8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine

Absorption
Midazolam is rapidly absorbed. The oral AUC ratio of metabolite to midazolam is higher than IV. Mean T max is 0.17 to 2.65 h and the absolute bioavailability is 36%.

Distribution
Midazolam exhibits linear pharmacokinetics (dose 0.25 to 1 mg/kg). Approximately 97% is protein bound (mainly to albumin). The mean steady-state Vd is 1.24 to 2.02 L/kg in children 6 mo to younger than 16 yr of age receiving 0.15 mg/kg IV.

Metabolism
Midazolam is subject to substantial intestinal and hepatic first-pass metabolism by CYP-450 3A4. Active metabolite is alpha-hydroxymidazolam.

Onset
Onset is 10 to 20 min.

Special Populations
Hepatic Function Impairment
Following oral administration (15 mg), C max and bioavailability were 43% and 100% higher, respectively. Cl was reduced 40% and t ½ increased 90%. Doses should be titrated.

CHF
Following oral administration (7.5 mg), t ½ increased 43%.

Anesthetics, inhalation
Inhalation anesthetics may need to be reduced if midazolam is used as an induction agent. IV administration decreases minimum alveolar concentration of halothane required for general anesthesia.

Azole antifungal agents
Serum concentration of certain benzodiazepines may be increased and prolonged, producing enhanced CNS depression and prolonged effects.

Barbiturates, alcohol, other CNS depressants
May prolong effect and increase risk of underventilation or apnea.

Cimetidine
May increase midazolam levels.

Contraceptives, oral
Coadministration may result in prolongation of benzodiazepine t ½ .

Droperidol, narcotics, secobarbital
May accentuate hypnotic effect of midazolam.

Ethanol
Increased CNS effects with acute ethanol ingestion.

Fluvoxamine
Reduced clearance, prolonged t ½ and increased serum concentrations of certain benzodiazepines may occur. Sedation or ataxia may be increased.

Indinavir
Possibly severe sedation and respiratory depression.

Propofol
Pharmacologic effects of propofol may be increased.

Rifamycins
Pharmacokinetic parameters of benzodiazepines may be altered.

Ritonavir
Possibly severe sedation and respiratory depression.

Theophyllines
Sedative effects of benzodiazepines may be antagonized.

Thiopental
Moderate reduction in induction dosage requirements has been noted following use of IM midazolam for premedication.

Valproic acid
Pharmacokinetic parameters of benzodiazepines may be increased. Liver metabolism may be decreased.

Verapamil
Effects of certain benzodiazepines may be increased, producing increased CNS depression and prolonged effects.

Incompatibility
Dimenhydrinate, pentobarbital, perphenazine, prochlorperazine, ranitidine.