Absorption: Midazolam is rapidly absorbed after oral administration and is subject to substantial intestinal and hepatic first-pass metabolism. The pharmacokinetics of midazolam and its major metabolite, α-hydroxymidazolam, and the absolute bioavailability of midazolam HCl syrup were studied in pediatric patients of different ages (6 months to <16 years old) over a 0.25 to 1.0 mg/kg dose range. Pharmacokinetic parameters from this study are presented in Table 1. The mean T max values across dose groups (0.25, 0.5, and 1.0 mg/kg) range from 0.17 to 2.65 hours. Midazolam exhibits linear pharmacokinetics between oral doses of 0.25 to 1.0 mg/kg (up to a maximum dose of 40 mg) across the age groups ranging from 6 months to <16 years. Linearity was also demonstrated across the doses within the age group of 2 years to <12 years having 18 patients at each of the three doses. The absolute bioavailability of the midazolam HCl syrup in pediatric patients is about 36%, which is not affected by pediatric age or weight. The AUC 0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose in pediatric patients is higher than for an IV dose (0.38 to 0.75 versus 0.21 to 0.39 across the age group of 6 months to <16 years), and the AUC 0-∞ ratio of α-hydroxymidazolam to midazolam for the oral dose is higher in pediatric patients than in adults (0.38 to 0.75 versus 0.40 to 0.56). 

Food effect has not been tested using midazolam HCl syrup. When a 15 mg oral tablet of midazolam was administered with food to adults, the absorption and disposition of midazolam was not affected. Feeding is generally contraindicated prior to sedation of pediatric patients for procedures.

Distribution: The extent of plasma protein binding of midazolam is moderately high and concentration independent. In adults and pediatric patients older than 1 year, midazolam is approximately 97% bound to plasma protein, principally albumin. In healthy volunteers, α-hydroxymidazolam is bound to the extent of 89%. In pediatric patients (6 months to <16 years) receiving 0.15 mg/kg IV midazolam, the mean steady-state volume of distribution ranged from 1.24 to 2.02 L/kg. 

Metabolism: Midazolam is primarily metabolized in the liver and gut by human cytochrome P450 IIIA4 (CYP3A4) to its pharmacologic active metabolite, α-hydroxymidazolam, followed by glucuronidation of the α-hydroxyl metabolite which is present in unconjugated and conjugated forms in human plasma. The α-hydroxymidazolam glucuronide is then excreted in urine. In a study in which adult volunteers were administered intravenous midazolam (0.1 mg/kg) and α-hydroxymidazolam (0.15 mg/kg), the pharmacodynamic parameter values of the maximum effect (E max) and concentration eliciting half-maximal effect (EC 50) were similar for both compounds. The effects studied were reaction time and errors in tracing tests. The results indicate that α-hydroxymidazolam is equipotent and equally effective as unchanged midazolam on a total plasma concentration basis. After oral or intravenous administration, 63% to 80% of midazolam is recovered in urine as α-hydroxymidazolam glucuronide. No significant amount of parent drug or metabolites is extractable from urine before beta-glucuronidase and sulfatase deconjugation, indicating that the urinary metabolites are excreted mainly as conjugates. 

Midazolam is also metabolized to two other minor metabolites: 4-hydroxy metabolite (about 3% of the dose) and 1,4-dihydroxy metabolite (about 1% of the dose) are excreted in small amounts in the urine as conjugates.

Elimination: The mean elimination half-life of midazolam ranged from 2.2 to 6.8 hours following single oral doses of 0.25, 0.5, and 1.0 mg/kg of midazolam HCl syrup. Similar results (ranged from 2.9 to 4.5 hours) for the mean elimination half-life were observed following IV administration of 0.15 mg/kg of midazolam to pediatric patients (6 months to <16 years old). In the same group of patients receiving the 0.15 mg/kg IV dose, the mean total clearance ranged from 9.3 to 11.0 mL/min/kg. 

Pharmacokinetic-Pharmacodynamic Relationships: The relationship between plasma concentration and sedation and anxiolysis scores of midazolam HCl syrup (single oral doses of 0.25, 0.5, or 1.0 mg/kg) was investigated in three age groups of pediatric patients (6 months to <2 years, 2 to <12 years, and 12 to <16 years old). In this study, the patient’s sedation scores were recorded at baseline and at 10-minute intervals up to 30 minutes after oral dosing until satisfactory sedation (“drowsy” or “asleep but responsive to mild shaking” or “asleep and not responsive to mild shaking”) was achieved. Anxiolysis scores were measured at the time when the patient was separated from his/her parents and at mask induction. The results of the analyses showed that the mean midazolam plasma concentration as well as the mean of midazolam plus α-hydroxymidazolam for those patients with a sedation score of 4 (asleep but responsive to mild shaking) is significantly different than the mean concentrations for those patients with a sedation score of 3 (drowsy), which is significantly different than the mean concentrations for patients with a sedation score of 2 (awake/calm). The statistical analysis indicates that the greater the midazolam, or midazolam plus α-hydroxymidazolam concentration, the greater the maximum sedation score for pediatric patients. No such trend was observed between anxiolysis scores and the mean midazolam concentration or mean of midazolam plus α-hydroxymidazolam concentration, however, anxiolysis is a more variable surrogate measurement of clinical response. 

Special Populations:Renal Impairment: Although the pharmacokinetics of intravenous midazolam in adult patients with chronic renal failure differed from those of subjects with normal renal function, there were no alterations in the distribution, elimination, or clearance of unbound drug in the renal failure patients. However, the effects of renal impairment on the active metabolite α-hydroxymidazolam are unknown. 

Hepatic Dysfunction: Chronic hepatic disease alters the pharmacokinetics of midazolam. Following oral administration of 15 mg of midazolam HCl syrup, C max and bioavailability values were 43% and 100% higher, respectively, in adult patients with hepatic cirrhosis than adult subjects with normal liver function. In the same patients with hepatic cirrhosis, following IV administration of 7.5 mg of midazolam, the clearance of midazolam was reduced by about 40% and the elimination half-life was increased by about 90% compared with subjects with normal liver function. Midazolam should be titrated for the desired effect in patients with chronic hepatic disease. 

Congestive Heart Failure: Following oral administration of 7.5 mg of midazolam HCl syrup, elimination half-life values were 43% higher in adult patients with congestive heart failure than in control subjects. 

Neonates: Midazolam HCl syrup has not been studied in pediatric patients less than 6 months of age. 

Drug-Drug Interactions: See PRECAUTIONS: Drug Interactions. 

Inhibitors of CYP3A4 Isozymes: Table 2 summarizes the changes in the C max and AUC of midazolam when drugs known to inhibit CYP3A4 were concurrently administered with oral midazolam HCl syrup in adult subjects. 

Other drugs known to inhibit the effects of CYP3A4, such as protease inhibitors, would be expected to have similar effects on these midazolam pharmacokinetic parameters.

Inducers of CYP3A4 Isozymes: Table 3 summarizes the changes in the C max and AUC of midazolam when drugs known to induce CYP3A4 were concurrently administered with midazolam HCl syrup in adult subjects. The clinical significance of these changes is unclear. 

Although not tested, phenobarbital, rifabutin and other drugs known to induce the effects of CYP3A4 would be expected to have similar effects on these midazolam pharmacokinetic parameters.

Drugs that did not affect midazolam pharmacokinetics are presented in Table 4.

Clinical Trials:Dose Ranging, Safety and Efficacy Study with Midazolam Hydrochloride Syrup in Pediatric Patients: The effectiveness of midazolam HCl syrup as a premedicant to sedate and calm pediatric patients prior to induction of general anesthesia was compared among three different doses in a randomized, double-blind, parallel-group study. Patients of ASA physical status I, II or III were stratified to 1 of 3 age groups (6 months to <2 years, 2 to <6 years, and 6 to <16 years), and within each age group randomized to 1 of 3 dosing groups (0.25, 0.5, and 1.0 mg/kg up to a maximum dose of 20 mg). Greater than 90% of treated patients achieved satisfactory sedation and anxiolysis at least one timepoint within 30 minutes posttreatment. Similarly high proportions of patients exhibited satisfactory ease of separation from parent or guardian and were cooperative at the time of mask induction with nitrous oxide and halothane administration. Onset time of satisfactory sedation or anxiolysis occurred within 10 minutes after treatment for >70% of patients who started with an unsatisfactory baseline rating. Whereas pairwise comparisons (0.25 mg/kg versus 0.5 mg/kg groups, and 0.5 mg/kg versus 1.0 mg/kg groups) on satisfactory sedation did not yield significant p-values (p=0.08 in both cases), comparative analysis of the clinical response between the high and low doses demonstrated that a higher proportion of patients in the 1.0 mg/kg dose group exhibited satisfactory sedation and anxiolysis as compared to the 0.25 mg/kg group (p<0.05).