ffect.
Risks from Concomitant Use with Other CNS Depressants
The potential for an increased CNS-depressant effect from concomitant use with alcohol orother CNS depressants (e.g., opioids) must be considered by the prescribing physician, andappropriate recommendations made to the patient and/or caregiver [see Warnings andPrecautions (5.1) and Drug Abuse and Dependence (9.3)].
Concomitant use of barbiturates, alcohol, or other CNS depressants may increase the risk ofhypoventilation, airway obstruction, desaturation, or apnea and may contribute to profoundand/or prolonged drug effect [see Drug Interactions (7.3)].
Risks from Concomitant Use with Moderate or Strong CYP3A4 InhibitorsThere is a potential for prolonged sedation from concomitant use with moderate or strong
CYP3A4 enzyme inhibitors because of much higher midazolam exposures [see DrugInteractions (7.2) and Clinical Pharmacology (12.2)].
5.4 Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including NAYZILAM, increase the risk of suicidal thoughts orbehavior in patients taking these drugs for any indication. Patients treated with any AED forany indication should be monitored for the emergence or worsening of depression, suicidalthoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of11 different AEDs showed that patients randomized to one of the AEDs had approximatelytwice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behaviorcompared to patients randomized to placebo. In these trials, which had a median treatmentduration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treatedpatients, 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 trialsand none in placebo-treated patients, but the number is too small to allow any conclusionabout drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as oneweek after starting drug treatment with AEDs and persisted for the duration of treatmentassessed. Because most trials included in the analysis did not extend beyond 24 weeks, therisk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk ofsuicidal thoughts or behavior was generally consistent among drugs in the data analyzed. Thfinding of increased risk with AEDs of varying mechanisms of action and across a range ofindications suggests that the risk applies to all AEDs used for any indication. The risk did notvary substantially by age (5-100 years) in the clinical trials analyzed. Table 1 shows absoluteand relative risk by indication for all eva luated AEDs.
Table 1. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication Placebo
Patients
with
Events/1000
Patients
Drug
Patients
with Events
per 1000
Patients
Relative Risk:
Incidence of Drug
Events in Drug
Patients /Incidence
in Placebo Patients
Risk Difference:
Additional Drug
Patients with
Events per 1000
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 epileps |
