Midazolam Hydrochloride 2 mg/mL Syrup, 118 mL — NDC 0054-3566-99 (Billing 00054-3566-99)

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), hyperactivi… [Excerpted — this section continues on DailyMed.]

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… [Excerpted — this section continues on DailyMed.]

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Benzodiazepines interact at GABA A sites, and opioids interact primarily at mu receptors. When benzodiazepines and opioids are combined, the potential for benzodiazepines to significantly worsen opioid-related respiratory depression exists.

Monitor patients closely for respiratory depression and sedation. Other CNS Depressants One case was reported of inadequate sedation with chloral hydrate and later with oral midazolam due to a possible interaction with methylphenidate administered chronically in a 2-year-old boy with a history of Williams syndrome. The difficulty in achieving adequate sedation may have been the result of decreased absorption of the sedatives due to both the gastrointestinal effects and stimulant effects of methylphenidate.

The sedative effect of midazolam HCl syrup is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), propofol, ketamine, nitrous oxide, secobarbital and droperidol. Consequently, the dose of midazolam HCl syrup should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see DOSAGE AND ADMINISTRATION ] . No significant adverse interactions with common premedications (such as atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, and other muscle relaxants) or local anesthetics have been observed.

Inhibitors of CYP3A4 Isozymes Caution is advised when midazolam is administered concomitantly with drugs that are known to inhibit the cytochrome P450 3A4 enzyme system (ie, some drugs in the drug classes of azole antimycotics, protease inhibitors, calcium channel antagonists, and macrolide antibiotics). Drugs such as diltiazem, erythromycin, fluconazole, itraconazole, ketoconazole, saquinavir, and verapamil were shown to significantly increase the C max and AUC of orally administered midazolam. These drug interactions may result in increased and prolonged sedation due to a decrease in plasma clearance of midazolam.

Although not studied, the potent cytochrome P450 3A4 inhibitors ritonavir and nelfinavir may cause intense and prolonged sedation and respiratory depression due to a decrease in plasma clearance of midazolam. Caution is advised when midazolam HCl syrup is used concomitantly with these drugs. Dose adjustments should be considered and possible prolongation and intensity of effect should be anticipated [see CLINICAL PHARMACOLOGY : Pharmacokinetics : Special Populations : Drug-Drug Interactions ].

Inducers of CYP3A4 Isozymes Cytochrome P450 inducers, such as rifampin, carbamazepine, and phenytoin, induce metabolism and cause a markedly decreased C max and AUC of oral midazolam in adult studies. Although clinical studies have not been performed, phenobarbital is expected to have the same effect. Caution is advised when administering midazolam to patients receiving these medications and if necessary dose adjustments should be considered.

Drug/Laboratory Test Interactions Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

PRECAUTIONS General The efficacy and safety of midazolam in clinical use are functions of the dose administered, the clinical status of the individual patient, and the use of concomitant medications capable of depressing the CNS. Anticipated effects may range from mild sedation to deep levels of sedation with a potential loss of protective reflexes, particularly when coadministered with anesthetic agents or other CNS depressants. Care must be taken to individualize the dose of midazolam HCl syrup based on the patient’s age, underlying medical/surgical conditions, concomitant medications, and to have the personnel, age- and size-appropriate equipment and facilities available for monitoring and intervention.

Practitioners administering midazolam must have the skills necessary to manage reasonably foreseeable adverse effects, particularly skills in airway management. Information for Patients To assure safe and effective use of midazolam HCl syrup, the following information and instructions should be communicated to the patient when appropriate: 1. Inform your physician about any alcohol consumption and medicine you are now taking, especially blood pressure medication, antibiotics, and protease inhibitors, including drugs you buy without a prescription.

Alcohol has an increased effect when consumed with benzodiazepines; therefore, caution should be exercised regarding simultaneous ingestion of alcohol during benzodiazepine treatment. 2. Inform your physician if you are pregnant or are planning to become pregnant.

3. Inform your physician if you are nursing. 4.

Patients should be informed of the pharmacological effects of midazolam HCl syrup, such as sedation and amnesia, which in some patients may be profound. 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. 5.

Midazolam should not be taken in conjunction with grapefruit juice. 6. For pediatric patients, particular care should be taken to assure safe ambulation.

7. Effect of Anesthetic and Sedation Drugs on Early Brain Development: Studies conducted in young animals and children suggest repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains. Discuss with parents and caregivers the benefits, risks, and timing and duration of surgery or procedures requiring anesthetic and sedation drugs.

Pregnancy Advise pregnant females that 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 newborns [see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and PRECAUTIONS: Pregnancy ] . Instruct patients to inform their healthcare provider if they are pregnant. Advise patients that there is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to midazolam HCl syrup during pregnancy [see PRECAUTIONS, Pregnancy ].

Nursing Instruct patients to notify their healthcare provider if they are breastfeeding or intend to breastfeed. Instruct breastfeeding patients receiving midazolam to monitor infants for excessive sedation, poor feeding, and poor weight gain, and to seek medical attention if they notice these signs. A lactating woman may consider pumping and discarding breastmilk for at least 4 to 8 hours after receiving midazolam for sedation or anesthesia to minimize drug exposure to a breastfed infant [see PRECAUTIONS, Nursing Mothers ].

Drug Interactions Effect of Concomitant Use of Benzodiazepines and Opioids The concomitant use of benzodiazepines and opioids increases the risk of respiratory depression because of actions at different receptor sites in the CNS that control respiration. Ben… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Midazolam HCl syrup is a benzodiazepine and is a Schedule IV controlled substance that can produce drug dependence of the diazepam-type. Therefore, midazolam HCl 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 HCl 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.