Midazolam 15 mg · Tablets

Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.

Pharmacodynamic properties of midazolam and its metabolites, which are similar to those of other benzodiazepines, include sedative, anxiolytic, amnesic and hypnotic activities. Benzodiazepine pharmacologic effects appear to result from reversible interactions with the γ-amino butyric acid (GABA) benzodiazepine receptor in the CNS, the major inhibitory neurotransmitter in the central nervous system. The action of midazolam is readily reversed by the benzodiazepine receptor antagonist, flumazenil.

Data from published reports of studies in pediatric patients clearly demonstrate that oral midazolam provides safe and effective sedation and anxiolysis prior to surgical procedures that require anesthesia as well as before other procedures that require sedation but may not require anesthesia. The most commonly reported effective doses range from 0.25 to 1.0 mg/kg in children (6 months to <16 years). The single most commonly reported effective dose is 0.5 mg/kg. Time to onset of effect is most frequently reported as 10 to 20 minutes.

The effects of midazolam on the CNS are dependent on the dose administered, the route of administration, and the presence or absence of other medications.

Following premedication with oral midazolam, time to recovery has been assessed in pediatric patients using various measures, such as time to eye opening, time to extubation, time in the recovery room, and time to discharge from the hospital. Most placebo-controlled trials (8 total) have shown little effect of oral midazolam on recovery time from general anesthesia; however, a number of other placebo-controlled studies (5 total) have demonstrated some prolongation in recovery time following premedication with oral midazolam. Prolonged recovery may be related to duration of the surgical procedure and/or use of other medications with central nervous system depressant properties.

Partial or complete impairment of recall following oral midazolam has been demonstrated in several studies. Amnesia for the surgical experience was greater after oral midazolam when used as a premedicant than after placebo and was generally considered a benefit. In one study, 69% of midazolam patients did not remember mask application versus 6% of placebo patients.

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been reported in <1% of pediatric patients following premedication (eg, sedation prior to induction of anesthesia) with midazolam HCl syrup; the potential for such adverse events are markedly increased when oral midazolam is combined with other central nervous system depressing agents and in patients with abnormal airway anatomy, patients with cyanotic congenital heart disease, or patients with sepsis or severe pulmonary disease [see WARNINGS] .

Concomitant use of barbiturates or other central nervous system depressants may increase the risk of hypoventilation, airway obstruction, desaturation or apnea, and may contribute to profound and/or prolonged drug effect. In one study of pediatric patients undergoing elective repair of congenital cardiac defects, premedication regimens (oral dose of 0.75 mg/kg midazolam or IM morphine plus scopolamine) increased transcutaneous carbon dioxide (PtcCO 2), decreased SpO 2 (as measured by pulse oximetry), and decreased respiratory rates preferentially in patients with pulmonary hypertension. This suggests that hypercarbia or hypoxia following premedication might pose a risk to children with congenital heart disease and pulmonary hypertension. In a study of an adult population 65 years and older, the preinduction administration of oral midazolam 7.5 mg resulted in a 60% incidence of hypoxemia (paO 2 <90% for over 30 seconds) at some time during the operative procedure versus 15% for the nonpremedicated group.

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.