This was because of an increase of approximately 50% in the volume ofdistribution (Vd) corrected fortotal body weight. The clearance was not significantly different between groups.
Patients with Renal Impairment
Patients with renal impairment may have longer elimination half-lives for midazolam and itsmetabolites [see Use in Specific Populations (8.6)].
Midazolam and 1-hydroxy-midazolam pharmacokinetics in 6 ICU patients who developedacute renal failure (ARF) were compared with a normal renal function control group.
Midazolam was administered as an infusion (5 to 15 mg/hr). Midazolam clearance wasreduced (1.9 vs 2.8 mL/min/kg) and the half-life was prolonged (7.6 vs 13 hours) in the ARFpatients. The renal clearance of the 1-hydroxy-midazolam glucuronide was prolonged in theARF group (4 vs 136 mL/min) and the half-life was prolonged (12 vs >25 hours). Plasmalevels accumulated in all ARF patients to about ten times that of the parent drug. Therelationship between accumulating metabolite levels and prolonged sedation is unclear.
In a study of chronic renal failure patients (n=15) receiving a single intravenous dose ofmidazolam, there was a 2-fold increase in the clearance and volume of distribution, but thehalf-life remained unchanged.
Patients with Hepatic Impairment
Midazolam pharmacokinetics were studied after an intravenous single dose (0.075 mg/kg)was administered to patients with biopsy proven alcoholic cirrhosis (n=7) and control patients(n=8). The mean half-life of midazolam increased 2.5-fold in the patients with cirrhosis.
Clearance was reduced by 50% and the Vd increased by 20%. In another study in malepatients with cirrhosis (n=21) without ascites and with normal kidney function as determinedby creatinine clearance, no changes in the pharmacokinetics of midazolam or 1-hydroxymidazolamwere observed when compared to healthy individuals. The clinical significance
of these findings is unknown.
Patients with Congestive Heart FailureIn patients suffering from congestive heart failure, a 2-fold increase in the elimination halflife,a 25% decrease in the plasma clearance, and a 40% increase in the volume ofdistribution of midazolam were observed.
Drug Interaction Studies
Since NAYZILAM is metabolized by CYP3A4, interactions with drugs that inhibit or induceCYP3A4 are likely.
Inhibitors of CYP3A4 Isozymes
Coadministration of CYP3A4 inhibitors with NAYZILAM has not been studied. However,the effects of inhibitors on midazolam exposure following NAYZILAM administration are
expected to be similar to those following IV midazolam administration. Concomitant use of CYP3A4 inhibitors may result in prolonged sedation because of a decrease in plasmaclearance of midazolam [Warnings and Precautions (5.3) and Drug Interactions (7.1)].
• The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine onsteady-state concentrations of oral midazolam was examined in a randomizedcrossover study (n=8). Cimetidine increased the mean midazolam steady-stateconcentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-stateconcentration to 62 ng/mL. No change in choice reaction time or sedation index wasdetected after dosing with the H2 receptor antagonists.
• In a placebo-controlled study, erythromycin administered as a 500 mg dose, threetimes a day, for 1 week (n=6), reduced the clearance of midazolam following a single
0.5 mg/kg IV dose. The half-life was approximately doubl |
