PERAMPANEL Drug Interactions: What You Need to Know

INTERACTIONS Contraceptives: 12 mg once daily may decrease the effectiveness of hormonal contraceptives containing levonorgestrel ( 7.1 ) Moderate and Strong CYP3A4 Inducers (including carbamazepine, oxcarbazepine, and phenytoin): increase clearance of perampanel and decrease perampanel plasma concentrations. When moderate or strong CYP3A4 inducers are introduced or withdrawn, monitor patients closely. Dose adjustment of perampanel tablets may be necessary ( 2.3 , 7.2 )

7.1 Contraceptives With concomitant use, perampanel at a dose of 12 mg per day reduced levonorgestrel exposure by approximately 40% <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . Use of perampanel with contraceptives containing levonorgestrel may render them less effective. Additional non-hormonal forms of contraception are recommended <span class="opacity-50 text-xs">[see Use in Specific Populations (8.3) ]</span> .

7.2 Moderate and Strong CYP3A4 Inducers The concomitant use of known moderate and strong CYP3A4 inducers including carbamazepine, phenytoin, or oxcarbazepine with perampanel decreased the plasma levels of perampanel by approximately 50% to 67% <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span> . The starting doses for perampanel should be increased in the presence of moderate or strong CYP3A4 inducers <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . When these moderate or strong CYP3A4 inducers are introduced or withdrawn from a patient&apos;s treatment regimen, the patient should be closely monitored for clinical response and tolerability. Dose adjustment of perampanel may be necessary <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span>.

7.3 Alcohol and Other CNS Depressants The concomitant use of perampanel and CNS depressants including alcohol may increase CNS depression. A pharmacodynamic interaction study in healthy subjects found that the effects of perampanel on complex tasks such as driving ability were additive or supra-additive to the impairment effects of alcohol <span class="opacity-50 text-xs">[see Clinical Pharmacology (12.3) ]</span>. Multiple dosing of perampanel 12 mg per day also enhanced the effects of alcohol to interfere with vigilance and alertness, and increased levels of anger, confusion, and depression. These effects may also be seen when perampanel is used in combination with other CNS depressants. Care should be taken when administering perampanel with these agents. Patients should limit activity until they have experience with concomitant use of CNS depressants (e.g., benzodiazepines, narcotics, barbiturates, sedating antihistamines). Advise patients not to drive or operate machinery until they have gained sufficient experience on perampanel to gauge whether it adversely affects these activities.

None. None ( 4 )

AND PRECAUTIONS Suicidal Behavior and Ideation: Monitor for suicidal thoughts or behavior ( 5.2 )

Neurologic

Effects: Monitor for dizziness, gait disturbance, somnolence, and fatigue ( 5.3 ) Patients should use caution when driving or operating machinery ( 5.3 ) Falls: Monitor for falls and injuries ( 5.4 )

Drug

Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Discontinue if no alternate etiology ( 5.5 ) Withdrawal of Antiepileptic Drugs: In patients with epilepsy, there may be an increase in seizure frequency ( 5.6 )

5.1 Serious Psychiatric and Behavioral Reactions In the controlled partial-onset seizure clinical trials, hostility- and aggression-related adverse reactions occurred in 12% and 20% of patients randomized to receive perampanel 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. Perampanel-treated patients experienced more hostility- and aggression-related adverse reactions that were serious, severe, and led to dose reduction, interruption, and discontinuation more frequently than placebo-treated patients. In general, in placebo-controlled partial-onset seizure clinical trials, neuropsychiatric events were reported more frequently in patients being treated with perampanel than in patients taking placebo. These events included irritability, aggression, anger, and anxiety, which occurred in 2% or greater of perampanel-treated patients and twice as frequently as in placebo-treated patients. Other symptoms that occurred with perampanel and were more common than with placebo included belligerence, affect lability, agitation, and physical assault. Some of these events were reported as serious and life-threatening. Homicidal ideation and/or threat were exhibited in 0.1% of 4,368 perampanel-treated patients in controlled and open label trials, including non-epilepsy trials. Homicidal ideation and/or threat have also been reported postmarketing in patients treated with perampanel. In the partial-onset seizure clinical trials, 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 preexisting psychiatric conditions. Patients with active psychotic disorders and unstable recurrent affective disorders were excluded from the clinical trials. The combination of alcohol and perampanel significantly worsened mood and increased anger. Patients taking perampanel should avoid the use of alcohol <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> . Similar serious psychiatric and behavioral events were observed in the primary generalized tonic-clonic seizure clinical trial. In healthy volunteers taking perampanel, observed psychiatric events included paranoia, euphoric mood, agitation, anger, mental status changes, and disorientation/confusional state. In the non-epilepsy trials, psychiatric events that occurred in perampanel-treated patients more often than placebo-treated patients included disorientation, delusion, and paranoia. In the postmarketing setting, there have been reports of psychosis (acute psychosis, hallucinations, delusions, paranoia) and delirium (delirium, confusional state, disorientation, memory impairment) in patients treated with perampanel <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Patients, their caregivers, and families should be informed that perampanel may increase the risk of psychiatric events. Patients should be monitored during treatment and for at least 1 month after the last dose of perampanel, and especially when taking higher doses and during the initial few weeks of drug therapy (titration period) or at other times of dose increases. Dose of perampanel should be reduced if these symptoms occur. Permanently discontinue perampanel for persistent severe or worsening psychiatric symptoms or behaviors and refer for psychiatric evaluation.

5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including perampanel, increase the 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 the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI: 1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as 1 week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table

1 shows absolute and relative risk by indication for all evaluated AEDs.

Table

1. Risk by indication for antiepileptic drugs in the pooled analysis Indication Placebo Patients with Events per 1,000 Patients Drug Patients with Events per 1,000 patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events per 1,000 Patients Epilepsy 1.0 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1.0 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing perampanel 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. 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 the illness being treated.

5.3 Neurologic Effects Dizziness and Gait Disturbance Perampanel caused dose-related increases in events related to dizziness and disturbance in gait or coordination <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In the controlled partial-onset seizure clinical trials, dizziness and vertigo were reported in 35% and 47% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 10% of placebo-treated patients. The gait disturbance related events (including ataxia, gait disturbance, balance disorder, and abnormal coordination) were reported in 12% and 16% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 2% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients. These adverse reactions occurred mostly during the titration phase and led to discontinuation in 3% of perampanel-treated patients compared to 1% of placebo-treated patients. These adverse reactions were also observed in the primary generalized tonic-clonic seizure clinical trial. Somnolence and Fatigue Perampanel caused dose-dependent increases in somnolence and fatigue-related events (including fatigue, asthenia, and lethargy). In the controlled partial-onset seizure clinical trials, 16% and 18% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, reported somnolence compared to 7% of placebo patients. In the controlled partial-onset seizure clinical trials, 12% and 15% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, reported fatigue-related events compared to 5% of placebo patients. Somnolence or fatigue-related events led to discontinuation in 2% of perampanel-treated patients and 0.5% of placebo-treated patients. Elderly patients had an increased risk of these adverse reactions compared to younger adults and pediatric patients. In the controlled partial-onset seizure clinical trials, these adverse reactions occurred mostly during the titration phase. These adverse reactions were also observed in the primary generalized tonic-clonic seizure clinical trial.

Risk Amelioration

Prescribers should advise patients against engaging in hazardous activities requiring mental alertness, such as operating motor vehicles or dangerous machinery, until the effect of perampanel is known. Patients should be carefully observed for signs of central nervous system (CNS) depression, such as somnolence and sedation, when perampanel is used with other drugs with sedative properties because of potential additive effects.

5.4 Falls An increased risk of falls, in some cases leading to serious injuries including head injuries and bone fracture, occurred in patients being treated with perampanel (with and without concurrent seizures). In the controlled partial-onset seizure clinical trials, falls were reported in 5% and 10% of patients randomized to receive perampanel at doses of 8 mg and 12 mg per day, respectively, compared to 3% of placebo-treated patients. Falls were reported as serious and led to discontinuation more frequently in perampanel-treated patients than placebo-treated patients. Elderly patients had an increased risk of falls compared to younger adults and pediatric patients.

5.5 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including perampanel. 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. It is 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. Perampanel should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.6 Withdrawal of Antiepileptic Drugs There is the potential of increased seizure frequency in patients with seizure disorders when antiepileptic drugs are withdrawn abruptly. Perampanel has a half-life of approximately 105 hours so that even after abrupt cessation, blood levels fall gradually. In epilepsy clinical trials perampanel 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.