Midazolam

Uses and Indications

NAYZILAM is indicated for the acute treatment of intermittent, stereotypic episodes of frequent seizure activity (i.e., seizure clusters, acute repetitive seizures) that are distinct from a patient's usual seizure pattern in patients with epilepsy aged 12 years and older.

Midazolam in Sodium Chloride Injection is 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. This indication applies to both 0.8% and 0.9% Sodium Chloride formulations.

Midazolam Injection is also indicated for the treatment of status epilepticus in adults.

Dosage and Administration

NAYZILAM is administered exclusively via the nasal route. The initial dose consists of one spray (5 mg) into one nostril. If the patient does not respond to the initial dose, a second dose of one additional spray (5 mg) may be administered into the opposite nostril after a minimum of 10 minutes. The maximum dosage for treating a seizure cluster is limited to two doses. It is advised that NAYZILAM should not be used to treat more than one episode every three days and should not exceed five episodes within a month.

For Midazolam formulations, administration is restricted to intravenous injection only, with a strong recommendation to avoid intra-arterial injection or extravasation. Dosing should be individualized and titrated to achieve the desired clinical response, considering factors such as patient age, clinical status, and the concurrent use of other CNS depressants. Detailed dosage and administration information can be found in the Full Prescribing Information.

In cases where Midazolam is administered via intramuscular injection, the recommended dose is a single 10 mg dose, delivered using a prefilled autoinjector into the mid-outer thigh (vastus lateralis muscle). Continuous monitoring of respiratory and cardiac function is essential during and after administration.

Contraindications

Patients are contraindicated from using this medication if they have a known hypersensitivity to midazolam. Additionally, the use of this medication is not recommended in patients with acute narrow-angle glaucoma.

Warnings and Precautions

CNS Depression and Concomitant Use Risks Nayzilam and Midazolam may cause increased CNS-depressant effects when used with alcohol, other CNS depressants, or moderate to strong CYP3A4 inhibitors, potentially leading to prolonged sedation due to decreased plasma clearance of midazolam. The concomitant use of benzodiazepines and opioids can result in profound sedation, respiratory depression, coma, and death. Continuous monitoring for respiratory depression and sedation depth is essential.

Suicidal Behavior and Ideation Antiepileptic drugs, including midazolam, are associated with an increased risk of suicidal ideation and behavior. Prior to prescribing, it is crucial to assess each patient's risk for abuse, misuse, and addiction.

Impaired Cognitive Function Midazolam is linked to partial or complete impairment of recall for several hours post-administration. Patients should refrain from operating hazardous machinery or vehicles until the effects have fully subsided.

Glaucoma Considerations Nayzilam can elevate intraocular pressure in patients with glaucoma. Those with open-angle glaucoma may require ophthalmologic evaluation following treatment. Midazolam is not recommended for patients with narrow-angle glaucoma.

Neonatal Risks Use of Nayzilam or Midazolam during pregnancy may lead to neonatal sedation and/or withdrawal syndrome. Special caution is advised when administering to pregnant patients.

Dependence and Withdrawal Prolonged use of midazolam can lead to physical dependence. Abrupt discontinuation or rapid dosage reduction may precipitate acute withdrawal reactions, which can be life-threatening. A gradual tapering schedule should be employed for patients using midazolam more frequently than recommended.

Serious Cardiorespiratory Adverse Reactions Serious cardiorespiratory adverse reactions, including death or permanent neurologic injury, have been reported following midazolam administration. Practitioners must possess the necessary skills to manage these reactions, including airway management.

Monitoring Requirements Continuous monitoring of vital signs during sedation and throughout the recovery period is mandatory. Resuscitative drugs and age-appropriate equipment for ventilation must be readily available during administration.

Special Populations Higher-risk adult and pediatric surgical patients, as well as elderly and debilitated patients, may require lower dosages of midazolam. In developing animals, exposure to midazolam for more than three hours has been associated with neurotoxicity, necessitating careful consideration of risks when performing elective procedures in children under three years old.

Injection Administration Precautions Only trained personnel should administer Midazolam Injection, and they must not be involved in the conduct of the diagnostic or therapeutic procedure. Rapid injection should be avoided in the neonatal population, and practitioners should be prepared to manage airway obstruction, hypoventilation, and apnea.

Side Effects

Patients receiving Nayzilam or Midazolam may experience a range of adverse reactions, which can vary in severity and frequency.

Serious Adverse Reactions

• Respiratory Depression: Concomitant use of benzodiazepines with opioids or other CNS depressants may lead to profound sedation, respiratory depression, coma, and death. Continuous monitoring for respiratory depression is essential.

• Cardiorespiratory Adverse Reactions: Serious reactions have occurred, sometimes resulting in death or permanent neurologic injury.

• Suicidal Behavior and Ideation: Antiepileptic drugs, including benzodiazepines, may increase the risk of suicidal ideation and behavior.

• Acute Withdrawal Reactions: Abrupt discontinuation or rapid dosage reduction may precipitate life-threatening withdrawal symptoms, including seizures, delirium, and psychosis.

• Neonatal Sedation and Withdrawal Syndrome: Use during pregnancy can result in neonatal sedation and/or withdrawal.

Common Adverse Reactions (≥5% in any treatment group)

• Nayzilam:

  • Somnolence: 10%

  • Headache: 7%

  • Nasal discomfort: 5%

  • Rhinorrhea: 3%

  • Throat irritation: 2%

• Midazolam:

  • Decreased tidal volume

  • Decreased respiratory rate

  • Apnea (≥15%)

Other Notable Adverse Reactions

• CNS Effects: Impaired cognitive function, including partial or complete impairment of recall, has been reported. Patients should avoid operating hazardous machinery or vehicles until the effects have subsided.

• Paradoxical Reactions: Agitation, involuntary movements, hyperactivity, and combativeness have been observed in both adult and pediatric patients.

• Dependence and Withdrawal: Long-term use may lead to physical dependence. Symptoms of withdrawal can include anxiety, depression, insomnia, and cognitive impairment.

• Tolerance: Patients may develop tolerance to Nayzilam with frequent use.

• Hypotension and Seizures: Severe hypotension and seizures have been reported, particularly following rapid intravenous administration.

Additional Reactions

• Gastrointestinal Symptoms: Nausea, vomiting, diarrhea, and decreased appetite may occur.

• Neurological Symptoms: Dizziness, fatigue, headache, and tremors have been reported.

• Visual Disturbances: Increased lacrimation and blurred vision may occur, particularly in patients with glaucoma.

• Local Reactions: Limited reports of local reactions following intra-arterial injection of midazolam have been noted.

Patients should be closely monitored for these adverse reactions, and healthcare providers should assess each patient's risk for abuse, misuse, and addiction before prescribing these medications.

Drug Interactions

Co-administration of Nayzilam with moderate or strong CYP3A4 inhibitors is contraindicated, as this may lead to significant increases in plasma levels and prolonged effects of the drug. Caution is advised when using Nayzilam alongside mild CYP3A4 inhibitors due to the potential for altered pharmacokinetics.

Midazolam, whether in its 0.8% sodium chloride formulation or other injectable forms, is also affected by CYP3A4 inhibitors, which can result in prolonged sedation due to decreased plasma clearance. The use of midazolam in conjunction with other central nervous system (CNS) depressants, including opioids and alcohol, significantly heightens the risk of respiratory depression and may lead to increased sedation.

The combination of benzodiazepines, such as midazolam, with opioids is particularly concerning, as it raises the likelihood of respiratory depression, hypoventilation, airway obstruction, desaturation, or apnea. Therefore, careful monitoring is recommended when these agents are used together to mitigate the risks of profound and/or prolonged drug effects.

Pediatric Use

Safety and effectiveness of Nayzilam have been evaluated in pediatric patients aged 12 to 17 years, supported by evidence from an adequate and well-controlled study in adults and adolescents with seizure clusters. However, safety and effectiveness in pediatric patients below the age of 12 years have not been established.

For midazolam, the safety and efficacy 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 mg/kg, requiring higher dosages than adults. Younger pediatric patients (less than six years) may require even higher dosages and 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. Health care practitioners should adhere to accepted professional guidelines for pediatric sedation. Rapid injection of midazolam should not be administered in the neonatal population due to the risk of severe hypotension and seizures, particularly with concomitant use of fentanyl.

Benzodiazepines are not recognized as a treatment for status epilepticus in neonates and should not be used in this population. Safety and effectiveness in pediatric patients for other formulations have not been established.

Geriatric Use

Elderly patients, particularly those aged 70 years and older, may exhibit altered drug distribution and diminished hepatic and renal function, which can affect the pharmacokinetics of midazolam. Safety and efficacy studies have not included sufficient numbers of subjects aged 65 and over to determine if they respond differently from younger individuals. Due to longer elimination half-lives of midazolam and its metabolites in geriatric patients, there is a potential for prolonged drug exposure.

Reduced doses of midazolam are recommended for elderly and debilitated patients, as they may be particularly sensitive to the drug's effects. Close monitoring is advised, especially in those receiving intravenous midazolam, as there have been rare reports of death associated with cardiorespiratory depression, often in conjunction with other central nervous system depressants, such as opioids.

Elderly patients may also take longer to recover completely after midazolam administration for the induction of anesthesia. Given that midazolam is substantially excreted by the kidneys, careful consideration of renal function is essential in this population, and dose adjustments may be necessary to mitigate the risk of adverse reactions.

Pregnancy

Neonates born to mothers using benzodiazepines, including NAYZILAM (midazolam), late in pregnancy have been reported to experience symptoms of sedation and/or neonatal withdrawal. These symptoms may include respiratory depression, hypotonia, lethargy, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties. Healthcare providers are advised to monitor neonates exposed to midazolam during pregnancy or labor for these signs and manage them accordingly.

Available data from published observational studies do not report a clear association between benzodiazepines and major birth defects. Although early studies suggested an increased risk of congenital malformations with certain benzodiazepines, such as diazepam and chlordiazepoxide, no consistent pattern has been noted. Most recent case-control and cohort studies, which adjusted for confounding factors such as alcohol and tobacco use, have not confirmed these earlier findings.

In animal studies, midazolam did not cause adverse effects on fetal development in pregnant rats and rabbits at doses up to 1.85 times the human induction dose. However, there is evidence suggesting that benzodiazepines may lead to neuronal cell death and long-term neurobehavioral effects in animal models following prenatal or early postnatal exposure. The clinical significance of these findings remains unclear.

The background risk of major birth defects and miscarriage in the general population is estimated to be 2 to 4% and 15 to 20%, respectively. All pregnancies carry a background risk of birth defects, loss, or other adverse outcomes. Therefore, healthcare providers are encouraged to recommend that pregnant patients taking NAYZILAM enroll in the North American Antiepileptic Drug Pregnancy Registry to monitor pregnancy outcomes in women exposed to antiepileptic drugs.

In summary, while the use of midazolam during pregnancy may not be associated with a clear risk of major birth defects, careful monitoring of neonates for withdrawal symptoms and other adverse effects is essential.

Lactation

Midazolam is excreted in human milk, with published studies indicating its presence at low levels 4 to 8 hours post-administration. Lactating mothers should be aware that there are reports of sedation, poor feeding, and poor weight gain in breastfed infants exposed to benzodiazepines, including midazolam, through breast milk.

The developmental and health benefits of breastfeeding must be weighed against the mother's clinical need for midazolam and any potential adverse effects on the breastfed infant. It is recommended that infants exposed to midazolam through breast milk be closely monitored for signs of excessive sedation, poor feeding, and poor weight gain.

To minimize drug exposure to breastfed infants, lactating women may consider interrupting breastfeeding and pumping and discarding breast milk for a duration of at least 4 to 8 hours following midazolam administration. While no safety signals have been identified in breastfed infants exposed to midazolam, the limitations of existing lactation studies, including poor methodology and lack of validated analytical methods, should be acknowledged.

Patients should inform their healthcare provider if they are breastfeeding or plan to breastfeed while receiving midazolam.

Renal Impairment

Patients with renal impairment may experience altered pharmacokinetics when administered midazolam, particularly in the context of NAYZILAM. A population pharmacokinetic analysis indicates that the pharmacokinetics of midazolam and its active metabolite, 1-OH midazolam, are expected to be similar in individuals with mild renal impairment compared to those with normal kidney function. However, patients with moderate to severe renal impairment may exhibit slower elimination of midazolam and its metabolites, potentially leading to prolonged drug exposure.

It is important to note that safety and efficacy studies for NAYZILAM did not include patients with severe renal impairment, and there was insufficient representation of those with moderate renal impairment for a comprehensive pharmacokinetic analysis. Consequently, caution is advised when considering the use of midazolam in patients with moderate to severe renal impairment, and careful monitoring may be warranted to mitigate the risk of prolonged effects due to altered drug clearance.

No specific dosage adjustments or additional monitoring guidelines have been provided for midazolam formulations in the context of renal impairment, indicating a need for clinical discretion when prescribing to this patient population.

Hepatic Impairment

Patients with hepatic impairment have not been specifically addressed in the available labeling for Nayzilam, Midazolam in 0.8% Sodium Chloride, or Midazolam in Sodium Chloride. There are no dosage adjustments, special monitoring requirements, or precautions outlined for this patient population in the provided information. Therefore, healthcare professionals should exercise caution and consider individual patient factors when administering these medications to patients with liver problems, as the lack of specific guidance may necessitate closer monitoring or alternative therapeutic strategies.

Overdosage

Overdosage of benzodiazepines, including formulations such as Nayzilam and Midazolam, is characterized by central nervous system depression that can range from drowsiness to coma. Symptoms may include confusion, lethargy, dysarthria, diminished reflexes, ataxia, and hypotonia in mild to moderate cases. In severe instances, patients may experience respiratory depression and coma, which can be fatal, particularly when benzodiazepines are combined with other central nervous system depressants such as alcohol and opioids.

Management of benzodiazepine overdosage should involve general supportive measures, including the administration of intravenous fluids and maintenance of the airway. Flumazenil, a specific benzodiazepine receptor antagonist, may be utilized to reverse the sedative effects of benzodiazepines; however, it carries the risk of withdrawal and adverse reactions, including seizures. This risk is particularly heightened in patients with long-term benzodiazepine use, those with a history of epilepsy, or in cases of mixed overdoses involving drugs that increase seizure risk, such as tricyclic and tetracyclic antidepressants. Flumazenil is contraindicated in patients who have received benzodiazepines for the control of potentially life-threatening conditions, such as status epilepticus.

Healthcare professionals are advised to consider contacting the Poison Help Line at 1-800-222-1222 or a medical toxicologist for additional recommendations regarding the management of benzodiazepine overdosage. Monitoring for markedly abnormal vital signs, including blood pressure, heart rate, and respiratory rate, is essential, as these may indicate the involvement of additional substances in the overdosage scenario.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Midazolam maleate was administered in the diet to mice and rats for 2 years at doses of 0, 1, 9, or 80 mg/kg/day. In female mice in the highest dose group, there was a marked increase in the incidence of hepatic tumors. In high-dose male rats, a small but statistically significant increase in benign thyroid follicular cell tumors was observed. The highest dose not associated with increased tumor incidences in mice and rats (9 mg/kg/day) is approximately 4 and 9 times, respectively, the recommended human dose (RHD) of 10 mg based on body surface area (mg/m²). The pathogenesis of tumor induction remains unknown, and these tumors were identified following chronic administration, whereas human use typically involves single or several doses.

Midazolam demonstrated no mutagenic activity in various assays, including in vitro tests (Ames test, mammalian cell clastogenicity) and in vivo assessments (mouse bone marrow micronucleus test).

In studies assessing fertility, male and female rats were administered midazolam (0, 1, 4, or 16 mg/kg) orally prior to and during mating, with treatment continuing in females throughout gestation and lactation. No adverse effects on male or female fertility were noted, and plasma exposures (AUC) at the highest dose tested were approximately 6 times that observed in humans at the RHD.

Animal Toxicology

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 up to approximately 3 years of age in humans. In primate studies, exposure to a 3-hour anesthetic regimen that produced a light surgical plane did not increase neuronal cell loss; however, 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 is not fully understood, and healthcare providers should weigh the benefits of appropriate anesthesia in neonates and young children against the potential risks suggested by the nonclinical data.

Storage and Handling

Nayzilam is supplied as a nasal spray. It is important to not open the blister packaging until ready to use, and the unit should not be tested or primed before use. The nasal spray must not be used if the unit appears damaged.

Midazolam in 0.8% Sodium Chloride and Midazolam in Sodium Chloride are both supplied as injections in solution form. These products should be stored at a controlled room temperature 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). They must be protected from freezing and light. The unused portion should be discarded, and the solutions should be stored in their original overwrap until ready to dispense, as the overwrap serves as a moisture and light barrier.

For all formulations, individual containers may be used up to 48 hours after initial penetration.