Midazolam In 0.8% Sodium Chloride
Injection, Solution · Intravenous
Uses
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.
Dosage and administration
• For intravenous injection only. Avoid intra-arterial injection or extravasation. ( 2.1 )
• Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. ( 2.1 )
• See Full Prescribing Information for complete dosage and administration information. ( 2 ) 2.1 Important Dosage and Administration Instructions Midazolam in Sodium Chloride Injection should only be administered intravenously. Avoid intra-arterial injection or extravasation [see Warnings and Precautions (5.7) ]. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Midazolam in Sodium Chloride Injection. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Supplemental oxygen, resuscitative drugs, and age- and size-appropriate equipment for bag/valve/mask assisted ventilation must be immediately available during administration of Midazolam in Sodium Chloride Injection. A benzodiazepine reversal agent should be immediately available. Continuously monitor vital signs during sedation and through the recovery period [see Warnings and Precautions (5.1) ]. Midazolam must never be used without individualization of dosage particularly when used with other medications capable of producing central nervous system depression [ Warnings and Precautions (5.2) ]. Midazolam in Sodium Chloride Injection can cause respiratory depression. It is a potent sedative agent that requires slow administration and individualization of dosage. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/ or arrest. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Warnings and Precautions (5.3) ]. Reactions such as agitation, involuntary movements, hyperactivity and combativeness have been reported in adult and pediatric patients. 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 patients [see Warnings and Precautions (5.4) ]. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. If solution is discolored or particulate matter is present, do not use. Once the bag has been penetrated, limit the infusion duration to 48 hours maximum. 2.2 General Dosing Information Individualize dosing and titrate to desired clinical response, taking into account patient age, clinical status, and concomitant use of other CNS depressants. Titrate to effect with multiple small doses while continuously monitoring respiratory and cardiac function (i.e., pulse oximetry). To minimize the potential for oversedation, allow adequate time between doses to achieve peak central nervous system effect (3 to 5 minutes). Adults and Pediatrics 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. Pediatrics Pediatric patients generally require higher dosages of midazolam (mg/kg) than adults. For deeply sedated pediatric patients a dedicated individual, other than the practitioner performing the procedure, should monitor the patient throughout the procedure. Elderly and Debilitated Patients Intravenous doses of midazolam should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6) ]. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia [see Warnings and Precautions (5.8) ]. Monitoring 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. This is especially true in pediatric patients. Continuously monitor vital signs during sedation and through the recovery period [see Warnings and Precautions (5.1) ]. 2.3 Dosing Recommendations Table 1 provides dosing recommendations for adult, pediatric, and neonatal patients. Table 1. Dosing Recommendations for Continuous Intravenous Infusion in Adult, Pediatric, and Neonatal Patients ADULT PATIENTS If a loading dose is necessary to rapidly initiate sedation, 0.01 mg/kg to 0.05 mg/kg (approximately 0.5 mg to 4 mg for a typical adult) may be given slowly or infused over several minutes. This dose may be repeated at 10 to 15 minute intervals until adequate sedation is achieved. For maintenance of sedation, the usual initial infusion rate is 0.02 mg/kg/hr to 0.10 mg/kg/hr (1 mg/hr to 7 mg/hr). Higher loading or maintenance infusion rates may occasionally be required in some patients. Use the lowest recommended doses in patients with residual effects from anesthetic drugs, or in those concurrently receiving other sedatives or opioids. Individual response to midazolam is variable. Titrate the infusion rate to the desired level of sedation, taking into account the patient's age, clinical status and current medications. In general, midazolam should be infused at the lowest rate that produces the desired level of sedation. Assess sedation at regular intervals and adjust the midazolam infusion rate.
Dosage forms and strengths
Midazolam in Sodium Chloride Injection, 50 mg per 50 mL (1 mg/mL) and 100 mg per 100 mL (1 mg/ mL), is a clear, colorless solution supplied in single-dose bag. Injection: 50 mg per 50 mL (1 mg/mL) and 100 mg per 100 mL (1 mg/mL) in a single-dose bag.
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.
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. ( 5.9 ) Neonatal Sedation and Withdrawal Syndrome : Receiving Midazolam in Sodium Chloride Injection during pregnancy can result in neonatal sedation and/or neonatal withdrawal. ( 5.10 , 8.1 ) Pediatric Neurotoxicity : In developing animals, exposures greater than 3 hours cause neurotoxicity. Weigh benefits against potential risks when considering elective procedures in children under 3 years old. ( 5.11 ) 5.1 Personnel and Equipment for Monitoring and Resuscitation Prior to the intravenous administration of midazolam in any dose, ensure 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. Only personnel trained in the administration of procedural sedation, and not involved in the conduct of the diagnostic or therapeutic procedure, should administer Midazolam in Sodium Chloride Injection. Administering personnel must be trained in the detection and management of airway obstruction, hypoventilation, and apnea, including the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation. Continuously monitor patients for early signs of hypoventilation, airway obstruction, or apnea, with means readily available (e.g., pulse oximetry). Hypoventilation, airway obstruction, and apnea can lead to hypoxia and/or cardiac arrest unless effective countermeasures are taken immediately. A benzodiazepine reversal agent (i.e., flumazenil) should be immediately available during administration of Midazolam in Sodium Chloride Injection. Continuously monitor vital signs during the recovery period. Because intravenous midazolam can depress respiration [see Clinical Pharmacology (12) ] , especially when used concomitantly with opioid agonists and other sedatives [see Dosage and Administration (2) ] , 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. 5.2 Risks from Concomitant Use with Opioids, Other Sedative Hypnotics, or Other Central Nervous System Depressants Concomitant use of benzodiazepines and opioids may result in profound sedation, respiratory depression, coma, and death. Monitor patients for respiratory depression and sedation [see Warnings and Precautions (5.2) and Drug Interactions (7.1) ]. Titrate the dose of Midazolam in Sodium Chloride Injection when administered with opioid analgesics and sedative-hypnotics to the desired clinical response. Continuously monitor sedated patients for hypotension, airway obstruction, hypoventilation, apnea, and oxygen desaturation. These cardiorespiratory effects may be more likely to occur in patients with obstructive sleep apnea, the elderly, and ASA-PS III or IV patients. 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. 5.3 Risk of Cardiorespiratory Adverse Reactions Serious cardiorespiratory adverse reactions have occurred after administration of midazolam. These have included respiratory depression, airway obstruction, oxygen desaturation, apnea, respiratory arrest and/or cardiac arrest, sometimes resulting in death or permanent neurologic injury. There have also been rare reports of hypotensive episodes requiring treatment during or after diagnostic or surgical manipulations particularly in adult or pediatric patients with hemodynamic instability. Hypotension occurred more frequently in the sedation studies in patients premedicated with an opioid. Excessive single doses or rapid intravenous administration may result in respiratory depression, airway obstruction and/or arrest. When used for sedation/anxiolysis/amnesia, midazolam should always be titrated slowly in adult or pediatric patients. Adverse hemodynamic events have been reported in pediatric patients with cardiovascular instability; rapid intravenous administration should also be avoided in this population. Continuously monitor patients for early signs of hypoventilation, airway obstruction, and apnea using capnography, pulse oximetry, and clinical assessment [see Dosage and Administration (2.2) ].
Side effects
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 (5.0%) 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 2.0%, 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 <1.0% 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. To report SUSPECTED ADVERSE REACTIONS, contact B. Braun Medical Inc. at 1-833-425-1464 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug 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 ) 7.1 Opioid 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) ]. 7.2 Cytochrome 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. 7.4 Thiopental A moderate reduction in induction dosage requirements of thiopental (about 15%) has been noted following use of intramuscular midazolam for premedication in adults. 7.5 Halothane 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. 7.6 Pancuronium 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. 7.7 Other 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. 7.8 Drug/Laboratory Test Interactions Midazolam has not been shown to interfere with results obtained in clinical laboratory tests.
Use in specific populations
Lactation: A lactating woman may pump and discard breast milk for 4 to 8 hours after treatment with midazolam ( 8.2 ). 8.1 Pregnancy 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) . 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 and 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) ]. 8.2 Lactation Risk Summary There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Based on data from published studies, midazolam is present in human milk in low levels (see Data). There are no data on the effects of midazolam on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Midazolam in Sodium Chloride Injection and any potential adverse effects on the breastfed infant form Midazolam in Sodium Chloride Injection or from the underlying maternal condition. Clinical Considerations Infants exposed to midazolam through breast milk should be monitored for sedation, poor feeding, and poor weight gain. A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk during treatment for a range of at least 4 to 8 hours after midazolam administration in order to minimize drug exposure to a breastfed infant.
Pregnancy
8.1 Pregnancy 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) . 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 and 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) ].
Pediatric use
8.4 Pediatric Use The safety and efficacy of midazolam for sedation/anxiolysis/amnesia following continuous infusion have been established in pediatric and neonatal patients. UNLIKE ADULT PATIENTS, PEDIATRIC PATIENTS GENERALLY RECEIVE INCREMENTS OF MIDAZOLAM ON A MG/KG BASIS. As a group, pediatric patients generally require higher dosages of midazolam (mg/kg) than do adults. Younger (less than six years) pediatric patients may require higher dosages (mg/kg) than older pediatric patients, and may require closer monitoring. In obese PEDIATRIC PATIENTS, the dose should be calculated based on ideal body weight. When midazolam is given in conjunction with opioids or other sedatives, the potential for respiratory depression, airway obstruction, or hypoventilation is increased. 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. Midazolam should not be administered by rapid injection in the neonatal population. Severe hypotension and seizures have been reported following rapid intravenous administration, particularly, with concomitant use of fentanyl. Animal Data Published juvenile animal studies demonstrate that the administration of anesthetic and sedation drugs, such as Midazolam in Sodium Chloride Injection, that either block NMDA receptors or potentiate the activity of GABA during the period of rapid brain growth or synaptogenesis, results in widespread neuronal and oligodendrocyte cell loss in the developing brain and alterations in synaptic morphology and neurogenesis. Based on comparisons across species, 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 3 years of age in humans. In primates, exposure to 3 hours of ketamine that produced a light surgical plane of anesthesia did not increase neuronal cell loss, however, treatment regimens of 5 hours or longer of isoflurane increased neuronal cell loss. Data from isoflurane-treated rodents and ketamine-treated primates suggest that the neuronal and oligodendrocyte cell losses are associated with prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings is not known, and healthcare providers should balance the benefits of appropriate anesthesia in pregnant women, neonates, and young children who require procedures with the potential risks suggested by the nonclinical data [see Warnings and Precautions (5.8) and Nonclinical Pharmacology (13.2) ].
Geriatric use
8.5 Geriatric Use Because geriatric patients may have altered drug distribution and diminished hepatic and/or renal function, reduced doses of midazolam are recommended. Doses of Midazolam in Sodium Chloride Injection should be decreased for elderly and for debilitated patients [see Warnings and Precautions (5.6) and Dosage and Administration (2) ] and subjects over 70 years of age may be particularly sensitive. These patients will also probably take longer to recover completely after midazolam administration for the induction of anesthesia. Administration of intravenous midazolam to elderly and/or high-risk surgical patients has been associated with rare reports of death under circumstances compatible with cardiorespiratory depression. In most of these cases, the patients also received other central nervous system depressants capable of depressing respiration, especially opioids [see Dosage and Administration (2) ]. Midazolam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Overdosage
Clinical Presentation Overdosage of benzodiazepines is characterized by central nervous system depression ranging from drowsiness to coma. In mild to moderate cases, symptoms can include drowsiness, confusion, dysarthria, lethargy, hypnotic state, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical or disinhibitory reactions (including agitation, irritability, impulsivity, violent behavior, confusion, restlessness, excitement, and talkativeness) may occur. In severe overdosage cases, patients may develop respiratory depression and coma. Overdosage of benzodiazepines in combination with other CNS depressants (including alcohol and opioids) may be fatal [see Warnings and Precautions (5.2) ]. Markedly abnormal (lowered or elevated) blood pressure, heart rate, or respiratory rate raise the concern that additional drugs and/or alcohol are involved in the overdosage. No evidence of specific organ toxicity from midazolam overdosage has been reported. Management of Overdosage In managing benzodiazepine overdosage, employ general supportive measures, including intravenous fluids and airway management. Flumazenil, a specific benzodiazepine receptor antagonist indicated for the complete or partial reversal of the sedative effects of benzodiazepines in the management of benzodiazepine overdosage, can lead to withdrawal and adverse reactions, including seizures, particularly in the context of mixed overdosage with drugs that increase seizure risk (e.g., tricyclic and tetracyclic antidepressants) and in patients with long-term benzodiazepine use and physical dependency. The risk of withdrawal seizures with flumazenil use may be increased in patients with epilepsy. Flumazenil is contraindicated in patients who have received a benzodiazepine for control of a potentially life-threatening condition (e.g., status epilepticus). If the decision is made to use flumazenil, it should be used as an adjunct to, not as a substitute for, supportive management of benzodiazepine overdosage. See the flumazenil injection Prescribing Information. Consider contacting the Poison Help Line (1-800-222-1222), or medical toxicologist for additional overdosage management for recommendations.
Description
Midazolam in 0.8% Sodium Chloride Injection is a benzodiazepine available as a sterile, preservative-free, nonpyrogenic solution of midazolam and sodium chloride in water for injection for intravenous use. Each single-dose bag of Midazolam in Sodium Chloride Injection contains either 50 mg/50 mL (1 mg/mL) or 100 mg/100 mL (1 mg/mL) of midazolam and 8 mg/mL of sodium chloride in water for injection. Midazolam in 0.8% Sodium Chloride Injection may contain hydrochloric acid and/or sodium hydroxide for pH adjustment. The pH is 3.0 – 4.0. Midazolam is a white to light yellow crystalline compound, insoluble in water, freely soluble in ethanol, soluble in methanol. Chemically, midazolam is 8-chloro-6-(2-fluorophenyl)-1-methyl-4 H -imidazo[1,5-a] [1,4]benzodiazepine. Midazolam has the empirical formula C 18 H 13 ClFN 3 , a calculated molecular weight of 325.8 and the following structural formula: Structural Formula
Mechanism of action
12.1 Mechanism of Action Midazolam is a short-acting benzodiazepine central nervous system (CNS) depressant.
How supplied
Midazolam in 0.8% Sodium Chloride Injection is a clear, colorless liquid supplied in 50 mL and 100 mL flexible container (bag), closed with an injection port, each bag is protected with an overwrap available as: Total Strength per Total Volume Strength per mL NDC REF 50 mg per 50 mL 1 mg/mL 0264-8005-31 DM8005 100 mg per 100 mL 1 mg/mL 0264-8002-32 DM8002 The bag and the injection port for the Midazolam in 0.8% Sodium Chloride Injection are not made with natural rubber latex. Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Protect from freezing. Protect from light. Discard unused portion. Overwrap label: Store in original overwrap protected from light until ready to dispense. The overwrap is a moisture and light barrier.
Patient information
Alcohol and Current Medication Advise patients to notify their healthcare provider about alcohol or medication use, especially blood pressure medication and antibiotics. Alcohol and other CNS depressants, such as opioid analgesic and benzodiazepines, can have an additive effect when administered with Midazolam in Sodium Chloride Injection [see Warnings and Precautions (5.2) , Drug Interactions (7.1) ]. 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 [see Warnings and Precautions (5.1) , Use in Specific Populations (8.1) ]. Pregnancy Advise pregnant females exposed to midazolam 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. Instruct patients to inform their healthcare provider if they are pregnant during treatment with Midazolam in Sodium Chloride Injection [see Warnings and Precautions (5.10) , Use in Specific Populations (8.1) ]. Lactation 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 Use in Specific Populations (8.2) ]. Residual Sedation and Amnesia Advise patients that they may experience residual sedation and amnesia. The decision as to when patients who have received injectable midazolam, 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 [see Warnings and Precautions (5.8) ]. Withdrawal Advise patients that receive midazolam in a critical care setting over an extended period of time that they may experience symptoms of withdrawal following abrupt discontinuation.
Label text from the FDA structured product label by B. Braun Medical Inc. (revised Oct 15, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Midazolam in 2 products
Midazolam In 0.8% Sodium Chloride NDC products (2)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0264-8002 | Midazolam 1 mg/mL Injection, Solution | B. Braun Medical Inc. | ANDA · DEA CIV |
| 0264-8005 | Midazolam 1 mg/mL Injection, Solution | B. Braun Medical Inc. | ANDA · DEA CIV |
Frequently asked questions
What is Midazolam In 0.8% Sodium Chloride used for?
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…
What are the side effects of Midazolam In 0.8% Sodium Chloride?
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… See the full label for the complete list.
Who makes Midazolam In 0.8% Sodium Chloride?
Midazolam In 0.8% Sodium Chloride is listed by 1 labeler in the FDA NDC directory, including B. Braun Medical Inc..