated October 2010. Accessed June 2017.
  2. Riviello JJ. Classification of seizures and epilepsy. Curr Neurol Neurosci Rep. 2003;3(4):325-331.
  3. National Institutes of Health. The epilepsies and seizures: Hope through research. https://catalog.ninds.nih.gov/pubstatic//15-156/15-156.pdf. Published August 2015. Accessed June 2017.
  4. Laxer KD, Trinka E, Hirsch LJ, et al. The consequences of refractory epilepsy and its treatment. Epilepsy Behav. 2014;37:59-70. doi: 10.1016/j.yebeh.2014.05.031.
  5. Koshy S. Role of pharmacists in the management of patients with epilepsy. Int J Pharm Pract. 2012;20(1):65-68. doi: 10.1111/j.2042-7174.2011.00156.x.
  6. Davis KL, Candrilli SD, Edin HM. Prevalence and cost of nonadherence with antiepileptic drugs in an adult managed care population. Epilepsia. 2008;49(3):446-454. doi: 10.1111/j.1528-1167.2007.01414.x.
  7. FYCOMPA [prescribing information]. Woodcliff Lake, NJ: Eisai Inc; 2017.
  8. French JA, Krauss GL, Wechsler RT, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy A randomized trial. Neurology. 2015;85(11):950-957. doi: 10.1212/WNL.0000000000001930.
  9. Data on file. Eisai Inc., Woodcliff Lake, NJ.

FYCO-US1055 September 2017


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