Midazolam in Sodium Chloride

Description

Midazolam in 0.9% Sodium Chloride Injection is a benzodiazepine presented as 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 9 mg/mL of sodium chloride in water for injection. The formulation may include hydrochloric acid and/or sodium hydroxide for pH adjustment, resulting in a pH of approximately 2.5 - 3.5. 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 325.77.

Uses and Indications

Midazolam in 0.9% 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.

Limitations of Use: There are no teratogenic or nonteratogenic effects associated with this drug.

Dosage and Administration

For intravenous injection only. Intra-arterial injection or extravasation should be avoided.

Dosing must be individualized and titrated to achieve the desired clinical response. Factors to consider include the patient's age, clinical status, and any concomitant use of other central nervous system (CNS) depressants.

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

Contraindications

Midazolam in 0.9% Sodium Chloride Injection is contraindicated in patients with known hypersensitivity to midazolam and those with acute narrow-angle glaucoma. The use of this medication is not recommended in these populations due to the potential for serious adverse reactions.

Additionally, caution is warranted due to the risk of abuse and dependence associated with midazolam, a Schedule IV controlled substance. Long-term use may lead to physical dependence, and abrupt discontinuation can precipitate acute withdrawal reactions, which may be life-threatening. Therefore, it is essential to avoid abrupt cessation after extended therapy and to taper the dosage gradually.

Warnings and Precautions

Serious cardiorespiratory adverse reactions associated with midazolam have been reported, with some cases resulting in death or permanent neurologic injury. Healthcare professionals should remain vigilant for signs of agitation, involuntary movements (including tonic/clonic movements and muscle tremor), hyperactivity, and combativeness, which have been observed in both adult and pediatric patients.

Midazolam may lead to physical dependence when used over several days to weeks. It is imperative that healthcare providers do not abruptly discontinue the medication; instead, a gradual tapering schedule tailored to the individual patient should be implemented. Special caution is warranted for higher-risk populations, including adult and pediatric surgical patients, elderly patients, and those who are debilitated, as these groups may require lower dosages, regardless of any concomitant sedating medications.

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.

Pregnant patients receiving midazolam in 0.9% Sodium Chloride Injection may experience neonatal sedation and/or withdrawal. Additionally, in developing animals, exposure to midazolam for more than three hours has been associated with neurotoxicity. Therefore, the benefits and risks should be carefully weighed when considering elective procedures in children under three years of age.

Only personnel trained in the administration of procedural sedation, who are not involved in the diagnostic or therapeutic procedure, should administer midazolam injection. These individuals must be proficient in recognizing and managing airway obstruction, hypoventilation, and apnea, including maintaining a patent airway, providing supportive ventilation, and performing cardiovascular resuscitation. It is essential that resuscitative drugs and age- and size-appropriate equipment for bag/valve/mask assisted ventilation are readily available during the administration of midazolam injection.

Continuous monitoring of vital signs is required during sedation and throughout the recovery period. The concomitant use of benzodiazepines with opioid analgesics can lead to profound sedation, respiratory depression, coma, and death; therefore, patients must be closely monitored for respiratory depression and the depth of sedation.

Side Effects

Serious cardiorespiratory adverse reactions have been reported in patients receiving midazolam in 0.9% sodium chloride injection, with some cases resulting in death or permanent neurologic injury. The concomitant use of benzodiazepines with opioid analgesics may lead to profound sedation, respiratory depression, coma, and death; therefore, continuous monitoring of patients for respiratory depression and depth of sedation is essential.

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

Long-term use of midazolam may lead to physical dependence. Patients should not abruptly discontinue the medication; instead, a gradual tapering of the dosage is recommended to mitigate withdrawal symptoms. Acute withdrawal signs and symptoms can include abnormal involuntary movements, anxiety, blurred vision, cognitive disorders, depersonalization, depression, derealization, dizziness, fatigue, gastrointestinal adverse reactions (e.g., nausea, vomiting, diarrhea, weight loss, decreased appetite), headache, hyperacusis, hypertension, irritability, insomnia, memory impairment, muscle pain and stiffness, panic attacks, photophobia, restlessness, tachycardia, and tremor. More severe reactions may include catatonia, convulsions, delirium tremens, depression, hallucinations, homicidal thoughts, mania, psychosis, and suicidality.

Protracted withdrawal syndrome has been characterized by persistent anxiety, cognitive impairment, depression, insomnia, formication, motor symptoms (e.g., weakness, tremor, muscle twitches), paresthesia, and tinnitus that can last beyond 4 to 6 weeks following initial benzodiazepine withdrawal.

In pediatric populations, exposure to midazolam for more than 3 hours in developing animals has been associated with neurotoxicity. Therefore, the benefits of midazolam should be weighed against potential risks when considering elective procedures in children under 3 years old. Additionally, rapid injection in preterm infants and neonates should be avoided due to the risk of hypotension and seizures.

Neonatal sedation and withdrawal syndrome may occur in infants exposed to midazolam during pregnancy. Patients receiving midazolam should be cautioned against operating hazardous machinery or motor vehicles until the effects of the drug have subsided.

Reports of intra-arterial injection of midazolam have included local reactions and isolated instances of seizure activity. Severe hypotension and seizures have also been noted following rapid intravenous administration, particularly when used in conjunction with fentanyl. Furthermore, the 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.

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 P450-3A4 inhibitors. Dosage adjustments may be necessary based on the clinical response and sedation levels observed in the patient.

Packaging & NDC

The table below lists all NDC Code configurations of Midazolam in Sodium Chloride (midazolam), 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. Unlike adult patients, pediatric patients generally receive increments of midazolam on a mg/kg basis. As a group, pediatric patients typically require higher dosages of midazolam (mg/kg) than adults.

Younger pediatric patients (less than six years) may require even higher dosages (mg/kg) compared to older pediatric patients and necessitate closer monitoring. In obese pediatric patients, the dose should be calculated based on ideal body weight.

When midazolam is administered in conjunction with opioids or other sedatives, there is an increased potential for respiratory depression, airway obstruction, or hypoventilation. Healthcare practitioners using this medication in pediatric patients should adhere to accepted professional guidelines for pediatric sedation relevant to their specific circumstances.

It is important to note that midazolam should not be administered by rapid injection in the neonatal population, as severe hypotension and seizures have been reported following rapid intravenous administration, particularly with concomitant use of fentanyl.

Geriatric Use

Elderly patients may experience altered drug distribution and diminished hepatic and/or renal function, necessitating reduced doses of midazolam. Specifically, doses of Midazolam in 0.9% Sodium Chloride Injection should be decreased for elderly and debilitated patients.

Patients over 70 years of age may exhibit heightened sensitivity to midazolam, which can result in prolonged recovery times following administration for the induction of anesthesia. Furthermore, the administration of intravenous midazolam in elderly and/or high-risk surgical patients has been associated with rare reports of death, particularly under circumstances indicative of cardiorespiratory depression. It is important to note that in many of these cases, patients were also receiving other central nervous system depressants, such as opioids, which can further compromise respiratory function.

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 have 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. Available data from published observational studies of pregnant women exposed to benzodiazepines do not report a clear association with major birth defects. Furthermore, data from randomized controlled trials, cohort studies, and case reports over several decades involving 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 reported exposures to midazolam occurred during cesarean delivery.

Rare case reports of prolonged midazolam use in pregnant women for sedation in critical care settings are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Animal studies have shown that midazolam did not cause adverse effects to the fetus in pregnant rats and rabbits at doses up to 1.85 times the human induction dose of 0.35 mg/kg based on body surface area comparisons. However, published studies in pregnant primates indicate that the administration of anesthetic and sedation drugs that block NMDA receptors and/or potentiate GABA activity during the period of peak brain development may increase 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.

The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies carry a background risk of birth defects, 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. Benzodiazepines cross the placenta and may produce respiratory depression, hypotonia, and sedation in neonates. Therefore, it is recommended to monitor neonates exposed to midazolam during pregnancy or 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 managed accordingly.

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, with published clinical lactation studies indicating this presence 4 to 8 hours after administration. However, these studies have limitations, including poor methodology and lack of validated analytical methods.

Lactating mothers should consider the developmental and health benefits of breastfeeding alongside their clinical need for Midazolam in 0.9% Sodium Chloride Injection and any potential adverse effects on the breastfed infant from the medication or the underlying maternal condition. 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. 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 outlined 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 and confusion to severe lethargy and coma. In instances of significant overdosage, patients are at risk of developing respiratory depression, which can be life-threatening, particularly when benzodiazepines are taken in conjunction with other CNS depressants.

In cases of severe overdosage, it is crucial to recognize that respiratory depression and coma can occur, potentially leading to fatal outcomes. Therefore, immediate medical intervention is essential.

Flumazenil is an antidote that can reverse the effects of benzodiazepines; however, its use must be approached with caution. Administration of flumazenil may precipitate withdrawal symptoms and seizures, particularly in patients who have been using benzodiazepines for an extended period or in cases of mixed overdosage involving other substances.

Healthcare professionals are advised 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 on the appropriate steps to take in managing the patient’s condition effectively.

Nonclinical Toxicology

Midazolam maleate was administered in the diet to mice and rats for a duration of 2 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, or in the micronucleus test in mice.

In studies assessing the impairment of fertility, male rats were treated orally with 1, 4, or 16 mg/kg of midazolam beginning 62 days prior to mating with female rats, who were treated with 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 indicate that the use 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. The window of vulnerability to these changes is believed to correlate with exposures during the third trimester through the first several months of life, potentially extending to approximately 3 years of age in humans. In primate studies, exposure to a 3-hour anesthetic regimen that produced a light surgical plane of anesthesia did not result in increased neuronal cell loss; however, treatment regimens lasting 5 hours or longer were associated with increased neuronal cell loss. Data from both rodents and primates suggest that these neuronal and oligodendrocyte cell losses 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 should weigh the benefits of appropriate anesthesia in neonates and young children requiring procedures against the potential risks indicated by the nonclinical data.

Postmarketing Experience

Postmarketing experience has identified several adverse reactions associated with midazolam. Reports indicate that newborns exposed to midazolam late in pregnancy may experience respiratory depression, lethargy, hypotonia, hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties.

Additionally, patients receiving midazolam in a critical care setting for an extended duration may exhibit symptoms of withdrawal following abrupt discontinuation of the medication.

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 highlight 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 0.9% 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. Studies indicate that repeated or prolonged use of general anesthetic or sedation drugs in children younger than 3 years may have negative effects on their developing brains.

Pregnant females should be informed that exposure to midazolam late in pregnancy can lead to sedation in newborns, which may 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 0.9% 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 symptoms of withdrawal following abrupt discontinuation.

Storage and Handling

The product is supplied in individual containers that should be stored at a temperature range of 20°C to 25°C (68°F to 77°F), in accordance with USP Controlled Room Temperature guidelines. It is essential to protect the product from freezing to maintain its integrity.

Once the container has been penetrated, it may be used for up to 48 hours. Any unused portion should be discarded to ensure safety and efficacy.

Additional Clinical Information

Patients who have received injectable midazolam should be counseled on the timing of resuming activities that require complete mental alertness, such as operating hazardous machinery or driving a motor vehicle. This decision must be individualized, taking into account the patient's response to the drug. It is generally recommended that patients refrain from such activities until the effects of midazolam, including drowsiness, have fully subsided, or for at least one full day following anesthesia and surgery, whichever period is longer. Special attention should be given to pediatric patients to ensure their safe ambulation.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Midazolam in Sodium Chloride as submitted by WG Critical Care, LLC.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)