iolytic, amnestic, and hypnotic activities. Theeffects of midazolam on the CNS are dependent on the dose administered, the route ofadministration, and the presence or absence of other medications.
Treatment with NAYZILAM was associated with effects on measures of sedation andmeasures of psychomotor performance [see Warnings and Precautions (5.3)]. Sedation and
psychomotor impairment effects generally began to occur within 10 minutes post dose withpeak effects observed within 30 minutes to 2 hours post dose. The pharmacodynamic effectsgenerally returned to near baseline levels by 4 hours post-dose.
12.3 Pharmacokinetics
Pharmacokinetics
Based on a population pharmacokinetic analysis, plasma exposures (Cmax and AUC) ofmidazolam in epilepsy patients increase approximately proportional to dose from 5.0 mg to15 mg, 0.5 and 1.5 times the recommended maximum total dose (5 mg Initial Dose + 5 mgSecond Dose), respectively.
Absorption
Following nasal administration of a single 5 mg midazolam dose to healthy adults,midazolam was absorbed with median Tmax (range) of 17.3 (7.8 to 28.2) minutes; midazolammean (±SD) Cmax and AUC0-∞ were 54.7 (±30.4) ng/mL and 126.2 (±59) ng∙hr/mL,respectively. The mean absolute bioavailability is approximately 44%.
DistributionIn adults and pediatric patients, midazolam is approximately 97% bound to plasma protein,principally albumin. In healthy volunteers, 1-hydroxy midazolam is bound to the extent of89%.
The estimated total volume of distribution of midazolam is 226.5 L.
In humans, midazolam has been shown to cross the placenta and enter into fetal circulationand has been detected in human milk and CSF [see Use in Specific Populations (8.1, 8.2)].
Elimination
Following administration of NAYZILAM in clinical trials, median midazolam and 1-hydroxy-midazolam elimination half-lives ranged from 2.1 to 6.2 hours and 2.7 to 7.2 hours,respectively, independent of dose.
Metabolism
Midazolam is primarily metabolized by liver and intestinal cytochrome P450 3A4 (CYP3A4)to its pharmacologic active metabolite, 1-hydroxy midazolam (also termed α-hydroxymidazolam).
Midazolam is also metabolized to two other minor metabolites: 4-hydroxy
metabolite and 1,4-dihydroxy metabolite. The principal urinary excretion products areglucuronide conjugates of the hydroxylated derivatives.
Studies of the intravenous administration of 1-hydroxy-midazolam in humans suggest that 1-hydroxy-midazolam is at least as potent as the parent compound and may contribute to thenet pharmacologic activity of midazolam.
Excretion
The principal urinary excretion product is 1-OH midazolam in the form of a glucuronideconjugate. Smaller amounts of the glucuronide conjugates of 4-hydroxy- and dihydroxymidazolamare detected as well.
Specific Populations
Geriatric Patients
In a parallel group study of 2.5 mg and 5 mg doses of NAYZILAM, mean systemic exposure(AUC) and peak plasma concentrations (Cmax) of midazolam were 21 to 45% higher ingeriatric subjects (> 65 years old) as compared to non-geriatric subjects. The terminal halflifewas increased by approximately 2 hours in the geriatric subjects because of a decrease inclearance [see Use in Specific Populations (8.5)].
Obesity
In a study comparing normal (n=20) and obese patients (n=20), the mean half-life of midazolam
administered by parental route was greater in the obese group (5.9 versus 2.3 hours). |
