SIDE EFFECTS

The distribution of adverse events occurring in patients evaluated in a randomized, double-blind, parallel-group trial are presented in Tables 5 and 6 by body system in order of decreasing frequency: for the pre-medication period (eg, sedation period prior to induction of anesthesia) alone, see Table 5; for over the entire monitoring period including premedication, anesthesia and recovery, see Table 6.

The distribution ofadverse events occurring during the premedication period, before inductionof anesthesia, is presented in Table 5. Emesis which occurred in 31/397 (8%) patients over the entire monitoring period, occurred in 3/397 (0.8%) of patients during the premedication period (from midazolamadministration to mask induction). Nausea, which occurred in 14/397 (4%) patients over the entire monitoring period (premedication, anesthesia and recovery), occurred in 2/397 (0.5%) patients during thepremedicationperiod.

This distribution of all adverse events occurring in ≥ 1% of patients over the entire monitoring period are presented in Table 6. For the entire monitoring period (premedication, anesthesia and recovery), adverse events were reported by 82/397 (21%) patients who received midazolam overall. The most frequently reported adverse events were emesis occurring in 31/397 (8%) patients and nausea occurring in 14/397 (4%) patients. Most of these gastrointestinal events occurred after the administration of other anesthetic agents.

For the respiratory system overall, adverse events (hypoxia, laryngospasm, rhonchi, coughing, respiratory depression, airway obstruction, upper-airway congestion, shallow respirations), occurred during the entire monitoring period in 31/397 (8%) patients and increased in frequency as dosage was increased: 7/132 (5%) patients in the 0.25 mg/kg dose group, 9/132 (7%) patients in the 0.5 mg/kg dose group, and 15/133 (11%) patients in the 1 mg/kg dose group.

Most of the respiratory adverse events occurred during induction, general anesthesia or recovery. One patient (0.25%) experienced a respiratory system adverse event (laryngospasm) during the premedication period. This adverse event occurred precisely at the time of induction. Although many of the respiratory complications occurred in settings of upper airway procedures or concurrently administered opioids, a number of these events occurred outside of these settings as well. In this study, administration of midazolam HCI syrup was generally accompanied by a slight decrease in both systolic and diastolic blood pressures, as well as a slight increase in heart rate.

Table 5. Adverse Events Occurring During the Premedication Period Before Mask Induction in the Randomized, Double-Blind, Parallel-Group Trial

Table 6. Adverse Events (≥1%) From the Randomized, Double-Blind, Parallel-Group Trial on Entire Monitoring Period (premedication, anesthesia, recovery)

There were no deaths during the study and no patient withdrew from the study due to adverse events. Serious adverse events (both respiratory disorders) were experienced postoperatively by two patients: one case of airway obstruction and desaturation (SpO₂ of 33%) in a patient given midazolam HCI syrup 0.25 mg/kg, and one case of upper airway obstruction and respiratory depression following 0.5 mg/kg. Both patients had received intravenous morphine sulfate (1.5 mg total for both patients).

Other adverse events that have been reported in the literature with the oral administration of midazolam (not necessarily midazolam syrup), are listed below. The incidence rate for these events was generally <1%.

Respiratory: apnea, hypercarbia, desaturation, stridor.

Cardiovascular: decreased systolic and diastolic blood pressure, increased heart rate. Gastrointestinal: nausea, vomiting, hiccoughs, gagging, salivation, drooling.

Central Nervous System: dysphoria, disinhibition, excitation, aggression, mood swings, hallucinations, adverse behavior, agitation, dizziness, confusion, ataxia, vertigo, dysarthria.

Special Senses: diplopia, strabismus, loss of balance, blurred vision.

Drug Abuse And Dependence

Midazolam HCI syrup is a benzodiazepine and is a Schedule IV controlled substance that can produce drug dependence of the diazepam-type. Therefore, midazolam HCI syrup may be subject to misuse, abuse and addiction. Benzodiazepines can cause physical dependence. Physical dependence results in withdrawal symptoms in patients who abruptly discontinue the drug. Withdrawal symptoms (ie, convulsions, hallucinations, tremors, abdominal and muscle cramps, vomiting and sweating), similar in characteristics to those noted with barbiturates and alcohol have occurred following abrupt discontinuation of midazolam following chronic administration. Abdominal distention, nausea, vomiting, and tachycardia are prominent symptoms of withdrawal in infants.

The handling of midazolam HCI syrup should be managed to minimize the risk of diversion, including restriction of access and accounting procedures as appropriate to the clinical setting and as required by law.

Read the entire FDA prescribing information for Midazolam Hydrochloride Syrup (Midazolam Hcl Syrup) »