MIDAZOLAM HYDROCHLORIDE

Midazolam is a benzodiazepine available as midazolam HCl syrup for oral administration. Midazolam, a white to light yellow crystalline compound, is insoluble in water, but can be solubilized in aqueous solutions by formation of the hydrochloride salt in situ under acidic conditions. Chemically, midazolam HCl is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a][1,4] benzodiazepine hydrochloride. Midazolam hydrochloride has the molecular formula C 18 H 13 ClFN 3 ∙HCl, a calculated molecular weight of 362.25 and the following structural formula: Each mL of the syrup contains midazolam hydrochloride equivalent to 2 mg midazolam compounded with bitterness modifier, artificial cherry-brandy flavor, citric acid anhydrous, D&C Red #33, edetate disodium, glycerin, sodium benzoate, sodium citrate, sodium saccharin, sorbitol solution, and water; the pH is adjusted to 2.8 to 3.6 with hydrochloric acid. Under the acidic conditions required to solubilize midazolam in the syrup, midazolam is present as an equilibrium mixture (shown below) of the closed ring form shown above and an open-ring structure formed by the acid-catalyzed ring opening of the 4,5-double bond of the diazepine ring. The amount of open-ring form is dependent upon the pH of the solution. At the specified pH of the syrup, the solution may contain up to about 40% of the open-ring compound. At the physiologic conditions under which the product is absorbed (pH of 5 to 8) into the systemic circulation, any open-ring form present reverts to the physiologically active, lipophilic, closed-ring form (midazolam) and is absorbed as such. The following chart below plots the percentage of midazolam present as the open-ring form as a function of pH in aqueous solutions. As indicated in the graph, the amount of open-ring compound present in solution is sensitive to changes in pH over the pH range specified for the product: 2.8 to 3.6. Above pH 5, at least 99% of the mixture is present in the closed-ring form. Chemical Structure Chemical Structure Image

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 ].

Midazolam HCl syrup is indicated for use as a single dose (0.25 to 1.0 mg/kg with a maximum dose of 20 mg) for preprocedural sedation and anxiolysis in pediatric patients. Midazolam HCl syrup is not intended for chronic administration. Monitoring Midazolam HCl syrup should only be used in hospital or ambulatory care settings, including physicians' and dentists' offices that can provide for continuous monitoring of respiratory and cardiac function. Immediate availability of resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask ventilation and intubation, and personnel trained in their use and skilled in airway management should be assured [see WARNINGS ] . For deeply sedated patients, a dedicated individual whose sole responsibility it is to observe the patient, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Continuous monitoring of respiratory and cardiac function is required. Midazolam HCl syrup must be given only to patients if they will be monitored by direct visual observation by a health care professional. Midazolam HCl syrup should only be administered by persons specifically trained in the use of anesthetic drugs and the management of respiratory effects of anesthetic drugs, including respiratory and cardiac resuscitation of patients in the age group being treated. Patient response to sedative agents, and resultant respiratory status, is variable. Regardless of the intended level of sedation or route of administration, sedation is a continuum; a patient may move easily from light to deep sedation, with potential loss of protective reflexes, particularly when coadministered with anesthetic agents, other CNS depressants, and concomitant medications which may potentially cause a more intense and prolonged sedation [see PRECAUTIONS: Drug Interactions ] . This is especially true in pediatric patients. The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. Sedation guidelines recommend a careful presedation history to determine how a patient's underlying medical conditions or concomitant medications might affect their response to sedation/analgesia as well as a physical examination including a focused examination of the airway for abnormalities. Further recommendations include appropriate presedation fasting. Intravenous access is not thought to be necessary for all pediatric patients sedated for a diagnostic or therapeutic procedure because in some cases the difficulty of gaining IV access would defeat the purpose of sedating the child; rather, emphasis should be placed upon having the intravenous equipment available and a practitioner skilled in establishing vascular access in pediatric patients immediately available. Midazolam HCl syrup must never be used without individualization of dosage, particularly when used with other medications capable of producing CNS depression. Younger (<6 years of age) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require close monitoring. When midazolam HCl syrup is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. For appropriate patient monitoring, see WARNINGS and DOSAGE AND ADMINISTRATION: Monitoring . The health care practitioner who uses this medication in pediatric patients should be aware of and follow accepted professional guidelines for pediatric sedation appropriate to their situation. The recommended dose for pediatric patients is a single dose of 0.25 to 0.5 mg/kg, depending on the status of the patient and desired effect, up to a maximum dose of 20 mg. In general, it is recommended that the dose be individualized and modified based on patient age, level of anxiety, concomitant medications, and medical need [see WARNINGS and PRECAUTIONS ] . The younger (6 months to <6 years of age) and less cooperative patients may require a higher than usual dose up to 1.0 mg/kg. A dose of 0.25 mg/kg may suffice for older (6 to <16 years of age) or cooperative patients, especially if the anticipated intensity and duration of sedation is less critical. For all pediatric patients, a dose of 0.25 mg/kg should be considered when midazolam HCl syrup is administered to patients with cardiac or respiratory compromise, other higher risk surgical patients, and patients who have received concomitant narcotics or other CNS depressants. As with any potential respiratory depressant, these patients must be monitored for signs of cardiorespiratory depression after receiving midazolam HCl syrup. In obese pediatric patients, the dose should be calculated based on ideal body weight. Midazolam HCl syrup has not been studied, nor is it intended for chronic use.

Midazolam HCl syrup is contraindicated in patients with a known hypersensitivity to the drug or allergies to cherries or formulation excipients. Benzodiazepines are contraindicated in patients with acute narrow-angle glaucoma. Benzodiazepines may be used in patients with open-angle glaucoma only if they are receiving appropriate therapy. Measurements of intraocular pressure in patients without eye disease show a moderate lowering following induction of general anesthesia with injectable midazolam; patients with glaucoma have not been studied.

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 This adverse event occurred precisely at the time of induction. (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%) 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 (11%) 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.

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.

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]