ed.
• The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times aday) on the pharmacokinetics and pharmacodynamics of midazolam were
investigated in a three-way crossover study (n=9). The half-life of midazolamincreased from 5 to 7 hours when midazolam was taken in conjunction withverapamil or diltiazem. No interaction was observed in healthy subjects betweenmidazolam and nifedipine.
• In a placebo-controlled study, where saquinavir or placebo was administered orally asa 1200 mg dose three times a day for 5 days (n=12), a 56% reduction in the clearanceof midazolam following a single 0.05 mg/kg IV dose was observed. The half-life wasapproximately doubled.
Inducers of CYP3A4 Isozymes
Exposures (e.g., combined Cmax or AUC of midazolam and the 1-OH-midazolam activemetabolite) are decreased 16 to 26% when NAYZILAM is co-administered with antiepileptic
drugs that are strong CYP3A4 inducers (e.g., phenytoin, phenobarbital, primidone,carbamazepine). Exposures (e.g., combined Cmax or AUC of midazolam and the 1-OHmidazolamactive metabolite) are decreased 8 to 15% when NAYZILAM is co-administeredwith anti-epileptic drugs that are weak to moderate CYP3A4 inducers (e.g., clobazam,eslicarbazepine, felbamate, oxcarbazepine, rufinamide, topiramate). These changes inexposures are not expected to be clinically significant.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis
Midazolam maleate was administered in the diet to mice and rats for 2 years at doses of 0, 19, or 80 mg/kg/day. In female mice in the highest dose group there was a marked increase inthe incidence of hepatic tumors. In high-dose male rats there was a smallbut statistically significant increase in benign thyroid follicular cell tumors. The highest dose not associated
with increased tumor incidences in mice and rats (9 mg/kg/day) is approximately 4 and 9times, respectively, the recommended human dose (RHD) of 10 mg based on body surfacearea (mg/m2).
The pathogenesis of induction of these tumors is not known. These tumorswere found after chronic administration, whereas human use will ordinarily be of single or
several doses.
Mutagenesis
Midazolam was negative for genotoxicity in in vitro (Ames, mammalian cell clastogenicity)and in vivo (mouse bone marrow micronucleus) assays.
Impairment of Fertility
When midazolam (0, 1, 4, or 16 mg/kg) was orally administered to male and female rats priorto and during mating and continuing in females throughout gestation and lactation, noadverse effects on male or female fertility were noted.
14 CLINICAL STUDIES
The effectiveness of NAYZILAM for the acute treatment of intermittent, stereotypic episodesof frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinctfrom a patient’s usual seizure pattern in patients with epilepsy 12 years of age and older wasestablished in a randomized, double-blind, placebo-controlled trial (Study 1; NCT01390220).
Study 1 enrolled patients with epilepsy on a stable regimen of antiepileptic drugs who wereidentified by their physicians as having intermittent, stereotypic episodes of frequent seizureactivity that were distinct from the patient’s usual seizure pattern.
Study 1 was conducted in two phases: an open-label Test Dose Phase followed by arandomized, double-blind, placebo-controlled, Comparative Phase. In the Test Dose Phase,tolerabili |
