N/a

Description

Midazolam is a white to light yellow crystalline compound that is insoluble in water. It is chemically 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. The hydrochloride salt of midazolam, which is formed in situ, is soluble in aqueous solutions.

Midazolam Injection is provided as a sterile, nonpyrogenic solution intended for intramuscular injection, available in a single-dose prefilled autoinjector. Each 0.7 mL of the injection contains 10 mg of midazolam, which is equivalent to 11.12 mg of midazolam hydrochloride. The formulation includes 0.7% sodium chloride and 1.1% hydrochloric acid, with the pH adjusted to approximately 3 using hydrochloric acid.

Uses and Indications

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

Limitations of Use: The safety and efficacy of Midazolam Injection have not been established in pediatric populations or in patients with conditions other than status epilepticus. There are no reported teratogenic or nonteratogenic effects associated with this medication.

Dosage and Administration

The recommended dose is a single 10 mg dose, administered via intramuscular injection using the prefilled autoinjector. The injection should be performed in the mid-outer thigh, specifically targeting the vastus lateralis muscle.

Healthcare professionals are advised to ensure continuous monitoring of respiratory and cardiac function during and after administration to promptly identify any potential adverse reactions.

Contraindications

Use of this product is contraindicated in patients with a known hypersensitivity to midazolam. Administration in such cases may lead to severe allergic reactions or other adverse effects.

Warnings and Precautions

Serious cardiorespiratory adverse reactions, including fatalities and permanent neurologic injury, have been reported following the administration of midazolam. Healthcare professionals must be vigilant in monitoring patients for these risks, particularly in settings where midazolam is administered.

The concomitant use of central nervous system (CNS) depressants with midazolam may heighten the risk of hypoventilation, airway obstruction, desaturation, or apnea, potentially leading to profound and/or prolonged drug effects. Practitioners administering Midazolam Injection should possess the necessary skills to manage serious cardiorespiratory adverse reactions, including airway management capabilities.

Additionally, the co-administration of benzodiazepines and opioids can result in profound sedation, respiratory depression, coma, and even death. Continuous monitoring of patients for signs of respiratory depression and sedation is essential during treatment.

The use of benzodiazepines, including midazolam, carries inherent risks of abuse, misuse, and addiction, which may culminate in overdose or death. Prior to prescribing Midazolam Injection and throughout the course of treatment, it is imperative to assess each patient's risk for these issues.

Although Midazolam Injection is indicated for intermittent use, frequent administration beyond the recommended guidelines may lead to acute withdrawal reactions upon abrupt discontinuation or rapid dosage reduction, which can be life-threatening. For patients requiring more frequent use, a gradual tapering strategy should be employed to mitigate the risk of withdrawal.

Impaired cognitive function may occur with midazolam use, resulting in 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.

Patients with open-angle glaucoma should have their ophthalmologic status evaluated following treatment with Midazolam Injection, as the drug is not recommended for those with narrow-angle glaucoma.

Furthermore, the use of Midazolam Injection during pregnancy may lead to neonatal sedation and/or withdrawal syndrome, necessitating careful consideration of the risks involved.

No specific laboratory tests are recommended for the safe use of Midazolam Injection.

Side Effects

Serious adverse reactions associated with Midazolam Injection include significant cardiorespiratory events, which have occasionally resulted in death or permanent neurologic injury. Patients receiving this medication are at risk for profound sedation, respiratory depression, coma, and death, particularly when used concomitantly with opioids or other central nervous system (CNS) depressants. It is essential for practitioners administering Midazolam Injection to possess the necessary skills for managing serious cardiorespiratory adverse reactions, including airway management.

Common adverse reactions observed in clinical trials include upper airway obstruction, agitation, and pyrexia. Agitation may also occur as a notable adverse effect. Patients should be monitored closely for signs of respiratory depression and sedation, especially when Midazolam Injection is used in conjunction with opioids, as this combination can exacerbate these risks.

Patients using Midazolam Injection more frequently than recommended may experience acute withdrawal reactions upon abrupt discontinuation or rapid dosage reduction, which can be life-threatening. To mitigate this risk, a gradual tapering of the medication is advised.

Impaired cognitive function is another concern, as patients may experience partial or complete impairment of recall. Consequently, individuals should refrain from operating hazardous machinery or motor vehicles until the effects of the drug have fully subsided.

In specific populations, such as those with open-angle glaucoma, an evaluation of ophthalmologic status may be necessary following treatment. Midazolam Injection is contraindicated in patients with narrow-angle glaucoma.

Additionally, the use of Midazolam Injection during pregnancy has been associated with neonatal sedation and/or withdrawal syndrome.

Hypersensitivity reactions to midazolam have been reported, and overdosage of benzodiazepines can lead to CNS depression ranging from drowsiness to coma. Symptoms of mild to moderate overdosage may include confusion, lethargy, diminished reflexes, and ataxia, while severe cases can result in respiratory depression and coma. The risk of fatal outcomes increases significantly when benzodiazepines are combined with other CNS depressants, including alcohol and opioids.

Drug Interactions

Benzodiazepines and opioids are known to significantly increase the risk of respiratory depression when used concurrently. Caution is advised when prescribing these agents together, and close monitoring of respiratory function is recommended.

The concomitant use of other central nervous system (CNS) depressants, including alcohol, can enhance the sedative effects of midazolam. Healthcare providers should consider dosage adjustments and monitor patients for increased sedation and respiratory depression in such cases.

Inhibition of the cytochrome P450-3A4 enzyme can lead to prolonged sedation due to decreased plasma clearance of midazolam. It is advisable to monitor patients closely for signs of excessive sedation and to consider dosage adjustments as necessary when midazolam is administered alongside CYP3A4 inhibitors.

Packaging & NDC

The table below lists all NDC Code configurations of N/a (midazolam injection, 10 mg), the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

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

Geriatric Use

Elderly patients may experience altered drug distribution and diminished hepatic and/or renal function, which can lead to longer elimination half-lives for midazolam and its metabolites. Those over 70 years of age may exhibit increased sensitivity to the effects of the drug.

The administration of intramuscular midazolam in geriatric patients has been associated with rare reports of death, particularly under circumstances compatible with cardiorespiratory depression. It is important to note that in most of these cases, patients were also receiving other central nervous system (CNS) depressants, such as narcotics, which can further compromise respiratory function.

Given these considerations, close monitoring of geriatric patients is strongly recommended to ensure safety and efficacy. Additionally, healthcare providers should be vigilant regarding potential drug interactions and the overall health status of elderly patients when prescribing midazolam.

Pregnancy

The use of Midazolam Injection during late pregnancy may pose risks to the fetus, including potential sedation effects such as respiratory depression, lethargy, and hypotonia, as well as withdrawal symptoms in newborns. These withdrawal symptoms can manifest as hyperreflexia, irritability, restlessness, tremors, inconsolable crying, and feeding difficulties.

Healthcare providers should advise pregnant patients to inform them if they are pregnant. Additionally, it is recommended that women of childbearing potential who become pregnant while using Midazolam Injection enroll in the North American Antiepileptic Drug Pregnancy Registry. This registry aims to collect valuable data regarding the safety of antiepileptic medications during pregnancy, contributing to a better understanding of their effects on fetal outcomes.

Lactation

Midazolam, the active ingredient in Midazolam Injection, is excreted in breast milk. Lactating mothers should inform their healthcare provider if they are breastfeeding or intend to breastfeed.

Breastfeeding patients who have received Midazolam Injection are advised to monitor their infants for signs of excessive sedation, poor feeding, and poor weight gain. If any of these signs are observed, medical attention should be sought promptly.

Renal Impairment

Patients with renal impairment have not been specifically addressed in the available data regarding dosage adjustments, special monitoring, or safety considerations. Therefore, healthcare professionals should exercise caution when prescribing this medication to patients with reduced kidney function, as the lack of information necessitates careful clinical judgment and monitoring.

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 central nervous system (CNS) depression, which can manifest in a spectrum of symptoms ranging from mild drowsiness to profound coma. Common symptoms associated with benzodiazepine overdosage include drowsiness, confusion, lethargy, and, in more severe instances, respiratory depression. The risk of respiratory depression and coma is significantly heightened when benzodiazepines are ingested in conjunction with other CNS depressants, such as alcohol and opioids, potentially leading to fatal outcomes.

In cases of severe overdosage, immediate medical intervention is critical. Flumazenil, a benzodiazepine antagonist, may be administered to reverse the sedative effects. However, caution is advised, as flumazenil can precipitate withdrawal symptoms and adverse reactions, including seizures, particularly in patients with a history of long-term benzodiazepine use or those experiencing mixed overdoses.

Healthcare professionals are encouraged to consider contacting a poison center at 1-800-221-2222 or consulting a medical toxicologist for further guidance on the management of benzodiazepine overdosage. This collaboration can provide valuable insights into the appropriate treatment protocols and enhance patient safety during the management of such cases.

Nonclinical Toxicology

When midazolam was administered orally at doses of 0, 1, 4, or 16 mg/kg to male and female rats prior to and during mating, as well as throughout gestation and lactation in females, no adverse effects on fertility were observed. The plasma exposures (AUC) of midazolam at the highest dose tested were approximately six times greater than those observed in humans at the recommended human dose (RHD).

Carcinogenesis studies involved the administration of midazolam maleate in the diet to mice and rats over a period of two years at doses of 0, 1, 9, or 80 mg/kg/day. In female mice receiving the highest dose, there was a significant 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. The highest dose that did not result in increased tumor incidences in both mice and rats (9 mg/kg/day) is approximately four and nine times, respectively, the RHD of 10 mg based on body surface area (mg/m²). The mechanism underlying the induction of these tumors remains unclear. It is noteworthy that these tumors were identified following chronic administration, while human use typically involves single or multiple doses.

In terms of mutagenesis, midazolam demonstrated negative results for genotoxicity in both in vitro assays (Ames test and mammalian cell clastogenicity) and in vivo assays (mouse bone marrow micronucleus test).

No information is available regarding animal pharmacology and toxicology.

Postmarketing Experience

No specific postmarketing experience details are available in the extracted data. As such, there are no additional adverse events or rare case reports to summarize at this time.

Patient Counseling

Healthcare providers should advise patients that Midazolam Injection is intended for administration by trained personnel and direct them to refer to the illustrated Instructions for Use for proper guidance. It is important to note that patients experiencing seizures may be unresponsive or have difficulty understanding counseling information.

Patients and caregivers should be informed about the potential for fatal additive effects when Midazolam Injection is used in conjunction with opioids. They should be cautioned against using these medications together unless under the supervision of a healthcare provider. Additionally, patients must be made aware that using Midazolam Injection more frequently than recommended, even at the prescribed dosages, increases the risk of abuse, misuse, and addiction, which can lead to overdose and death, particularly when combined with other medications, alcohol, or illicit substances.

Healthcare providers should educate patients on the signs and symptoms of benzodiazepine abuse, misuse, and addiction, encouraging them to seek medical help if they experience any of these indicators. Patients should also be instructed on the proper disposal of any unused medication. It is crucial to inform patients that exceeding the recommended use of Midazolam Injection may result in clinically significant physical dependence. Abrupt discontinuation or rapid dosage reduction can precipitate acute withdrawal reactions, which may be life-threatening. In some cases, patients may experience a protracted withdrawal syndrome, with symptoms lasting from weeks to over 12 months.

Patients should be advised to inform their healthcare provider about any alcohol consumption and all medications they are currently taking, particularly blood pressure medications and antibiotics, including over-the-counter drugs. Caution should be exercised regarding the simultaneous ingestion of alcohol during benzodiazepine treatment, as it can enhance the effects of the medication.

Healthcare providers should counsel patients not to operate hazardous machinery or a motor vehicle until the effects of Midazolam Injection, such as drowsiness, have subsided. Pregnant females should be informed that using Midazolam Injection late in pregnancy may lead to sedation and/or withdrawal symptoms in newborns. Patients should be instructed to notify their healthcare provider if they are pregnant and encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry if they become pregnant, as this registry collects information on the safety of antiepileptic drugs during pregnancy.

It is also important to inform patients that midazolam, the active ingredient in Midazolam Injection, is excreted in breast milk. Patients should be instructed to inform their healthcare provider if they are breastfeeding or plan to breastfeed. Breastfeeding patients who have received Midazolam Injection should monitor their infants for signs of excessive sedation, poor feeding, and poor weight gain, and seek medical attention if these signs are observed.

Storage and Handling

The product is supplied in various package configurations, with specific NDC numbers available upon request. It should be stored at a temperature range of 20 ºC to 25 ºC (68 ºF to 77 ºF). Temporary excursions are permissible between 15 ºC and 30 ºC (59 ºF and 86 ºF) in accordance with USP Controlled Room Temperature guidelines. It is imperative to note that the product must not be frozen to maintain its integrity and efficacy.

Additional Clinical Information

Midazolam Injection is intended for administration by trained personnel, and patients experiencing seizures may be unresponsive or have difficulty understanding counseling information. Clinicians should inform patients and caregivers about the risks associated with concomitant use of Midazolam Injection and opioids, as this combination can lead to potentially fatal additive effects. Patients should be cautioned against using Midazolam more frequently than recommended due to the risks of abuse, misuse, and addiction, which can result in overdose and death, particularly when combined with other substances such as alcohol or illicit drugs.

Patients should also be made aware of the potential for withdrawal reactions, which can occur with abrupt discontinuation or rapid dosage reduction, leading to life-threatening symptoms. It is essential for patients to disclose any current medications, including over-the-counter drugs and alcohol consumption, to their healthcare provider, as these can interact with Midazolam. Additionally, patients should be advised against operating hazardous machinery or vehicles until the effects of the drug have subsided. Pregnant females should be informed of the risks to newborns if Midazolam is used late in pregnancy and are encouraged to enroll in the North American Antiepileptic Drug Pregnancy Registry. Breastfeeding patients should be counseled about the excretion of midazolam in breast milk and monitor infants for signs of excessive sedation or feeding difficulties.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for N/a as submitted by Rafa Laboratories, Ltd.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)