N/A

Midazolam Injection is indicated for the treatment of status epilepticus in adults. Midazolam Injection is a benzodiazepine indicated for the treatment of status epilepticus in adults. (1)

Recommended Dose The recommended dose of Midazolam Injection is a single 10 mg dose, administered by intramuscular injection [see Dosage and Administration (2.2)]. Important Administration Instructions Midazolam Injection should be administered by trained personnel who have had adequate training in the recognition and treatment of status epilepticus and first aid/basic airway management. Midazolam Injection is for intramuscular use only as a single dose. Inject in the mid-outer thigh (vastus lateralis muscle) using the prefilled autoinjector. The Midazolam autoinjector can inject through clothing. Move all objects from in and around the patient’s clothing that may interfere with the injection. For people who do not have a lot of fat at the mid-outer thigh, bunch up the thigh at the injection site to provide a thicker area for administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit [see Dosage Forms and Strengths (3)]. Refer to the illustrated Midazolam Injection Instructions for Use for autoinjector administration instructions. Monitoring After administration of Midazolam Injection, continuous monitoring of respiratory and cardiac function is recommended until the patient is stabilized. Serious and life-threatening cardiorespiratory adverse reactions, such as hypoventilation, airway obstruction, apnea, and hypotension have been reported with the use of midazolam. Patients should be monitored in a setting that allows for immediate access to resuscitative drugs. Appropriate resuscitation equipment and personnel trained in their use and skilled in airway management should be available [see Warnings and Precautions (5.4), Adverse Reactions (6.1)]. Observation for signs of cardiorespiratory depression is particularly important in patients with chronic obstructive pulmonary disease (COPD), patients 60 or more years of age, and patients who have received concomitant narcotics or other central nervous system (CNS) depressants. The recommended dose is a single 10 mg dose, administered by intramuscular injection using the prefilled autoinjector. (2.1) Inject in the mid-outer thigh (vastus lateralis muscle). (2.2) Continuous monitoring of respiratory and cardiac function is recommended. (2.3)

Risks from Concomitant Use with Opioids Concomitant use of benzodiazepines, including Midazolam Injection, and opioids may result in profound sedation, respiratory depression, coma, and death. If a decision is made to use midazolam concomitantly with opioids, monitor patients closely for respiratory depression and sedation [see Drug Interactions (7.1)]. Trained personnel administering Midazolam Injection must have the skills necessary to manage serious cardiorespiratory adverse reactions, including skills in airway management. Abuse, Misuse, and Addiction The use of benzodiazepines, including Midazolam Injection, exposes users to the risks of abuse, misuse, and addiction, which can lead to overdose or death. Abuse and misuse of benzodiazepines often (but not always) involve the use of doses greater than the maximum recommended dosage and commonly involve concomitant use of other medications, alcohol, and/or illicit substances, which is associated with an increased frequency of serious adverse outcomes, including respiratory depression, overdose, or death [see Drug Abuse and Dependence (9.2)]. Before prescribing Midazolam Injection and throughout treatment, assess each patient’s risk for abuse, misuse, and addiction. Use of Midazolam Injection, particularly in patients at elevated risk, necessitates counseling about the risks and proper use of Midazolam Injection along with monitoring for signs and symptoms of abuse, misuse, and addiction. Do not exceed the recommended dosing frequency; avoid or minimize concomitant use of CNS depressants and other substances associated with abuse, misuse, and addiction (e.g., opioid analgesics, stimulants); and advise patients on the proper disposal of unused drug. If a substance use disorder is suspected, evaluate the patient and institute (or refer them for) early treatment, as appropriate. Dependence and Withdrawal Reactions After Use of Midazolam Injection More Frequently Than Recommended For patients using Midazolam Injection more frequently than recommended, to reduce the risk of withdrawal reactions, use a gradual taper to discontinue Midazolam Injection (a patient-specific plan should be used to taper the dose). Patients at an increased risk of withdrawal adverse reactions after benzodiazepine discontinuation or rapid dosage reduction include those who take higher dosages, and those who have had longer durations of use. Acute Withdrawal Reactions The continued use of benzodiazepines may lead to clinically significant physical dependence. Although Midazolam Injection is indicated only for intermittent use [see Indications and Usage (1) and Dosage and Administration (2)], if used more frequently than recommended, abrupt discontinuation or rapid dosage reduction of Midazolam Injection, or administration of flumazenil (a benzodiazepine antagonist) may precipitate acute withdrawal reactions, which can be life-threatening (e.g., seizures) [see Drug Abuse and Dependence (9.3)]. Protracted Withdrawal Syndrome In some cases, benzodiazepine users have developed a protracted withdrawal syndrome with withdrawal symptoms lasting weeks to more than 12 months [see Drug Abuse and Dependence (9.3)]. Risks 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 patients with hemodynamic instability. Hypotension occurs more frequently in patients premedicated with a narcotic. The danger of hypoventilation, airway obstruction, or apnea is greater in elderly patients and those with chronic disease states or decreased pulmonary reserve [see Use in Specific Populations (8.5, 8.7)]; patients with C…

Midazolam Injection is contraindicated in patients with a known hypersensitivity to midazolam. Hypersensitivity to midazolam. (4)

Effect of Concomitant Use of Benzodiazepines and Opioids 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 GABAA 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. Limit dosage and duration of concomitant use of benzodiazepines and opioids. Monitor patients closely for respiratory depression and sedation. Other CNS Depressants and Alcohol The sedative effect of Midazolam Injection is accentuated by concomitantly administered medication that depresses the central nervous system, particularly opioids (e.g., morphine, meperidine, and fentanyl), secobarbital, and droperidol, and also by alcohol [see Warnings and Precautions (5.1, 5.4, 5.6)]. Cytochrome P450-3A4 Inhibitors Caution is advised when Midazolam Injection is administered concomitantly with drugs that are known to inhibit the P450-3A4 enzyme system (e.g., cimetidine, erythromycin, diltiazem, verapamil, ketoconazole, and itraconazole). These drug interactions may result in prolonged sedation caused by a decrease in plasma clearance of midazolam [see Clinical Pharmacology (12.3)]. Benzodiazepines and Opioids: Risk of respiratory depression is increased. (7.1) Other CNS Depressants and Alcohol: Sedative effect of midazolam is increased. (7.2) Cytochrome P450-3A4 Inhibitors: May result in prolonged sedation due to decreased plasma clearance of midazolam. (7.3)

The following serious adverse reactions are discussed in greater detail in other sections: Risks from Concomitant Use with Opioids [see Warnings and Precautions (5.1)] Abuse, Misuse, and Addiction [see Warnings and Precautions (5.2)] Dependence and Withdrawal Reactions After Use of Midazolam Injection More Frequently Than Recommended [see Warnings and Precautions (5.3)] Risks of Cardiorespiratory Adverse Reactions [see Warnings and Precautions (5.4)] Other Adverse Reactions [see Warnings and Precautions (5.5)] Risks from Concomitant Use of Central Nervous System Depressants [see Warnings and Precautions (5.6)] Impaired Cognitive Function [see Warnings and Precautions (5.7)] Glaucoma [see Warnings and Precautions (5.8)] Neonatal Sedation and Withdrawal Syndrome [see Warnings and Precautions (5.9)] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of Midazolam Injection has been established by data from an adequate and well-controlled study of a different midazolam injection in adult patients with status epilepticus [see Clinical Studies (14)]. Below is a display of the adverse reactions of midazolam injection in this adequate and well-controlled study. Adverse Reactions in the Controlled Study of Intramuscular Midazolam in Patients with Status Epilepticus In a double-blind, randomized, active-controlled clinical study, 448 patients were assigned to receive intramuscular (IM) midazolam via an autoinjector, and 445 were assigned to receive intravenous (IV) lorazepam. Approximately 45% of patients were female, and the mean age was 43 years. Patients were administered treatment by a healthcare professional (e.g., paramedic) prior to arrival at a hospital. Table 1 lists the adverse reactions occurring in 2% or more of the IM midazolam-treated patients and at a rate greater than the IV lorazepam-treated patients. Table 1 Adverse Reactions in 2% or More of IM Midazolam-Treated Patients and More Frequent than in IV Lorazepam-Treated Patients in Out of Hospital Treatment of Status Epilepticus Adverse Reactions in Other Midazolam Studies Midazolam Injection is only indicated for status epilepticus, but for uses other than that for which Midazolam Injection is indicated, 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 [11% of patients following intramuscular administration], as well as variations in blood pressure and pulse rate. The majority of serious adverse effects, particularly those associated with oxygenation and ventilation, have been reported when midazolam was administered with other medications capable of depressing the CNS. The incidence of such events was higher in patients undergoing procedures involving the airway without the protective effect of an endotracheal tube (e.g., upper endoscopy and dental procedures). The following additional adverse reactions were reported after intramuscular administration in adults: Headache (1.3%), and local effects at the IM injection site including pain (3.7%), induration (0.5%), redness (0.5%), and muscle stiffness (0.3%). The most common adverse reactions (incidence >3%) in clinical trials in patients with status epilepticus were upper airway obstruction, agitation, and pyrexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Rafa Laboratories, Ltd. at 1-386-418-7911 or FDA at 1-800-FDA-1088 or www.fda.gov.medwatch. AEs clinical trials