FDA

Midazolam Hydrochloride

Approved 30 Apr 2002OralSyrup

The FDA lists this product in 50 strengths and forms.

Indications

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 ].

Contraindications

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.

Warnings and precautions

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.

At a glance

Brand name: Midazolam Hydrochloride
Route: Oral
Dosage form: Syrup
Applicant: Hikma
Status: Prescription
FDA approval: 30 Apr 2002
Application: ANDA075873-001

Indications

Contraindications

Warnings and precautions

Interactions

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.

Pregnancy and breastfeeding

Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors pregnancy outcomes in women exposed to psychiatric medications, including midazolam HCl syrup, during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Psychiatric Medications at 1-866-961-2388 or visiting online at https:// womensmentalhealth.org/pregnancyregistry/. Risk Summary Neonates born to mothers using benzodiazepines late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see WARNINGS: Neonatal Sedation and Withdrawal Syndrome and Clinical Considerations ].

Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with benzodiazepines and major birth defects (see Data ) . The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations Fetal/Neonatal Adverse Reactions Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia and sedation in neonates. Monitor neonates exposed to midazolam HCl syrup during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam HCl syrup during pregnancy for signs of withdrawal. Manage these neonates accordingly [see WARNINGS: Neonatal Sedation and Withdrawal Syndrome ].

Data Human Data Published data from observational studies on the use of benzodiazepines during pregnancy do not report a clear association with benzodiazepines and major birth defects. Although early studies reported an increased risk of congenital malformations with diazepam and chlordiazepoxide, there was no consistent pattern noted. In addition, the majority of more recent case-control and cohort studies of benzodiazepine use during pregnancy, which were adjusted for confounding exposures to alcohol, tobacco and other medications, have not confirmed these findings.

Animal Data Pregnant rats were treated with midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 through 15). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose. All doses produced slight to moderate ataxia.

The high dose produced a 5% decrease in maternal body weight gain compared to control. Pregnant rabbits were treated with midazolam using intravenous doses of 0.2, 0.6, and 2 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during the period of organogenesis (Gestation Day 7 to 18). Midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose.

The high dose was associated with findings of ataxia and sedation but no evidence of maternal toxicity. Pregnant rats were administered midazolam using intravenous doses of 0.2, 1, and 4 mg/kg/day (0.09, 0.46, and 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons) during late gestation and through lactation (Gestation Day 15 through Lactation Day 21). All doses produced ataxia. The high dose produced a slight decrease in maternal body weight gain compared to control.

There were no clear adverse effects noted in the offspring. The study included no functional assessments of the pups, such as learning and memory testing or reproductive capacity. In a published study in primates, administration of an anesthetic dose of ketamine for 24 hours on Gestation Day 122 increased neuronal apoptosis in the developing brain of the fetus. In other published studies, administration of either isoflurane or propofol for 5 hours on Gestation Day 120 resulted in increased neuronal and oligodendrocyte apoptosis in the developing brain of the offspring.

With respect to brain development, this time period corresponds to the third trimester of gestation in the human. The clinical significance of these findings is not clear; however, studies in juvenile animals suggest neuroapoptosis correlates with long-term cognitive deficits [see WARNINGS; Pediatric Neurotoxicity , PRECAUTIONS; Pediatric Use , and ANIMAL PHARMACOLOGY AND/OR TOXICOLOGY ].

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 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.

Midazolam Hydrochloride

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Midazolam Hydrochloride

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Interactions

Pregnancy and breastfeeding

Adverse reactions

Composition

Strengths and forms

Official product information