FDA

Midazolam in 0.9% Sodium Chloride

Approved 17 Apr 2023IntravenousSolution

The FDA lists this product in 6 strengths and forms.

Indications

Midazolam in sodium chloride injection is indicated: Continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting. Midazolam in sodium chloride injection is a benzodiazepine indicated for: continuous intravenous infusion for sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients as a component of anesthesia or during treatment in a critical care setting.

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Contraindications

Midazolam in sodium chloride injection is contraindicated in patients with: Known hypersensitivity to midazolam Acute narrow-angle glaucoma Midazolam in sodium chloride injection is contraindicated in patients with: known hypersensitivity to midazolam. ( 4 ) acute narrow-angle glaucoma. ( 4 )

Warnings and precautions

Cardiorespiratory Adverse Reactions : Serious cardiorespiratory adverse reactions have occurred, sometimes resulting in death or permanent neurologic injury. ( 5.3 ) Paradoxical Behavior : Agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity and combativeness have been reported in both adult and pediatric patients. ( 5.4 ) Dependence and Withdrawal with Long-Term Use : Use for several days to weeks may lead to physical dependence to midazolam.

Do not abruptly discontinue midazolam. Gradually taper the dosage using a tapering schedule that is individualized to the patient. ( 5.5 ) Debilitation and Comorbid Considerations : Higher risk adult and pediatric surgical patients, elderly patients and debilitated adult and pediatric patients require lower dosages, whether or not concomitant sedating medications have been administered. ( 5.6 ) Risk of Intra-Arterial Injection : There have been limited reports of intra- arterial injection of midazolam.

Adverse events have included local reactions, as well as isolated reports of seizure activity in which no clear causal relationship was established. ( 5.7 ) Impaired Cognitive Function : Because of partial or complete impairment of recall, patients should not operate hazardous machinery or a motor vehicle until drug effects have subsided. ( 5.8 ) Hypotension and Seizure in Preterm Infants and Neonates : Avoid rapid injection in the neonatal population.

Indications

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Warnings and precautions

Interactions

Opioid Analgesics and Other Sedative Hypnotics : Risk of respiratory depression is increased ( 7.1 ) Cytochrome P450-3A4 Inhibitors : May result in prolonged sedation due to decreased plasma clearance of midazolam. ( 7.2 )

7.1Opioid Analgesics and Other Sedative Hypnotics

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.

The sedative effect of intravenous midazolam is accentuated by any concomitantly administered medication which depresses the central nervous system, particularly opioids (e.g., morphine, meperidine and fentanyl) and also secobarbital and droperidol. Consequently, the dosage of midazolam should be adjusted according to the type and amount of concomitant medications administered and the desired clinical response [see Dosage and Administration (2) ].

7.2Cytochrome P450-3A4 Inhibitors

Concomitant administration with drugs that are known to inhibit the P450-3A4 enzyme system, such as cimetidine (not ranitidine), erythromycin, diltiazem, verapamil, ketoconazole and itraconazole, may result in prolonged sedation due to a decrease in plasma clearance of midazolam. The effect of single oral doses of 800 mg cimetidine and 300 mg ranitidine on steady-state concentrations of midazolam was examined in a randomized crossover study (n=8).

Cimetidine increased the mean midazolam steady-state concentration from 57 to 71 ng/mL. Ranitidine increased the mean steady-state concentration to 62 ng/mL. No change in choice reaction time or sedation index was detected after dosing with the H2 receptor antagonists. In a placebo-controlled study, erythromycin administered as a 500 mg dose, three times a day, for 1 week (n=6), reduced the clearance of midazolam following a single 0.5 mg/kg intravenous dose.

The half-life was approximately doubled. The effects of diltiazem (60 mg three times a day) and verapamil (80 mg three times a day) on the pharmacokinetics and pharmacodynamics of oral midazolam were investigated in a three-way crossover study (n=9). The half-life of midazolam increased from 5 to 7 hours when midazolam was taken in conjunction with verapamil or diltiazem. No interaction was observed in healthy subjects between midazolam and nifedipine.

7.3 Saquinavir In a placebo-controlled study, saquinavir administered as a 1200 mg dose, tid, for 5 days (n=12), a 56% reduction in the clearance of midazolam following a single 0.05 mg/kg intravenous dose was observed. The half-life was approximately doubled.

7.4Thiopental

A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults.

7.5Halothane

The intravenous administration of midazolam decreases the minimum alveolar concentration (MAC) of halothane required for general anesthesia. This decrease correlates with the dose of midazolam administered; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

7.6Pancuronium Although

the possibility of minor interactive effects has not been fully studied, midazolam and pancuronium have been used together in patients without noting clinically significant changes in dosage, onset or duration in adults. Midazolam does not protect against the characteristic circulatory changes noted after administration of succinylcholine or pancuronium and does not protect against the increased intracranial pressure noted following administration of succinylcholine.

Midazolam does not cause a clinically significant change in dosage, onset or duration of a single intubating dose of succinylcholine; no similar studies have been carried out in pediatric patients but there is no scientific reason to expect that pediatric patients would respond differently than adults.

7.7Other Drugs Used in the Surgical Setting

No significant adverse interactions with commonly used premedications or drugs used during anesthesia and surgery (including atropine, scopolamine, glycopyrrolate, diazepam, hydroxyzine, d-tubocurarine, succinylcholine and other nondepolarizing muscle relaxants) or topical local anesthetics (including lidocaine, dyclonine HCl and Cetacaine) have been observed in adults or pediatric patients. In neonates, however, severe hypotension has been reported with concomitant administration of fentanyl.

This effect has been observed in neonates on an infusion of midazolam who received a rapid injection of fentanyl and in patients on an infusion of fentanyl who have received a rapid injection of midazolam.

7.8Drug/Laboratory Test Interactions

Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Neonates born to mothers using benzodiazepines, including midazolam, late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal [see Warnings and Precautions (5.10 ), 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) .

Available data from randomized controlled trials, cohort studies and case reports over several decades with midazolam use in pregnant women for anesthesia have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Most of the reported exposures to midazolam occurred at the time of cesarean delivery . Rare case reports of the prolonged use of midazolam in pregnant women for sedation in a critical care setting are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes (see Data).

In pregnant rats and rabbits, midazolam did not cause adverse effects to the fetus at doses of up to 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons. Published studies in pregnant primates demonstrate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development increases neuronal apoptosis in the developing brain of the offspring when used for longer than 3 hours.

There are no data on pregnancy exposures in primates corresponding to periods prior to the third trimester in humans (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 background risk of major birth defects and 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 during pregnancy or labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Monitor neonates exposed to midazolam during pregnancy for signs of withdrawal. Manage these neonates accordingly [see Warnings and Precautions (5.2 )].

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 and Precautions (5.8 ), Use in Specific Populations (8.4 ), Nonclinical Pharmacology (13.2) ].

Adverse reactions

The following serious adverse reactions are discussed in greater detail in other sections: Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.3 )] Paradoxical Behavior [see Warnings and Precautions (5.4 )] Dependence and Withdrawal [see Warnings and Precautions (5.5 )] Impaired Cognitive Function [see Warnings and Precautions (5.8) ] Hypotension and Seizure in Preterm Infants and Neonates [see Warnings and Precautions (5.9 )] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.10 ), Use in Specific Populations (8.1) ] Pediatric Neurotoxicity [see Warnings and Precautions (5.11 )] The following adverse reactions have been identified from literature or postmarketing reports of midazolam.

Because some of these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Fluctuations in vital signs were the most frequently seen findings following parenteral administration of midazolam in adults and included decreased tidal volume and/or respiratory rate decrease (23.3% of patients following intravenous administration) and apnea (15.4% of patients following intravenous administration), as well as variations in blood pressure and pulse rate.

The majority of serious adverse reactions, particularly those associated with oxygenation and ventilation, have been reported when midazolam is administered with other medications capable of depressing the central nervous system. The incidence of such events is higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube, (e.g., upper endoscopy and dental procedures).

Adults Table 2: Additional Adverse Reactions Reported Subsequent to Intravenous Administration as a Single Sedative/anxiolytic/amnestic Agent in Adult Patients: hiccoughs (3.9%) Local effects at the intravenous site nausea (2.8%) tenderness (5.6%) vomiting (2.6%) pain during injection (5%) coughing (1.3%) redness (2.6%) "oversedation" (1.6%) induration (1.7%) headache (1.5%) phlebitis (0.4%) drowsiness (1.2%) Pediatric Patients The following adverse events related to the use of intravenous midazolam in pediatric patients were reported in the medical literature: desaturation 4.6%, apnea 2.8%, hypotension 2.7%, paradoxical reactions 2%, hiccough 1.2%, seizure-like activity 1.1% and nystagmus 1.1%.

The majority of airway-related events occurred in patients receiving other CNS depressing medications and in patients where midazolam was not used as a single sedating agent. Neonates There have been reports of hypotensive episodes and seizures following the administration of midazolam to neonates, [see Warnings and Precautions (5.9 )]. Other Adverse Reactions Occurring at an Incidence of <1% Following Intravenous Injection as a Single Sedative/Anxiolytic/Amnesia Agent Respiratory : Laryngospasm, bronchospasm, dyspnea, hyperventilation, wheezing, shallow respirations, airway obstruction, tachypnea Cardiovascular : Bigeminy, premature ventricular contractions, vasovagal episode, bradycardia, tachycardia, nodal rhythm Gastrointestinal : Acid taste, excessive salivation, retching CNS/Neuromuscular : Retrograde amnesia, euphoria, hallucination, confusion, argumentativeness, nervousness, anxiety, grogginess, restlessness, emergence delirium or agitation, prolonged emergence from anesthesia, dreaming during emergence, sleep disturbance, insomnia, nightmares, athetoid movements, seizure-like activity, ataxia, dizziness, dysphoria, slurred speech, dysphonia, paresthesia Special Senses : Blurred vision, diplopia, nystagmus, pinpoint pupils, cyclic movements of eyelids, visual disturbance, difficulty focusing eyes, ears blocked, loss of balance, light-headedness Integumentary : Hive-like elevation at injection site, swelling or feeling of burning, warmth or coldness at injection site Hypersensitivity : Allergic reactions including anaphylactic reactions, hives, rash, pruritus Miscellaneous : Yawning, lethargy, chills, weakness, toothache, faint feeling, hematoma The most common adverse reactions (≥15%) were decreased tidal volume, decreased respiratory rate, and apnea.

( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA Inc. at 1-877-845-0689 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Midazolam in 0.9% Sodium Chloride

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

Midazolam in 0.9% Sodium Chloride

Indications

Contraindications

Warnings and precautions

Two medicines in one question?

5.3Risk of Cardiorespiratory Adverse Reactions

5.4Risk of Paradoxical Behavior

5.6Debilitation and Comorbid Considerations

Interactions

7.1Opioid Analgesics and Other Sedative Hypnotics

7.2Cytochrome P450-3A4 Inhibitors

7.4Thiopental

7.5Halothane

7.6Pancuronium Although

7.7Other Drugs Used in the Surgical Setting

7.8Drug/Laboratory Test Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

Composition

Strengths and forms

Official product information

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