( ). ( ). Serious respiratory adverse events have occurred after administration of oral midazolam hydrochloride syrup, most often when midazolam hydrochloride syrup was used in combination with other central nervous system depressants. These adverse events have included respiratory depression, airway obstruction, oxygen desaturation, apnea, and rarely, respiratory and/or cardiac arrestseeBOX WARNINGWhen oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequentlyseeDOSAGE AND ADMINISTRATION

Prior to the administration of midazolam hydrochloride syrup in any dose, the immediate availability of oxygen, resuscitative drugs, age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and skilled personnel for the maintenance of a patent airway and support of ventilation should be ensured. Midazolam hydrochloride syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

Midazolam hydrochloride syrup should be used only in hospital or ambulatory care settings, including physicians’ and dentists’ offices, that are equipped to provide continuous monitoring of respiratory and cardiac function. Midazolam hydrochloride syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional. If midazolam hydrochloride syrup will be administered in combination with other anesthetic drugs or drugs which depress the central nervous system, patients must be monitored by persons specifically trained in the use of these drugs and, in particular, in the management of respiratory effects of these drugs, including respiratory and cardiac resuscitation of patients in the age group being treated.

For deeply sedated patients, a dedicated individual whose sole responsibility is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure.

. The immediate availability of specific reversal agents (flumazenil) is highly recommended. Vital signs should continue to be monitored during the recovery period. Because midazolam can depress respiration (see ), especially when used concomitantly with opioid agonists and other sedatives (see ), it should be used for sedation/anxiolysis/amnesia only in the presence of personnel skilled in early detection of hypoventilation, maintaining a patent airway, and supporting ventilation. Patients should be continuously monitored for early signs of hypoventilation, airway obstruction, or apnea with means for detection readily available (eg, pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediatelyCLINICAL PHARMACOLOGYDOSAGE AND ADMINISTRATION

Episodes of oxygen desaturation, respiratory depression, apnea, and airway obstruction have been occasionally reported following premedication (sedation prior to induction of anesthesia) with oral midazolam; such 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.

Reactions such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. Consideration should be given to the possibility of paradoxical reaction. Should such reactions occur, the response to each dose of midazolam hydrochloride syrup and all other drugs, including local anesthetics, should be evaluated before proceeding. Reversal of such responses with flumazenil has been reported in pediatric and adult patients.

Concomitant use of barbiturates, alcohol 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. Narcotic premedication also depresses the ventilatory response to carbon dioxide stimulation.

Coadministration of oral midazolam in patients who are taking ketoconazole, intraconazole, and saquinavir has been shown to result in large increases in C and AUC of midazolam due to a decrease in plasma clearance of midazolam (see : and ). Due to the potential for intense and prolonged sedation and respiratory depression, midazolam syrup should only be coadministered with these medications if absolutely necessary and with appropriate equipment and personnel available to respond to respiratory insufficiency. maxPharmacokineticsDrug-Drug InteractionsPRECAUTIONS

Higher risk pediatric surgical patients may require lower doses, whether or not concomitant sedating medications have been administered. Pediatric patients with cardiac or respiratory compromise may be unusually sensitive to the respiratory depressant effect of midazolam hydrochloride syrup. Pediatric patients undergoing procedures involving the upper airway such as upper endoscopy or dental care, are particularly vulnerable to episodes of desaturation and hypoventilation due to partial airway obstruction. Patients with chronic renal failure and patients with congestive heart failure eliminate midazolam more slowly (see ). CLINICAL PHARMACOLOGY

The decision as to when patients who have received midazolam hydrochloride syrup, particularly on an outpatient basis, may again engage in activities requiring complete mental alertness, operate hazardous machinery or drive a motor vehicle must be individualized. Gross tests of recovery from the effects of midazolam hydrochloride syrup (see ) cannot be relied upon to predict reaction time under stress. It is recommended that no patient operate hazardous machinery or a motor vehicle until the effects of the drug, such as drowsiness, have subsided or until one full day after anesthesia and surgery, whichever is longer. Particular care should be taken to assure safe ambulation. CLINICAL PHARMACOLOGY