Midazolam

Description

Midazolam in 0.8% Sodium Chloride Injection is a sterile, preservative-free, nonpyrogenic solution intended for intravenous use. Each single-dose bag contains either 50 mg of midazolam in 50 mL (1 mg/mL) or 100 mg of midazolam in 100 mL (1 mg/mL), along with 8 mg/mL of sodium chloride. The pH of the solution ranges from 3.0 to 4.0. Midazolam is characterized as a white to light yellow crystalline compound that is insoluble in water, freely soluble in ethanol, and soluble in methanol. The chemical structure of midazolam is defined as 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo1,5-abenzodiazepine, with an empirical formula of C18H13ClFN3 and a calculated molecular weight of 325.8.

Uses and Indications

Midazolam in Sodium Chloride Injection is indicated for continuous intravenous infusion for the sedation of intubated and mechanically ventilated adult, pediatric, and neonatal patients. This medication is utilized as a component of anesthesia or during treatment in a critical care setting.

There are no specific teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For intravenous injection only. It is imperative to avoid intra-arterial injection or extravasation during administration.

Dosing should be individualized and titrated to achieve the desired clinical response. Factors such as patient age, clinical status, and the concomitant use of other central nervous system (CNS) depressants must be considered when determining the appropriate dosage.

Healthcare professionals are advised to consult the Full Prescribing Information for comprehensive details regarding dosage and administration.

Contraindications

Midazolam in Sodium Chloride Injection is contraindicated in patients with known hypersensitivity to midazolam and in those with acute narrow-angle glaucoma. Use in these populations may lead to serious adverse effects.

Warnings and Precautions

Serious cardiorespiratory adverse reactions associated with the use of midazolam have been reported, with some cases resulting in death or permanent neurologic injury. Healthcare professionals should remain vigilant for these potential outcomes during treatment.

Agitation, involuntary movements—including tonic/clonic movements and muscle tremor—hyperactivity, and combativeness have been observed in both adult and pediatric patients. These reactions necessitate careful monitoring of patient behavior and responsiveness.

Prolonged use of midazolam, spanning several days to weeks, may lead to physical dependence. It is critical that midazolam not be abruptly discontinued; instead, a gradual tapering schedule should be implemented, tailored to the individual patient's needs.

Particular caution is warranted for higher-risk populations, including adult and pediatric surgical patients, elderly patients, and those who are debilitated. These patients may require lower dosages, regardless of whether concomitant sedating medications are being administered.

Reports of intra-arterial injection of midazolam have been limited, but adverse events such as local reactions and isolated seizure activity have been noted, although a clear causal relationship has not been established.

Due to the potential for partial or complete impairment of recall, patients should be advised against operating hazardous machinery or motor vehicles until the effects of the drug have fully subsided.

In the neonatal population, rapid injection should be avoided to minimize the risk of adverse effects. Additionally, administration of midazolam in sodium chloride injection during pregnancy may lead to neonatal sedation and/or withdrawal symptoms.

In animal studies, exposure to midazolam for durations exceeding three hours has been associated with neurotoxicity. Therefore, the benefits of elective procedures in children under three years old should be carefully weighed against the potential risks.

Only personnel who are trained in the administration of procedural sedation and are not involved in the diagnostic or therapeutic procedure should administer midazolam in sodium chloride injection. These individuals must also be proficient in recognizing and managing airway obstruction, hypoventilation, and apnea, ensuring the maintenance of a patent airway, supportive ventilation, and cardiovascular resuscitation.

It is imperative that resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask assisted ventilation are readily available during the administration of midazolam in sodium chloride injection. Continuous monitoring of vital signs is essential throughout the sedation process and during the recovery period.

Healthcare professionals should be aware that the concomitant use of benzodiazepines with opioid analgesics can lead to profound sedation, respiratory depression, coma, and even death. Patients must be continuously monitored for signs of respiratory depression and the depth of sedation during treatment.

Side Effects

Serious adverse reactions associated with the use of midazolam include significant cardiorespiratory events, which have occasionally resulted in death or permanent neurologic injury. Patients receiving midazolam should be closely monitored for respiratory depression and sedation depth, particularly when used concomitantly with opioid analgesics and other sedative-hypnotics, as this combination may lead to profound sedation, respiratory depression, coma, and death.

Common adverse reactions observed in clinical trials include decreased tidal volume, decreased respiratory rate, and apnea occurring in 15% or more of patients. Additionally, patients may experience paradoxical behaviors such as agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness, which have been reported in both adult and pediatric populations.

Long-term use of midazolam may lead to physical dependence; therefore, it is crucial to avoid abrupt discontinuation. A gradual tapering schedule should be individualized for each patient to mitigate withdrawal symptoms.

In the neonatal population, caution is advised due to the risk of hypotension and seizures, particularly with rapid injection. Pregnant individuals receiving midazolam in sodium chloride injection may expose their neonates to sedation and/or withdrawal syndrome. Furthermore, in developing animals, exposure to midazolam for durations exceeding three hours has been associated with neurotoxicity, necessitating careful consideration of the benefits versus risks when planning elective procedures for children under three years of age.

Overdosage of benzodiazepines, including midazolam, is characterized by central nervous system depression, which can range from drowsiness to coma. Symptoms in mild to moderate cases may include confusion, dysarthria, lethargy, diminished reflexes, ataxia, and hypotonia. Rarely, paradoxical reactions such as agitation, irritability, impulsivity, and violent behavior may occur. In severe cases of overdosage, respiratory depression and coma may develop, particularly when benzodiazepines are combined with other central nervous system depressants, including alcohol and opioids, which can be fatal.

Patients should be advised against operating hazardous machinery or motor vehicles until the effects of the drug have fully subsided, due to the potential for impaired cognitive function. Additionally, there have been limited reports of intra-arterial injection of midazolam, with adverse events including local reactions and isolated instances of seizure activity, although no clear causal relationship has been established.

Drug Interactions

Cytochrome P450-3A4 inhibitors are known to interact with midazolam, leading to prolonged sedation. This interaction occurs due to the decreased plasma clearance of midazolam when co-administered with these inhibitors.

It is advisable to monitor patients closely for signs of excessive sedation when midazolam is used in conjunction with cytochrome P450-3A4 inhibitors. Dosage adjustments of midazolam may be necessary to mitigate the risk of prolonged sedation in these cases.

Packaging & NDC

The table below lists all NDC Code configurations of Midazolam in 0.8% Sodium Chloride, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

The safety and efficacy of midazolam for sedation, anxiolysis, and amnesia following continuous infusion have been established in pediatric and neonatal patients. Pediatric patients generally receive midazolam in increments based on a mg/kg dosing regimen, which differs from adult dosing practices. As a group, pediatric patients typically require higher dosages of midazolam (mg/kg) compared to adults, with younger patients (less than six years) often necessitating even higher dosages and closer monitoring.

In obese pediatric patients, dosing should be calculated based on ideal body weight. Caution is advised when midazolam is administered in conjunction with opioids or other sedatives, as this combination increases the risk of respiratory depression, airway obstruction, or hypoventilation. Healthcare practitioners should adhere to accepted professional guidelines for pediatric sedation relevant to their specific clinical context.

Midazolam should not be administered by rapid injection in the neonatal population due to the risk of severe hypotension and seizures, particularly when used alongside fentanyl. Additionally, there is a recognized window of vulnerability to neuronal and oligodendrocyte cell loss associated with anesthetic and sedation drugs, which is believed to extend from the third trimester of gestation through the first several months of life, potentially lasting up to approximately three years of age in humans.

Geriatric Use

Elderly patients may exhibit altered drug distribution and diminished hepatic and/or renal function, necessitating a reduction in the dosage of midazolam. Specifically, doses of Midazolam in Sodium Chloride Injection should be decreased for elderly and debilitated patients.

Particularly, subjects over 70 years of age may demonstrate heightened sensitivity to the effects of midazolam. Consequently, these patients may require a longer recovery period following midazolam administration for the induction of anesthesia.

The administration of intravenous midazolam in elderly and/or high-risk surgical patients has been associated with rare reports of death, particularly under circumstances compatible with cardiorespiratory depression. In many of these instances, patients were also receiving other central nervous system depressants, such as opioids, which can further depress respiration.

Given that midazolam is substantially excreted by the kidneys, the risk of adverse reactions may be increased in patients with impaired renal function. As elderly patients are more likely to experience decreased renal function, careful consideration should be given to dose selection, and it may be beneficial to monitor renal function in this population.

Pregnancy

Neonates born to mothers using benzodiazepines, including midazolam, late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal. While available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with major birth defects, the background risk of major birth defects and miscarriage for the indicated population remains unknown. All pregnancies carry a background risk of birth defect, loss, or other adverse outcomes, with the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies in the U.S. general population being 2 to 4% and 15 to 20%, respectively.

Benzodiazepines, including midazolam, cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Therefore, it is recommended that healthcare professionals monitor neonates exposed to midazolam during pregnancy and labor for signs of sedation, respiratory depression, hypotonia, and feeding problems. Additionally, neonates exposed to midazolam during pregnancy should be monitored for signs of withdrawal, and appropriate management should be provided.

Animal studies have shown that midazolam did not cause adverse effects to the fetus in pregnant rats and rabbits at doses of up to 1.85 times the human induction dose of 0.35 mg/kg, based on body surface area comparisons. Specifically, pregnant rats were treated with intravenous doses of midazolam during the period of organogenesis (Gestation Day 7 through 15) and did not exhibit adverse fetal effects. Similarly, pregnant rabbits treated with midazolam during the period of organogenesis (Gestation Day 7 to 18) also showed no adverse fetal effects at comparable doses.

Although early studies indicated an increased risk of congenital malformations with diazepam and chlordiazepoxide, no consistent pattern has been noted in the literature regarding benzodiazepines and major birth defects. It is important to consider these findings when prescribing midazolam to pregnant patients, weighing the potential risks and benefits.

Lactation

There are reports of sedation, poor feeding, and poor weight gain in infants exposed to benzodiazepines through breast milk. Midazolam is present in human milk at low levels, as indicated by data from published studies. However, there are no data on the effects of midazolam on milk production.

The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for Midazolam in Sodium Chloride Injection and any potential adverse effects on the breastfed infant. Infants exposed to midazolam through breast milk should be monitored for signs of sedation, poor feeding, and poor weight gain.

To minimize drug exposure to a breastfed infant, a lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for a range of at least 4 to 8 hours after midazolam administration. Published clinical lactation studies support this recommendation, noting the presence of midazolam in human milk at low levels during this timeframe. It is important to note that these studies have limitations, including poor methodology and lack of validated analytical methods. No safety signals have been identified in breastfed infants exposed to midazolam.

Renal Impairment

There is no specific information available regarding dosage adjustments, special monitoring, or safety considerations for patients with renal impairment. Healthcare professionals should exercise caution when prescribing to patients with reduced kidney function, as the absence of detailed guidance necessitates careful clinical judgment. Regular monitoring of renal function may be advisable in this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically studied in relation to the use of this medication. Consequently, there are no established dosage adjustments, special monitoring requirements, or precautions for individuals with compromised liver function. It is recommended that healthcare providers exercise caution when prescribing this medication to patients with hepatic impairment, given the lack of data on its safety and efficacy in this population. Regular monitoring of liver function may be prudent in these cases, although specific parameters are not defined in the available information.

Overdosage

Overdosage of benzodiazepines is primarily characterized by varying degrees of central nervous system (CNS) depression. Symptoms may range from mild drowsiness to profound coma, with common manifestations including confusion, lethargy, and respiratory depression.

In instances of severe overdosage, patients are at an increased risk of developing significant respiratory depression and coma, which can be life-threatening, particularly when benzodiazepines are taken in conjunction with other CNS depressants.

Management of benzodiazepine overdosage may involve the administration of flumazenil, an antagonist that can reverse the effects of benzodiazepines. However, caution is advised, as flumazenil may precipitate withdrawal symptoms and seizures, particularly in patients with a history of long-term benzodiazepine use or in cases of mixed overdoses.

Healthcare professionals are encouraged to consider contacting the Poison Help Line at 1-800-222-1222 for further management recommendations in cases of suspected benzodiazepine overdosage. This resource can provide additional guidance tailored to the specific circumstances of the overdose.

Nonclinical Toxicology

Midazolam maleate was administered in the diet to mice and rats for a duration of two years at dosages of 1, 9, or 80 mg/kg/day. In female mice receiving the highest dose, there was a marked increase in the incidence of hepatic tumors. Additionally, high-dose male rats exhibited a small but statistically significant increase in benign thyroid follicular cell tumors. Notably, dosages of 9 mg/kg/day of midazolam maleate, which is four times the human induction dose of 0.35 mg/kg based on body surface area comparison, did not result in an increased incidence of tumors. The pathogenesis underlying the induction of these tumors remains unknown. It is important to note that these tumors were observed following chronic administration, while human use typically involves single or multiple doses.

Midazolam did not demonstrate mutagenic activity in various assays, including tests conducted with Salmonella typhimurium (five bacterial strains), Chinese hamster lung cells (V79), human lymphocytes, and the micronucleus test in mice.

In studies assessing fertility, male rats were treated orally with midazolam at doses of 1, 4, or 16 mg/kg, beginning 62 days prior to mating with female rats that received the same doses for 14 days prior to mating until Gestation Day 13 or Lactation Day 21. The high dose resulted in an equivalent exposure (AUC) comparable to 4 mg/kg intravenous midazolam, which is 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparison. No adverse effects on fertility were observed in either male or female rats.

Published studies in animals indicate that the administration of anesthetic agents during periods of rapid brain growth or synaptogenesis can lead to widespread neuronal and oligodendrocyte cell loss in the developing brain, as well as alterations in synaptic morphology and neurogenesis. Comparisons across species suggest that the window of vulnerability to these changes correlates with exposures during the third trimester through the first several months of life, potentially extending to approximately three years of age in humans.

In primate studies, exposure to a light surgical plane of anesthesia for three hours did not result in increased neuronal cell loss; however, treatment regimens lasting five hours or longer were associated with increased neuronal cell loss. Data from both rodents and primates indicate that the losses of neuronal and oligodendrocyte cells may be linked to subtle but prolonged cognitive deficits in learning and memory. The clinical significance of these nonclinical findings remains uncertain, and healthcare providers are advised to weigh the benefits of appropriate anesthesia in neonates and young children requiring procedures against the potential risks suggested by the nonclinical data.

Postmarketing Experience

Patients receiving midazolam in a critical care setting for an extended duration may experience withdrawal symptoms following abrupt discontinuation. This information is based on postmarketing experience and has been reported voluntarily or through surveillance programs.

Patient Counseling

Patients should be advised to notify their healthcare provider about any alcohol or medication use, particularly blood pressure medications and antibiotics. It is important to understand that alcohol and other central nervous system (CNS) depressants, such as opioid analgesics and benzodiazepines, can have an additive effect when administered with Midazolam in Sodium Chloride Injection.

Healthcare providers should discuss with parents and caregivers the benefits, risks, and timing and duration of surgeries or procedures that require anesthetic and sedation drugs, especially for children younger than 3 years.

Pregnant females should be informed that exposure to midazolam late in pregnancy may lead to sedation in newborns, which can manifest as respiratory depression, lethargy, and hypotonia, as well as withdrawal symptoms such as hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. Patients should be instructed to inform their healthcare provider if they are pregnant during treatment with Midazolam in Sodium Chloride Injection.

Patients who are breastfeeding or intend to breastfeed should notify their healthcare provider. Breastfeeding patients receiving midazolam should monitor their infants for signs of excessive sedation, poor feeding, and poor weight gain, and seek medical attention if these signs occur. 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.

Patients should be made aware that they may experience residual sedation and amnesia. The decision regarding when patients who have received injectable midazolam, particularly on an outpatient basis, may resume activities requiring complete mental alertness, operate hazardous machinery, or drive a motor vehicle must be individualized.

Finally, patients receiving midazolam in a critical care setting for an extended period should be informed that they may experience withdrawal symptoms following abrupt discontinuation of the medication.

Storage and Handling

The product is supplied in its original overwrap, which serves as a moisture and light barrier, ensuring optimal protection until it is ready for dispensing. It is essential to store the product at a temperature range of 20°C to 25°C (68°F to 77°F), with permissible excursions between 15°C to 30°C (59°F to 86°F).

To maintain product integrity, it must be protected from freezing and light exposure. Any unused portion should be discarded to ensure safety and efficacy.

Additional Clinical Information

Midazolam in Sodium Chloride Injection is indicated for intravenous administration only. Clinicians should counsel patients regarding the timing of resuming activities that require full mental alertness, such as operating hazardous machinery or driving. This decision should be individualized, taking into account the patient's response to the drug. It is generally advised that patients refrain from such activities until the effects of midazolam, including drowsiness, have resolved, or for at least one full day following anesthesia and surgery, whichever period is longer.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Midazolam in 0.8% Sodium Chloride as submitted by B. Braun Medical Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)