INDICATIONS AND USAGE Midazolam HCl syrup is indicated for use in pediatric patients for sedation, anxiolysis and amnesia prior to diagnostic, therapeutic or endoscopic procedures or before induction of anesthesia.

Midazolam HCl syrup is intended for use in monitored settings only and not for chronic or home use [see WARNINGS] .

WARNINGS Personnel and Equipment for Monitoring and Resuscitation Midazolam HCl 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 HCl syrup must only be administered to patients if they will be monitored by direct visual observation by a health care professional.

If midazolam HCl 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.

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 immediately.

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 CLINICAL PHARMACOLOGY] , especially when used concomitantly with opioid agonists and other sedatives [see DOSAGE AND ADMINISTRATION] , 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.

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.

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including midazolam, and opioids may result in profound sedation, respiratory depression, coma and death.

If a decision is made to use midazolam concomitantly with opioids, monitor patients for respiratory depression and sedation [see PRECAUTIONS/Drug Interactions] .

Risk of Respiratory Adverse Events Serious respiratory adverse events have occurred after administration of oral midazolam, most often when midazolam 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 arrest [see BOX WARNING] .

When oral midazolam is administered as the sole agent at recommended doses respiratory depression, airway obstruction, oxygen desaturation, and apnea occur infrequently [see DOSAGE AND ADMINISTRATION] .

Prior to the administration of midazolam 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.

Individualization of Dosage Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing central nervous system depression.

See DOSAGE AND ADMINISTRATION for complete information.

Other Adverse Events 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 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 Central Nervous System Depressants 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.

Drug-Drug Interactions Coadministration of oral midazolam in patients who are taking ketoconazole and intraconazole, and saquinavir has been shown to result in large increases in Cmax and AUC of midazolam due to a decrease in plasma clearance of midazolam [see CLINICAL PHARMACOLOGY: Pharmacokinetics: Special Populations: Drug-Drug Interactions and PRECAUTIONS] .

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.

Debilitation and Comorbidity Considerations 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.

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] .

Return to Cognitive Function Midazolam is associated with a high incidence of partial or complete impairment of recall for the next several hours.

The decision as to when patients who have received midazolam HCl 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 HCl syrup [see CLINICAL PHARMACOLOGY] 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.

Neonatal Sedation and Withdrawal Syndrome Use of midazolam HCl syrup late in pregnancy can result in sedation (respiratory depression, lethargy, hypotonia) and/or withdrawal symptoms (hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties) in the neonate ( see PRECAUTIONS: Pregnancy).

Monitor neonates exposed to midazolam HCl syrup during pregnancy or labor for signs of sedation and monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal; manage these neonates accordingly.

Usage in Preterm Infants and Neonates Midazolam HCl syrup has not been studied in patients less than 6 months of age.

Pediatric Neurotoxicity Published animal studies demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity increase neuronal apoptosis in the developing brain and result in long-term cognitive deficits when used for longer than 3 hours.

The clinical significance of these findings is not clear.

However, based on the available data, the window of vulnerability to these changes is believed to correlate with exposures in the third trimester of gestation through the first several months of life, but may extend out to approximately three years of age in humans [see PRECAUTIONS; Pregnancy, Pediatric Use and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY] .

Some published studies in children suggest that similar deficits may occur after repeated or prolonged exposures to anesthetic agents early in life and may result in adverse cognitive or behavioral effects.

These studies have substantial limitations, and it is not clear if the observed effects are due to the anesthetic/sedation drug administration or other factors such as the surgery or underlying illness.

Anesthetic and sedation drugs are a necessary part of the care of children and pregnant women needing surgery, other procedures, or tests that cannot be delayed, and no specific medications have been shown to be safer than any other.

Decisions regarding the timing of any elective procedures requiring anesthesia should take into consideration the benefits of the procedure weighed against the potential risks.

ADVERSE REACTIONS 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 premedication 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 of adverse events occurring during the premedication period, before induction of 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 midazolam administration 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 the premedication period.

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 1.0 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 HCl 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 Body System Treatment Regimen Overall No.

Patients with Adverse Events 0.25 mg/kg (n=132) 0.50 mg/kg (n=132) 1.0 mg/kg (n=133) (n=397) No.

(%) No.

(%) No.

(%) No.

(%) Gastrointestinal System Disorders Emesis 1 (0.76%) 1 (0.76%) 1 (0.75%) 3 (0.76%) Nausea 2 (1.5%) 2 (0.50%) Respiratory System Disorders Laryngospasm 1* (0.75%) 1 (0.25%) Sneezing/Rhinorrhea 1 (0.75%) 1 (0.25%) ALL BODY SYSTEMS 1 (0.76%) 1 (0.76%) 5 (3.8%) 7 (1.8%) *This adverse event occurred precisely at the time of induction.

Table 6: Adverse Events (≥1%) From the Randomized, Double-Blind, Parallel-Group Trial on Entire Monitoring Period (premedication, anesthesia, recovery) Body System Treatment Regimen Overall No.

Patients with Adverse Events 0.25 mg/kg (n=132) 0.50 mg/kg (n=132) 1.0 mg/kg (n=133) (n=397) No.

(%) No.

(%) No.

(%) No.

(%) Gastrointestinal System Disorders Emesis 11 (8%) 5 (4%) 15 (11%) 31 (8%) Nausea 6 (5%) 2 (2%) 6 (5%) 14 (4%) Overall 16 (12%) 8 (6%) 16 (12%) 40 (10%) Respiratory System Disorders Hypoxia 0 5 (4%) 4 (3%) 9 (2%) Laryngospasm 0 1 (<1%) 5 (4%) 6 (2%) Respiratory Depression 2 (2%) 1 (<1%) 2 (2%) 5 (1%) Rhonchi 2 (2%) 1 (<1%) 2 (2%) 5 (1%) Airway Obstruction 2 (2%) 2 (2%) 0 4 (1%) Upper Airway Congestion 2 (2%) 0 2 (2%) 4 (1%) Overall 7 (5%) 9 (7%) 15 (11%) 31 (8%) Psychiatric Disorders Agitated 1 (<1%) 2 (2%) 3 (2%) 6 (2%) Overall 1 (<1%) 3 (2%) 4 (3%) 8 (2%) Heart Rate, Rhythm Disorders Bradycardia 1 (<1%) 3 (2%) 0 4 (1%) Bigeminy 2 (2%) 0 0 2 (<1%) Overall 3 (2%) 3 (2%) 1 (<1%) 7 (2%) Central & Peripheral Nervous System Disorders Prolonged Sedation 0 0 2 (2%) 2 (<1%) Overall 2 (2%) 0 3 (2%) 5 (1%) Skin and Appendages Disorders Rash 2 (2%) 0 0 2 (<1%) Overall 2 (2%) 2 (2%) 0 4 (1%) ALL BODY SYSTEMS 26 (20%) 23 (17%) 33 (25%) 82 (21%) 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 (SpO 2 of 33%) in a patient given midazolam HCl 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 HCl 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.